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  • Analysis & Opinion

Race, Mass Incarceration, and the Disastrous War on Drugs

Unravelling decades of racially biased anti-drug policies is a monumental project.

  • Nkechi Taifa
  • Cutting Jail & Prison Populations
  • Social & Economic Harm

This essay is part of the  Brennan Center’s series  examining  the punitive excess that has come to define America’s criminal legal system .

I have a long view of the criminal punishment system, having been in the trenches for nearly 40 years as an activist, lobbyist, legislative counsel, legal scholar, and policy analyst. So I was hardly surprised when Richard Nixon’s domestic policy advisor  John Ehrlichman  revealed in a 1994 interview that the “War on Drugs” had begun as a racially motivated crusade to criminalize Blacks and the anti-war left.

“We knew we couldn’t make it illegal to be either against the war or blacks, but by getting the public to associate the hippies with marijuana and blacks with heroin and then criminalizing them both heavily, we could disrupt those communities. We could arrest their leaders, raid their homes, break up their meetings, and vilify them night after night in the evening news. Did we know we were lying about the drugs? Of course we did,” Ehrlichman said.

Before the War on Drugs, explicit discrimination — and for decades, overtly racist lynching — were the primary weapons in the subjugation of Black people. Then mass incarceration, the gradual progeny of a number of congressional bills, made it so much easier. Most notably, the 1984  Comprehensive Crime Control and Safe Streets Act  eliminated parole in the federal system, resulting in an upsurge of  geriatric prisoners . Then the 1986  Anti-Drug Abuse Act  established mandatory minimum sentencing schemes, including the infamous 100-to-1 ratio between crack and powder cocaine sentences.  Its expansion  in 1988 added an overly broad definition of conspiracy to the mix. These laws flooded the federal system with people convicted of low-level and nonviolent drug offenses.

During the early 1990s, I walked the halls of Congress lobbying against various omnibus crime bills, which culminated in the granddaddy of them all — the  Violent Crime Control and Safe Streets Act  of 1994. This bill featured the largest expansion of the federal death penalty in modern times, the gutting of habeas corpus, the evisceration of the exclusionary rule, the trying of 13-year-olds as adults, and 100,000 new cops on the streets, which led to an explosion in racial profiling. It also included the elimination of Pell educational grants for prisoners, the implementation of the federal three strikes law, and monetary incentives to states to enact “truth-in-sentencing” laws, which subsidized an astronomical rise in prison construction across the country, lengthened the amount of time to be served, and solidified a mentality of meanness.

The prevailing narrative at the time was “tough on crime.” It was a narrative that caused then-candidate Bill Clinton to leave his presidential campaign trail to oversee the execution of a mentally challenged man in Arkansas. It was the same narrative that brought about the crack–powder cocaine disparity, supported the transfer of youth to adult courts, and popularized the myth of the Black child as “superpredator.”

With the proliferation of mandatory minimum sentences during the height of the War on Drugs, unnecessarily lengthy prison terms were robotically meted out with callous abandon. Shockingly severe sentences for drug offenses — 10, 20, 30 years, even life imprisonment — hardly raised an eyebrow. Traumatizing sentences that snatched parents from children and loved ones, destabilizing families and communities, became commonplace.

Such punishments should offend our society’s standard of decency. Why haven’t they? Most flabbergasting to me was the Supreme Court’s 1991  decision  asserting that mandatory life imprisonment for a first-time drug offense was not cruel and unusual punishment. The rationale was ludicrous. The Court actually held that although the punishment was cruel, it was not unusual.

The twisted logic reminded me of another Supreme Court  case  that had been decided a few years earlier. There, the Court allowed the execution of a man — despite overwhelming evidence of racial bias — because of fear that the floodgates would be opened to racial challenges in other aspects of criminal sentencing as well. Essentially, this ruling found that lengthy sentences in such cases are cruel, but they are usual. In other words, systemic racism exists, but because that is the norm, it is therefore constitutional.

In many instances, laws today are facially neutral and do not appear to discriminate intentionally. But the disparate treatment often built into our legal institutions allows discrimination to occur without the need of overt action. These laws look fair but nevertheless have a racially discriminatory impact that is structurally embedded in many police departments, prosecutor’s offices, and courtrooms.

Since the late 1980s, a combination of federal law enforcement policies, prosecutorial practices, and legislation resulted in Black people being disproportionately arrested, convicted, and imprisoned for possession and distribution of crack cocaine. Five grams of crack cocaine — the weight of a couple packs of sugar — was, for sentencing purposes, deemed the equivalent of 500 grams of powder cocaine; both resulted in the same five-year sentence. Although household surveys from the National Institute for Drug Abuse have revealed larger numbers of documented white crack cocaine users, the overwhelming number of arrests nonetheless came from Black communities who were disproportionately impacted by the facially neutral, yet illogically harsh, crack penalties.

For the system to be just, the public must be confident that at every stage of the process — from the initial investigation of crimes by police to the prosecution and punishment of those crimes — people in like circumstances are treated the same. Today, however, as yesterday, the criminal legal system strays far from that ideal, causing African Americans to often question, is it justice or “just-us?”

Fortunately, the tough-on-crime chorus that arose from the War on Drugs is disappearing and a new narrative is developing. I sensed the beginning of this with the 2008  Second Chance Reentry  bill and 2010  Fair Sentencing Act , which reduced the disparity between crack and powder cocaine. I smiled when the 2012 Supreme Court ruling in  Miller v. Alabama  came out, which held that mandatory life sentences without parole for children violated the Eighth Amendment’s prohibition against cruel and unusual punishment. In 2013, I was delighted when Attorney General Eric Holder announced his  Smart on Crime  policies, focusing federal prosecutions on large-scale drug traffickers rather than bit players. The following year, I applauded President Obama’s executive  clemency initiative  to provide relief for many people serving inordinately lengthy mandatory-minimum sentences. Despite its failure to become law, I celebrated the  Sentencing Reform and Corrections Act  of 2015, a carefully negotiated bipartisan bill passed out of the Senate Judiciary Committee in 2015; a few years later some of its provisions were incorporated as part of the 2018  First Step Act . All of these reforms would have been unthinkable when I first embarked on criminal legal system reform.

But all of this is not enough. We have experienced nearly five decades of destructive mass incarceration. There must be an end to the racist policies and severe sentences the War on Drugs brought us. We must not be content with piecemeal reform and baby-step progress.

Indeed, rather than steps, it is time for leaps and bounds. End all mandatory minimum sentences and invest in a health-centered approach to substance use disorders. Demand a second-look process with the presumption of release for those serving life-without-parole drug sentences. Make sentences retroactive where laws have changed. Support categorical clemencies to rectify past injustices.

It is time for bold action. We must not be satisfied with the norm, but work toward institutionalizing the demand for a standard of decency that values transformative change.

Nkechi Taifa is president of The Taifa Group LLC, convener of the Justice Roundtable, and author of the memoir,  Black Power, Black Lawyer: My Audacious Quest for Justice.

Related Issues:

  • Cutting Jail & Prison Populations
  • Social & Economic Harm

prison

The American ‘Punisher’s Brain’

U.S. sentencing practices seem especially extreme when compared with countries like Canada, Germany, and the Netherlands.

prison

Treating All Kids as Kids

Persistent and longstanding racism has fueled harsher treatment of young Black people in the justice system.

incarcerated people

What Did You Call Me?

An incarcerated person writes about how dehumanizing language like “inmate” is destructive.

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  • Int J Pharm Investig
  • v.2(1); Jan-Mar 2012

Drug delivery systems: An updated review

Gaurav tiwari.

Department of Pharmaceutics, Pranveer Singh Institute of Technology, Kanpur, Uttar Pradesh, India

Ruchi Tiwari

Birendra sriwastawa.

1 Department of Pharmaceutics, Jaipur National University, Jagatpura, Jaipur, Rajasthan, India

2 Mankind Research Centre, Manesar, Gurgaon, India

Saurabh K Bannerjee

3 Department of Pharmaceutics, SVKM's Narsee Monjee Institute of Management Studies (NMIMS), School of Pharmacy and Technology Management, Dhule, Maharashtra, India

Drug delivery is the method or process of administering a pharmaceutical compound to achieve a therapeutic effect in humans or animals. For the treatment of human diseases, nasal and pulmonary routes of drug delivery are gaining increasing importance. These routes provide promising alternatives to parenteral drug delivery particularly for peptide and protein therapeutics. For this purpose, several drug delivery systems have been formulated and are being investigated for nasal and pulmonary delivery. These include liposomes, proliposomes, microspheres, gels, prodrugs, cyclodextrins, among others. Nanoparticles composed of biodegradable polymers show assurance in fulfilling the stringent requirements placed on these delivery systems, such as ability to be transferred into an aerosol, stability against forces generated during aerosolization, biocompatibility, targeting of specific sites or cell populations in the lung, release of the drug in a predetermined manner, and degradation within an acceptable period of time.

INTRODUCTION

Development of new drug molecule is expensive and time consuming. Improving safety efficacy ratio of “old” drugs has been attempted using different methods such as individualizing drug therapy, dose titration, and therapeutic drug monitoring. Delivering drug at controlled rate, slow delivery, targeted delivery are other very attractive methods and have been pursued vigorously. It is interesting to note that considerable work and many publications from USA, Europe are authored by Indian researchers.[ 1 – 3 ] Numerous animal and human investigations have provided an increased understanding of the pharmacokinetic and pharmacodynamic principles that govern the action and disposition of potent opioid analgesics, inhalation anesthetic agents, sedative/hypnotics, and muscle relaxants. These studies suggest that skin and buccal and nasal mucous membranes may have use as alternate routes of analgesic and anesthetic delivery. Similar developments with other compounds have produced a plethora of new devices, concepts, and techniques that have together been termed controlled-release technology (CRT). Some examples of CRTs are transdermal and transmucosal controlled-release delivery systems, ml6 nasal and buccal aerosol sprays, drug-impregnated lozenges, encapsulated cells, oral soft gels, iontophoretic devices to administer drugs through skin, and a variety of programmable, implanted drug-delivery devices. There are a number of factors stimulating interest in the development of these new devices, concepts, and techniques. Conventional drug administration methods, while widely utilized, have many problems that may be potentially overcome by these methods. Equally important, these advances may appear attractive relative to the costs of new drug development. Rising research and development costs, alternative investment opportunities for drug firms, fewer firms conducting pharmaceutical research, and erosion of effective patent life have resulted in a decline in the introduction of new chemical entities since the late 1950s. Bringing a new drug through discovery, clinical testing, development, and regulatory approval is currently estimated to take a decade and cost well over $ 120 million. Novel drug delivery systems may account for as much as 40% of US marketed drug products by 2000.[ 4 – 6 ]

BEADED DELIVERY SYSTEMS

Although not used with oxybutylin, beaded delivery formulations are another method used to achieve long-acting drug levels associated with the convenience of once-a-day dosing. This system has been successfully linked to tolterodine tartrate and is available as Detrol LA (Pharmacia, Peapack, NJ). Essentially, the beaded system consists of multiple, small beads that are composed of inert substances (such as polystyrene). The active drug is overlaid on the beads and encased in a delivery capsule. The drug delivery from this system is acid sensitive, in that drug levels are dependent on gastric acidity for release. This process produces a pharmacokinetic pattern roughly similar to a zero-order pattern, with C max obtained approximately 4 to 6 hours after ingestion and sustained levels observed for 24 hours after initial dosing. Comparative advantages are seen for both efficacy (improved incontinence rates) and tolerability with Detrol LA over immediate-release tolterodine. In a double-blind, placebo-controlled, randomized study of 1529 patients the LA formulation resulted in 18% less incontinence episodes than the immediate-release tolterodine, whereas both formulations were statistically superior to placebo in reducing urinary frequency and increasing voided urinary volume. The overall dry mouth rate was 23% lower for tolterodine LA than immediate-release tolterodine. Rates of withdrawal were similar across all arms. Van Kerrebroeck concluded that the LA formulation of tolterodine was superior to the immediate-release formulation.[ 7 – 8 ]

LIPOSOMAL AND TARGETED DRUG DELIVERY SYSTEM

Drug delivery systems can in principle provide enhanced efficacy and/or reduced toxicity for anticancer agents. Long circulating macromolecular carriers such as liposomes can exploit the ‘enhanced permeability and retention’ effect for preferential extravasation from tumor vessels.[ 4 ] Liposomal anthracyclines have achieved highly efficient drug encapsulation, resulting in significant anticancer activity with reduced cardiotoxicity, and include versions with greatly prolonged circulation such as liposomal daunorubicin and pegylated liposomal doxorubicin. Pegylated liposomal doxorubucin has shown substantial efficacy in breast cancer treatment both as monotherapy and in combination with other chemotherapeutics. Additional liposome constructs are being developed for the delivery of other drugs. The next generation of delivery systems will include true molecular targeting; immunoliposomes and other ligand-directed constructs represent an integration of biological components capable of tumor recognition with delivery technologies.[ 5 ]

As discussed, currently approved liposomal drug delivery systems provide stable formulation, provide improved pharmacokinetics, and a degree of ‘passive’ or ‘physiological’ targeting to tumor tissue.[ 6 ] However, these carriers do not directly target tumor cells. The design modifications that protect liposomes from undesirable interactions with plasma proteins and cell membranes, and which contrast them with reactive carriers such as cationic liposomes, also prevent interactions with tumor cells. Instead, after extravasation into tumor tissue, liposomes remain within tumor stroma as a drug-loaded depot. Liposomes eventually become subject to enzymatic degradation and/or phagocytic attack, leading to release of drug for subsequent diffusion to tumor cells. The next generation of drug carriers under development features direct molecular targeting of cancer cells via antibody-mediated or other ligand-mediated interactions.

Immunoliposomes, in which mAb fragments are conjugated to liposomes, represent a strategy for molecularly targeted drug delivery.[ 9 ] Anti-HER2 immunoliposomes have been developed with either Fab’ or scFv fragments linked to long-circulating liposomes. In preclinical studies, anti-HER2 immunoliposomes bound efficiently to and internalized in HER2-overexpressing cells, resulting in efficient intracellular delivery of encapsulated agents. Anti-HER2 immunoliposomes loaded with doxorubicin displayed potent and selective anticancer activity against HER2-overexpressing tumors, including significantly superior efficacy versus all other treatments tested (free doxorubicin, liposomal doxorubicin, free mAb [trastuzumab], and combinations of trastuzumab plus doxorubicin or liposomal doxorubicin).[ 10 ] Anti-HER2 immunoliposomes are currently undergoing scale up for clinical studies.[ 9 , 11 ]

The immunoliposome approach offers a number of theoretical advantages as compared with other antibody-based strategies. Anti-HER2 immunoliposome delivery of doxorubicin may circumvent the prohibitive cardiotoxicity associated with combined trastuzumab plus doxorubicin treatment. Anti-HER2 immunoliposomes can be constructed using scFv that, unlike trastuzumab, lack antiproliferative activity, are incapable of antibody-dependent cellular cytotoxicity, and require threshold levels of HER2 expression for delivery. In contrast to drug immunoconjugates, which consist of a small number of drugs (typically <10 drugs per mAb) directly coupled via linkers to selected residues on the mAb, immunoliposomes exploit the exponentially greater capacity of drug-loaded liposomes (up to 10 4 drugs per liposome). Immunoliposomes also appear to be nonimmunogenic and capable of long circulation even with repeated administration.[ 12 ] Antibody-based targeting is also being developed in conjunction with polymer systems. Similarly, ligand-based targeting using growth factors, hormones, vitamins (e.g., folate), peptides or other specific ligands is being pursued in conjunction with both liposomes and polymers. Liposomes are concentric bilayered structures made of amphipathic phospholipids and depending on the number of bilayer, liposomes are classified as multilamellar (MLV), small unilamellar (SUVs), or large unilamellar (LUVs). They range in size from 0.025-10 μ in diameter. The size and morphology of liposomes are regulated by the method of preparation and composition. Liposomes are used for delivery of drugs, vaccines, and genes for a variety of disorders.[ 13 ]

Infectious diseases

Bacchawat and co-workers developed liposomal amphotericin and investigated it in animal models of fungal infection and leishmaniasis. Kshirsagar and co-workers modified the formulation, developed a “Patient Worthy” sterile pyrogen free liposomal amphotericin preparation and investigated it in patients with systemic fungal infections and leishmaniasis. It was found to be safe producing significantly less adverse effects compared to plain amphotericin in patients with systemic fungal infection, did not produce nephrotoxicity and could be given to patients with renal damage. It was effective in patients resistant to fluconazole and plain amphotericin. Unlike Ambisome (USA), which needs to be used in dose of 3 mg/kg/day this is effective at 1 mg/kg/day dose. The same group studied different dosage regimens of liposomal amphotericin using Aspergillus murine mode. It was found that liposomal amphotericin was more effective than equal dose of free amphotericin B given after fungal spore challenge. A large single dose of liposomal amphotericin was more effective, whether given before or after spore challenge, than given as two divided doses.[ 14 ] It was investigated in patients with visceral leishmaniasis and found to be effective in patients who had not responded to antimony, pentamidine, and amphotericin. Because of its safety, it can be given at 3 mg/kg/day dose thus reducing total duration of treatment. It was successfully used in a child suffering from visceral leishmaniasis. This is the first liposomal preparation developed outside of USA, which has been used in patients. In an attempt to improve efficacy and reduce toxicity further, liposomes with grafted ligand have been developed. Pentamidine isethionate and its methoxy derivative were encapsulated in sugar grafted liposomes and tested against experimental leishmaniasis in vivo. It was seen that sugar grafted liposomes specially the mannose grafted ones were potent in comparison to normal liposome encapsulated drug or free drug.[ 15 ]

Anticancer drugs

Anticancer drugs provide current information on the clinical and experimental effects of toxic and non-toxic cancer agents and is specifically directed towards breakthroughs in cancer treatment. Mukhopadhya developed conjugate of antineoplastic drug daunomycin (DNM) with maleylated bovine serum albumin. It was taken up with high efficiency by multi drug resistant variant JD100 of the murine-macrophage tumor cell line J774A.1 through the scavenger receptors resulting in cessation of DNA synthesis. A thermosensitive liposomal taxol formulation (heat mediated targeted drug delivery) in murine melanoma was developed and studied by another group of workers. Cremophor which is used as excipient due to the low aqueous solubility of taxol has toxic side effects. Temperature-sensitive liposomes encapsulating taxol were prepared using egg phosphatidylcholine and cholesterol in combination with ethanol. The liposomes have a phase transition temperature of 43°C.[ 16 ] A significant reduction in tumor volume was noted in tumor bearing mice treated with a combination of hyperthermia and theromosensitive liposome encapsulated taxol, compared to animals treated with free taxol with or without hyperthermia in B16F 10 murine melanoma transplanted into C57BI/6 mice. Sharma et al . also investigated the use of polyvinylpyrrolidone nanoparticles containing taxol prepared by reverse micro-emulsion method. The size of nanoparticle was found to be 50-60 nm. The antitumor effect of taxol was evaluated in B16F10 murine melanoma transplanted in C57 B 1/6 mice. in vivo efficacy of taxol containing nanoparticles as measured by reduction in tumor volume and increased survival time was significantly greater than that of an equivalent concentration of free taxol.[ 17 ]

Lung-specific drug delivery

Pulmonary drug delivery offers several advantages in the treatment of respiratory diseases over other routes of administration. Inhalation therapy enables the direct application of a drug within the lungs. The local pulmonary deposition and delivery of the administered drug facilitates a targeted treatment of respiratory diseases, such as pulmonary arterial hypertension (PAH), without the need for high dose exposures by other routes of administration. The intravenous application of short acting vasodilators has been the therapy of choice for patients with PAH over the past decade. The relative severity of side effects led to the development of newprostacyclin analogues and alternative routes of administration. One such analogue, iloprost (Ventavis ® ), is a worldwide approved therapeutic agent for treatment of PAH. Inhalation of this compound is an attractive concept minimizing the side effects by its pulmonary selectivity. Unfortunately, the short half-life of iloprost requires frequent inhalation manoeuvres, ranging up to 9 times a day. Therefore, an aerosolizable controlled release formulation would improve a patient's convenience and compliance. Controlled drug delivery systems have become increasingly attractive options for inhalation therapies. A large number of carrier systems have been developed and investigated as potential controlled drug delivery formulations to the lung, including drug loaded lipid and polymer based particles. The use of colloidal carrier systems for pulmonary drug delivery is an emerging field of interest in nanomedicine. The objective of this study was to compare the pulmonary absorption and distribution characteristics of the hydrophilic model drug 5(6)-carboxyfluorescein (CF) after aerosolization as solution or entrapped into nanoparticles in an isolated rabbit lung model (IPL). CF-nanoparticles were prepared from a new class of biocompatible, fast degrading, branched polyesters by a modified solvent displacement method. Physicochemical properties, morphology, encapsulation efficiency, in vitro drug release, stability of nanoparticles to nebulization, aerosol characteristics as well as pulmonary dye absorption and distribution profiles after nebulization in an IPL were investigated Among the various drug delivery systems considered for pulmonary application, nanoparticles demonstrate several advantages for the treatment of respiratory diseases, such as prolonged drug release, cell-specific targeted drug delivery or modified biological distribution of drugs, both at the cellular and organ level. It must first be recognized that formulating compounds and delivering them as aerosols is complex. Not only does it involve the formulation of a stable solution or suspension in a medium (propellant) that is not as well characterized as other systems, but the resultant system is also subject to performance limitations. In order to efficiently reach the lung, the formulation must be atomized into particles having aerodynamic sizes between approximately 1 and 5 μ. Due to these particle size constraints, as well as inhalation toxicology concerns, the range of possible excipients to choose from during the formulation phase is substantially reduced. Additionally, limiting the concentration of excipients in a formulation is crucial for maintaining adequate aerosol performance. Thus, given the complexity of this relationship, formulating aerosols is a challenging endeavor. Although complex, the successful formulation of drugs for pulmonary delivery provides a valuable therapeutic route. Upon introduction of the metered dose inhaler (MDI), medical treatment of lung diseases changed significantly. Since that time, MDIs have become the most effective means of controlling symptoms of lung diseases such as asthma and chronic obstructive pulmonary disorder (COPD). More recently, formulation modifications were merited when chlorofluorocarbon (CFC) propellants were linked to the depletion of the ozone layer (Molina and Rowland, 1974). With the successful transition to new propellant systems, MDIs are still well accepted and highly utilized by patients across the globe today. Looking forward, the effectiveness, ease of use, and relatively low cost of aerosol preparations in combination with modifications in delivery technology and formulation sciences, will likely expand the treatment of diseases. Another, therapeutically undesirable aspect of pulmonary drug delivery is rapid absorption of most drugs from the lung, necessitating frequent dosing, e.g., of bronchodilators and corticosteroids. Liposomes are believed to alleviate some of the problems encountered with conventional aerosol delivery due to their ability to: (i) serve as a solubilization matrix for poorly soluble agents; (ii) act as a pulmonary sustained release reservoir; and (iii) facilitate intracellular delivery of[ 18 ]

Targeting to brain

The great interest in mucosal vaccine delivery arises from the fact that mucosal surfaces represent the major site of entry for many pathogens. Among other mucosal sites, nasal delivery is especially attractive for immunization, as the nasal epithelium is characterized by relatively high permeability, low enzymatic activity and by the presence of an important number of immunocompetent cells. In addition to these advantageous characteristics, the nasal route could offer simplified and more cost-effective protocols for vaccination with improved patient compliance. The use of nanocarriers provides a suitable way for the nasal delivery of antigenic molecules. Besides improved protection and facilitated transport of the antigen, nanoparticulate delivery systems could also provide more effective antigen recognition by immune cells. These represent key factors in the optimal processing and presentation of the antigen, and therefore in the subsequent development of a suitable immune response. In this sense, the design of optimized vaccine nanocarriers offers a promising way for nasal mucosal vaccination.[ 21 ]

The usual noninvasive approach to solving the brain drug delivery problem istolipidizethe drug, The water -soluble parts of the drugs restricts BBB transport conversion of water-soluble drug into lipid-soluble prodrug is the traditional chemistry driven solution to the BBB problem as in [ Figure 1 ].

An external file that holds a picture, illustration, etc.
Object name is IJPI-2-2-g001.jpg

Outline of a program for developing blood-brain drug targeting strategies derived from either chemistry based or biology-based disciplines

The treatment of CNS diseases is particularly challenging because the delivery of drug molecules to the brain is often precluded by a variety of physiological, metabolic and biochemical obstacles that collectively comprise the Blood Brain barrier, blood cerebrospinal fluid barrier, Blood tumor barrier. The present outlook for patients suffering from many types of brain diseases remains poor, but recent developments in drug delivery techniques provide reasonable hope that the formidable barriers shielding the brain may ultimately be overcome. Drug delivery directly to the brain interstitium has recently been markedly enhanced through the rational design of polymer-based drug delivery systems. Substantial progress will only come about, however, if continued vigorous research efforts to develop more therapeutic and less toxic drug molecules are paralleled by the aggressive pursuit of more effective mechanisms for delivering those drugs to brain targets.[ 19 ] Jain et al . developed dopamine hydrochloride bearing positively charged small liposomes by sonicating multilamellar vesicles and studied their physical attributes and drug leakage and release pattern. In vivo performance was assessed by periodic measurement of chlorpromazine induced catatonia in Sprague Dawley rats and was compared with plain dopamine hydrochloride, dopamine and levodopa carbidopa. The studies showed that dopamine can be effectively delivered into the brain and its degradation in circulation can be prevented by incorporating it into liposomes.[ 20 ]

Strategies for drug delivery to the brain

Several drugs do not have adequate physiochemical characteristics such as high lipid solubility, low molecular size and positive charge which are essential to succeed in traversing BBB.[ 21 ]

Disruption of the BBB

The thought behind this approach was to break down the barrier momentarily by injecting mannitol solution into arteries in the neck. The resulting high sugar concentration in brain capillaries takes up water out of the endothelial cells, shrinking them, thus opening tight junction. The effect lasts for 20-30 minute, during which time drugs diffuse freely, that would not normally cross the BBB. This method permitted the delivery of chemotherapeutic agents in patients with cerebral lymphoma, malignant glioma and disseminated CNS germ cell tumors. Physiological stress, transient increase in intracranial pressure, and unwanted delivery of anticancer agents to normal brain tissues are the undesired side-effects of this approach in humans.[ 10 ]

Intraventricular/intrathecaldelivery

Here, using a plastic reservoir, which implanted subcutaneously in the scalp and connected to the ventricles within the brain by an outlet catheter. Drug injection into the CSF is a suitable strategy for sites close to the ventricles only.[ 22 ]

Intra nasal drug delivery

After nasal delivery drugs first reach the respiratory epithelium, where compounds can be absorbed into the systemic circulation by tran cellular and para cellular passive absorption, carrier-mediated transport, and absorption through trancytosis. When a nasal drug formulation is delivered deep and high enough into the nasal cavity, the olfactory mucosa may be reached and drug transport into the brain and/or CSF via the olfactory receptor neurons may occur.[ 23 ]

Possible systems for drug delivery-colloidal drug carriers

Colloidal drug carrier systems such as micellar solutions, vesicle and liquid crystal dispersions, as well as nanoparticle dispersions consisting of small particles show great promise as drug delivery systems. The goal is to obtain systems with optimized drug loading and release properties, long shelf-life and low toxicity. The incorporated drug participates in the microstructure of the system, and may even influence it due to molecular interactions, especially if the drug possesses amphiphilic and/or mesogenic properties.[ 24 ]

Micelles formed by self-assembly of amphiphilic block copolymers (5-50 nm) in aqueous solutions are of great interest for drug delivery applications. The drugs can be physically entrapped in the core of block copolymer micelles and transported at concentrations that can exceed their intrinsic water- solubility. Moreover, the hydrophilic blocks can form hydrogen bonds with the aqueous surroundings and form a tight shell around the micellar core. As a result, the contents of the hydrophobic core are effectively protected against hydrolysis and enzymatic degradation. In addition, the corona may prevent recognition by the reticuloendothelial system and therefore preliminary elimination of the micelles from the bloodstream. The fact that their chemical composition, total molecular weight and block length ratios can be easily changed, which allows control of the size and morphology of the micelles. Functionalization of block copolymers with cross linkable groups can increase the stability of the corresponding micelles and improve their temporal control.[ 25 ]

Liposomes were first produced in England in 1961 by Alec D. Bangham. One end of each molecule is water soluble, while the opposite end is water insoluble. Water-soluble medications added to the water were trapped inside the aggregation of the hydrophobic ends; fat-soluble medications were incorporated into the phospholipid layer as in [ Figure 2 ].

An external file that holds a picture, illustration, etc.
Object name is IJPI-2-2-g002.jpg

Liposomes, micelles, bilayer sheet

In some cases liposomes attach to cellular membranes and appear to fuse with them, releasing their or drugs into the cell. In the case of phagocytic cells, the liposomes are taken up, the phospholipid walls are acted upon by organelles called lysosomes, and the medication is released. Liposomal delivery systems are still largely experimental; the precise mechanisms of their action in the body are under study, as are ways in which to target them to specific diseased tissues.[ 26 ]

Nano technology

Nanoparticulate systems for brain delivery of drugs.

One of the possibilities to deliver drugs to the brain is the employment of nanoparticles. Nanopartiacles are polymeric particles made of natural or artificial polymers ranging in size between about 10 and 1000 nm (1 mm). Drugs may be bound inform of a solid solution or dispersion or be adsorbed to the surface or chemically attached. Poly (butylcyanoacrylate) nanoparticles represent the onlynanoparticles that were so far successfully used for the in vivo delivery of drugs to the brain. The first drug that was de-livered to the brain using nanoparticles was the hexapeptidedalargin (Tyr-D-Ala- Gly- Phe-Leu-Arg), a Leu-enkephalin analogue with opioid activity.[ 27 ]

Nanoparticles and nanoformulations have already been applied as drug delivery systems with great success; and nanoparticulate drug delivery systems have still greater potential for many applications, including anti-tumors therapy, gene therapy, and AIDS therapy, radiotherapy, in the delivery of proteins, antibiotics, virostatics, and vaccines and as vesicles to pass the blood-brain barrier.[ 28 ]

Nanoparticles provide massive advantages regarding drug targeting, delivery and release, and with their additional potential to combine diagnosis and therapy, emerge as one of the major tools in nanomedicine. The main goals are to improve their stability in the biological environment, to mediate the bio-distribution of active compounds, improve drug loading, targeting, transport, release, and interaction with biological barriers. The cytotoxicity of nanoparticles or their degradation products remains a major problem, and improvements in biocompatibility obviously are a main concern of future research.[ 29 , 30 ]

Nowadays nanotechnology is proved to be more efficient for enhancing drug delivery to brain. The nanoparticles are the drug carrier system which is made from a broad number of materials such as poly (alkylcyanoacrylates) (pacas),polyacetates, polysaccharides, and copolymers. The methods of preparation of nanoparticles, their characterization and medical application have been reviewed in detail.[ 31 ] The exact mechanism of nanoparticle transport into brain is not understood, but it is thought to depend on the particles size, material composition, and structure. In some cases it is reported to mimic molecules that would normally be transported to brain. For example, polysorbate-coated nanoparticles are thought to mimic low-density lipoprotein (LDL), allowing them to be transported across the capillary wall and into the brain by hitching a ride on the LDL receptor.[ 32 ]

The nanotechnology includes:

  • Coated nanoparticles
  • Pegylated nanoparticles
  • Solid Lipid nanoparticles (SLN)

Transdermal delivery

Bioadhesive liposomes bearing levonorgestrel as controlled drug delivery system has been studied.[ 26 ] Mesophasic proliposomal system for levonorgestral was prepared. The vesicles were mostly unilamellar and some were multilamellar. Release was of zero order kinetics. Alcohol as compared to oils had greater effect on transdermal flux. In vivo studies showed that a significant lag phase was observed before the therapeutic levels were reached indicating the requirement for a loading dose. This proliposomes system was found to be superior to PEG-based ointment system. Liposomal reservoir system bearing local anesthetic benzocaine was developed[ 33 ] for controlled and localized delivery via topical route. The liposomal suspension was incorporated into an ointment and gel base. The systems delivered the drug at a controlled rate ever 24 hr compared to plain ointment which had a rapidly decreased release rate. The drug delivery across human cadaver skin was very slow. In vivo studies showed a longer duration of action in the case of liposomal formulation.[ 34 ]

Miscellaneous

Nabar studied the effect of size and charge of liposome in the bio-distribution of 99m TC-DTPA encapsulated in liposome after intravenous injection in rats. They observed that multilamellar vesicles (MLV) were taken up to a greater extent as compared to SUVs in liver spleen and lungs. Positively charged MLVs than negative or neutral ones, were taken up more in liver, positively charged SUVs were taken up more in kidneys and neutral MLVs were taken up more in lungs than charged ones.[ 35 ] An attempt was made to improve stability of liposome by coupling the drug with the lipid bilayer using a cross linking agent.[ 36 ] Soya phosphatidylcholine (SPC) containing liposomes were prepared by calcium induced fusion method. Positively charged stearylamine was introduced in the bilayer. The liposomes were coupled to entrapped ibuprofen by EDAC (1-ethyl 3-(3-dimethyl aminopropyl) carbodiimide HCI) and the coupling was confirmed by UV spectrum. It was observed that EDAC in SPC containing stearylamine liposomes retarded the release of ibuprofen significantly. In albino rats, the various factors affecting systemic absorption of nasally applied gentamycin sulphate using in situ nasal perfusion technique was studied.[ 37 ] Tween 80 which is a surfactant increases permeation by altering membrane structure and permeability. In this study Tween 80 upto 1% w/v concentrations, increased permeability. Betacyclodextrin at 0.25% w/v concentration, another permeability enhancer was found to significantly increase permeability initially but was found to plateau off later on. However, both these permeability enhancer were found to decrease stability and potency of gentamycin.[ 38 ]

OTHER CONTROLLED DRUG DELIVERY SYSTEMS

Extended release, slow release and sustained release preparation have been developed by pharmaceutical industry and pharmacy departments and investigated in vitro for release pattern and in vivo for bio-equivalence.[ 39 ]

There is a great need in oral delivery of protein and peptide drugs, suitable devices for delivering the therapeutic agent incorporated microspheres selectively in the intestine. Gelatin capsules were coated with various concentrations of sodium alginate and cross-linked with appropriate concentrations of calcium chloride and tested in vitro for resistance to gastric and intestinal medium. Gelatin capsules coated with 20% w/v of the polymer, which gave the most promising result in vitro , were evaluated in human volunteers for their in vivo gastro intestinal tract behaviour. The radiographical studies show that while the un-coated gelatin capsules disintegrated in the stomach within 15 min of ingestion, the alginate-coated gelatin capsules remained intact as long as they were retained in the stomach (up to 3 h) and then migrated to the ileocecal region of the intestine and disintegrated.[ 40 – 43 ] Vanarase and Nagarsenkar prepared pellets of 1 mm and 1.65 mm size of prochlorperazine maleate using a modern pelletization technique. The pellets were coated with ethylcellulose and evaluated for in vitro release, using USP dissolution apparatus. They noted that release of PCPM can be reduced with increasing amount of ethylcellulose.[ 44 – 46 ] Rangaiah et al . prepared and studied the sustained release tablets of theophylline using Eudragit RL, RS, and Hydroxy propyl methyl cellulose. Bioavailability studies in volunteers showed that HPMC and Eudragit formulation produced sustained plasma concentration of the drug. Another group 35 formulated sustained release capsules of nifedipine containing an initial rapidly available loading dose in the form of solid dispersion and a sustained release part as micro particles coated with polyvinyl acetate (M.wt 45,000) film using a modified Wurster coating apparatus.[ 47 ] The products provided release of initial therapeutic dose of drug in less than 45 min and sustained release over 11-12 hours. The same group developed a diffusion cell for the determination of drug release from a topical aerosol formulation.[ 48 ]

Kushwaha used a blend of synthetic polymer polyvinyl alcohol and natural macromolecule gum Arabica and found that duration and release of drug depends on the amount of drug loaded in the matrix and solubility of the drug in the matrix and the release medium. The advantage of this system is that the release kinetics of the drug from the system can be tailored by adjusting the plasticizer, homopolymer and cross linker composition. Chitosan microspheres of 45-300 μ were used for controlled delivery of progesterone.[ 49 ] In vitro and in vivo release was tested. It was seen that highly cross linked spheres released only 35% of incorporated steroids in 40 days compared to 70% from lightly cross linked spheres. Determination of in vivo bioavailability of the steroid from microsphere formulation by intramuscular injection in rabbits showed that a plasma concentration of 1-2 μg/ ml was maintained upto 5 months without a high burst effect. The data suggests that cross linked chitosan microspheres would be an interesting system for long term delivery of steroids. Cross linked dextran beads were developed as a carrier for development of a single contact vaccine delivery system.[ 50 – 54 ] There has been extensive research on drug delivery by biodegradable polymeric devices since bioresorbable surgical sutures entered the market two decades ago. Among the different classes of biodegradable polymers, the thermoplastic aliphatic poly (esters) such as poly (lactide) (PLA), poly (glycolide) (PGA), and especially the copolymer of lactide and glycolide referred to as poly (lactide-co-glycolide) (PLGA) have generated tremendous interest because of their excellent bio-compatibility, biodegradability, and mechanical strength.[ 55 ] They are easy to formulate into various devices for carrying a variety of drug classes such as vaccines, peptides, proteins, and micromolecules. Most importantly, they have been approved by the United States Food and Drug.

Administration (FDA) for drug delivery. Dhiman and Khuller[ 56 , 57 , 58 , 59 ] found that mice immunized with microparticles of poly (DL-lactide-co-glycolide) (DLPLG) as delivery vehicles for 71-KDa cell wall associated protein of mycobacterium tuberculosis H37 Ra, exhibited significantly higher T cell stimulation and cytokine release in comparison to 71-KDa emulsified in Freund's incomplete adjuvant (FIA) as well as BCG vaccinated group. Further, the protective effect of 71KDa- PLG was compared with 71-KDa FIA on the basis of survival rates and viable bacilli load in different organs at 30 days post challenge and median lethal dose (LCD50) of Mycobacterium tuberculosis H37Rv. The 71-KDa PLG was more effective when challenge was given 16 week after immunization. Further, 71KaDa- PLG immunized group exhibited a significantly higher clearance of bacterial load from the lungs and livers in comparison to the 71KDa FIA immunized group. Poly (lactide-co-glycolide) (PLG) was used to deliver diclofenac in the form of microspheres and in situ gel-forming systems, subcutaneously. The pharmacokinetic and pharmacodynamics studies in the adjuvant - induced arthritic rats showed that microspheres produced steady therapeutic levels of the drug in the plasma for about 16 days following a single subcutaneous injection. The in situ gel-forming provided significantly higher maximum plasma concentration and inhibition of inflammation was maintained for about 10 days.[ 60 – 63 ]

Dental product

Somayaji et al . used an ethylcellulose strip as delivery medium for tetracycline and metronidazole to reduce sub-gingival microorganisms in periodontal pockets. Patients were given supragingival scaling and then divided into five groups, depending on the length of time the medication was in place. Sites were marked for tetracycline, metronidazole, and placebo. Sites were wiped and isolated, and baseline microbiology samples were taken for gram staining and culture methods.[ 64 ] After treatment, subgingival microbiological samples were taken again. The ethyl cellulose strips were removed and analyzed for any remaining drug. Results showed that tetracycline and metronidazole could both be applied locally to periodontal sites using ethyl cellulose strips and markedly supress the subgingival bacteria over a period of several days. The tetracycline showed a faster release; however, the metronidazole required a lesser concentration to achieve complete reduction of the subgingival flora. A saliva activated bio-adhesive drug delivery system was developed[ 65 ] for lidocaine hydrochloride and compared its effect with topical gel preparation in dentistry. It was found that DDS adhered to gingival within a minute and produced peak effect in 15 minutes and produced greater depth of anesthesia than the marketed topical gel.

Colon-specific drug delivery

The increasing number of peptide and protein drugs being investigated demands the development of dosage forms which exhibit site-specific release. Delivery of drugs into systemic circulation through colonic absorption represents a novel mode of introducing peptide and protein drug molecules and drugs that are poorly absorbed from the upper gastrointestinal (GI) tract.[ 66 ] Oral colon-specific drug delivery systems offer obvious advantages over parenteral administration. Colon targeting is naturally of value for the topical treatment of diseases of the colon such as Crohn's disease, ulcerative colitis and colorectal cancer. Sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Peptides, proteins, oligonucleotides, and vaccines are the potential candidates of interest for colon-specific drug delivery. Sulfasalazine, ipsalazide, and olsalazine have been developed as colon-specific delivery systems for the treatment of inflammatory bowel disease (IBD).[ 65 ] The vast microflora and distinct enzymes present in the colon are being increasingly exploited to release drugs in the colon. Although the large intestine is a potential site for absorption of drugs, some difficulties are involved in the effective local delivery of drugs to the colon bypassing the stomach and small intestine.[ 67 ] Furthermore, differential pH conditions and long transit time during the passage of drug formulations from mouth to colon create numerous technical difficulties in the safe delivery of drugs to the colon. However, recent developments in pharmaceutical technology, including coating drugs with pH-sensitive and bacterial degradable polymers, embedding in bacterial degradable matrices and designing into prodrugs, have provided renewed hope to effectively target drugs to the colon. The use of pH changes is analogous to the more common enteric coating and consists of employing a polymer with an appropriate pH solubility profile. The concept of using pH as a trigger to release a drug in the colon is based on the pH conditions that vary continuously down the GI tract.[ 68 ] Polysaccharide and azopolymer coating, which is refractory in the stomach and small intestine yet degraded by the colonic bacteria, have been used as carriers for colon-specific targeting. Finally, the availability of optimal preclinical models and clinical methods fueled the rapid development and evaluation of colon-specific drug delivery systems for clinical use. Future studies may hopefully lead to further refinements in the technology of colon-specific drug delivery systems and improve the pharmacotherapy of peptide drugs.[ 69 ]

The necessity and advantages of colon-specific drug delivery systems have been well recognized and documented.[ 70 ] In the past, the primary approaches to obtain colon-specific delivery achieved limited success and included prodrugs, pH- and time-dependent systems, and microflora-activated systems. Precise colon drug delivery requires that the triggering mechanism in the delivery system only respond to the physiological conditions particular to the colon. Hence, continuous efforts have been focused on designing colon-specific delivery systems with improved site specificity and versatile drug release kinetics to accommodate different therapeutic needs.[ 71 ]

Among the systems developed most recently for colon-specific delivery, four systems were unique in terms of achieving in vivo site specificity, design rationale, and feasibility of the manufacturing process (pressure-controlled colon delivery capsules (PCDCs), CODES, colonic drug delivery system based on pectin and galactomannan coating, and Azo hydrogels). The focus of this review is to provide detailed descriptions of the four systems, in particular, and in vitro / in vivo evaluation of colon-specific drug delivery systems, in general. Specific targeting of drugs to the colon is recognized to have several therapeutic advantages.[ 72 ] Drugs, which are destroyed by the stomach acid and/or metabolized by pancreatic enzymes, are slightly affected in the colon, and sustained colonic release of drugs can be useful in the treatment of nocturnal asthma, angina and arthritis. Treatment of colonic diseases such as ulcerative colitis, colorectal cancer and Crohn's disease is more effective with direct delivery of drugs to the affected area. Likewise, colonic delivery of vermicides and colonic diagnostic agents require smaller doses. Prasad et al . developed a colon-specific oral tablet using guar gum as carrier.[ 73 ]

Colonic drug delivery has gained increased importance not just for the delivery of the drugs for the treatment of local diseases associated with the colon but also for its potential for the delivery of proteins and therapeutic peptides.[ 74 ] To achieve successful colonic delivery, a drug needs to be protected from absorption and/or the environment of the upper gastrointestinal tract (GIT) and then be abruptly released into the proximal colon, which is considered the optimum site for colon-targeted delivery of drugs. Colon targeting is naturally of value for the topical treatment of diseases of colon such as Chron's diseases, ulcerative colitis, colorectal cancer and amebiasis. Peptides, proteins, oligonucleotides, and vaccines pose potential candidature for colon targeted drug delivery.[ 75 ]

Drug release studies under conditions mimicking mouth to colon transit have showed that guar gum protects the drug from being released completely in the physiological environment of stomach and small intestine. Guar gum at pH. 6.8 is susceptible to colonic bacterial enzyme action, with drug release. Pre-treatment of rats orally with aqueous dispersion of guar gum for 3 days, induced enzyme specifically acting on guar gum,[ 76 ] thereby increasing drug release. The result indicates usefulness of guar gum as a potential carrier for colon specific drug delivery. A novel colon-specific drug delivery system based on a polysaccharide, guar gum was evaluated in healthy human male volunteers, with gamma scintigraphic study using technetium 99m-DTPA as tracer. It was seen that some amount of tracer present on the surface of the tablets was released in stomach and small intestine and the bulk of the tracer present in the tablet mass was delivered to the colon. The colonic arrival time of the tablets was 2-4 hr. On entering the colon, the tablets were found to degrade. In vitro release studies of the incorporated 5-flurouracil was carried out in simulated gastric and intestinal fluids. In vitro release profile in presence of azoreductase in the culture of intestinal flora followed a zero order pattern.[ 77 ]

Pharmaceutical development of drug delivery system is being pursued enthusiastically in many laboratories in India. These are being investigated in vitro for release pattern and in some cases in vivo in animals for pharmacokinetics but less frequently for efficacy. There is a paucity of data on clinical studies and utility of the DDS in patients. It is necessary that pharmacologists should be involved in the investigation of pharmacokinetics and pharmacodynamics of DDS if the products have reached their meaningful outcome - the clinical use.

Source of Support: Nil

Conflict of Interest: None declared.

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Essay: Drug administration and Drug Delivery Systems

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1. INTRODUCTION The oral route of drug administration is the most important method of administering drugs for systemic effects. The parentral route is not routinely used or not possible to self-administration of medication. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects. It is probable that at least 90 % of all drugs used to produce systemic effects are administered by the oral route. When a new drug is discovered, one of the first questions a pharmaceutical company asks is whether or not the drug can be effectively administered for its intended effect by the oral route. If it cannot, the drug is primarily relegated to administration in a hospital setting or physician’s office. Of drugs that are administered orally, solid oral dosage forms represent the preferred class of product. The reasons for this preference are well known1. 1.1 Novel Drug Delivery System: Today, a pharmaceutical scientist is well versed with the fact that the overall action of a drug molecule is not merely dependent on its inherent therapeutic activity, rather on the efficiency of its delivery at the site of action. An increasing appreciation of the latter has led to the evolution and development of several drug delivery systems (DDS) aimed at performance enhancement of the potential drug molecules. A review of the literature has revealed the recent several technical advancements have led to the development of various Novel Drug Delivery Systems (NDDS) that could revolutionize method of drug delivery and hence could provide definite therapeutic benefits 2. Till date, remedies have been found for most of the diseases; but still research is going on inorder to improve the existing therapy. To bring a new drug molecule in the market, it involves a lot more than investment of time and money. In the pre GATT era the patents of drug molecules/formulations are expiring. The new way of patenting the drug is to use. ‘Novel Drug Delivery Systems’ i.e. NDDS with improved bioavailability (BA). To formulate a drug or to re-formulate it in a form of NDDS is not a Herculean task if one goes methodically and skillfully. This is where the formulation development studies play an important role. 1.2 Oral Controlled Drug Delivery: Drug absorption at the desired rate means, first to reach the effective plasma level within an acceptable short time period; second, to avoid an overshoot in the case of rapidly absorbed drugs and third to maintain effective plasma levels over the desired time period. Although the intensity of pharmacological effect is related to the drug concentration at the site of action, which is in turn, related to the plasma drug concentration, an ideal situation is obtained when the concentration is continuously maintained between minimum effective and maximum safe levels (Therapeutic Index). Invariably, conventional drug dosage forms do not maintain the drug. Blood levels within the therapeutic range for an extended period of time. To achieve the same, a drug may be administered repetitively using a fixed dosing interval. This causes several potential problems as like saw tooth kinetics characterized by large peaks and troughs in the drug concentration-time curve (Fig.1), frequent dosing for drugs with short elimination half-life, and above all the patient noncompliance. Controlled release drug delievery systems(CRDDS) attempt to sustain drug blood concentration at relatively constant and effective levels in the body by spatial placement or temporal delivery. Thus CRDDS offer various advantages viz. reduce blood level fluctuations, minimize drug accumulation, employ less total drug, improve patient compliance, and minimize local and systemic side effects3-7. Fig 1.1: Plasma level profiles following conventional and controlled release dosing Modified release DDS, in general, can broadly divided into four categories: ‘ Delayed release ‘ Site specific release ‘ Receptor release ‘ Sustained release a) Controlled release b) Prolonged release For the oral controlled administration of drug, several research and development activities have shown encouraging signs of progress in the development of programmable controlled release dosage forms as well as in the search for new approaches to overcome the potential problems associated with oral drug administration8. Drugs that are easily absorbed from the gastrointestinal tract (GIT) and having a short half-life are eliminated quickly from the blood circulation. To avoid this problem, the oral controlled release (CR) formulations have been developed as these will release the drug slowly into the GIT and maintain a constant drug concentration in the serum for a longer period of time1. Oral controlled release dosage forms (CRDFs) are being developed for the past three decades due to their advantages. The design of oral controlled drug delivery systems (CDDS) should primarily be aimed at achieving more predictable and increased bioavailability of drugs. Orally administered controlled release dosage forms suffer from mainly two adversities: 1.3 Gastroretentive drug delivery system (GRDDS) : Recent scientific and patent literature shows increased interest in academics and industrial research groups regarding the novel dosage forms that can be retained in the stomach for a prolonged and predictable period of time. One of the most feasible approaches for achieving a prolonged and predictable drug delivery profile in the GI tract is to control the gastric residence time (GRT), using gastroretentive drug delivery system (GRDDS) that will provide us with new and important therapeutic options8. A major constraint in oral controlled drug delivery is that not all drug candidates are absorbed uniformly throughout the GIT. Some drugs are absorbed in a particular portion of the GIT only or are absorbed to a different extent in various segments of the GIT. Such drugs are said to have an absorption window, which identifies the drug’s primary region of absorption in the GIT 11 Figure1. 2: (a) Conventional drug delivery system (b) GRDDS An absorption window exists because of physiological, physicochemical, or biochemical factors. Drugs having site-specific absorption are difficult to design as oral CRDDS because only the drug released in the region preceding and in close vicinity to the absorption window is available for absorption. After crossing the absorption window, the released drug goes waste with negligible or no absorption (Fig.2a). This phenomenon drastically decreases the time available for drug absorption after its release and jeopardize the success of the delivery system. The GRDDS can improve the controlled delivery of the drugs which exhibit an absorption window by continuously releasing the drug for a prolonged period before it reaches its absorption site, thus ensuring its optimal bioavailability (Fig.2b) 12. Pharmaceutical aspects of gastroretentive drug delivery system (GRDDS) : In designing GRDDS, the following characteristics should be sought: convenient intake, retention in the stomach according to clinical demand; ability to load substantial amount of drugs with different physicochemical properties and release them in controlled manner; complete degradation, preferable in the stomach13 .Gastric retention will provide advantages such as the delivery of drug with narrow absorption window in the small intestinal region. Also longer residence time in the stomach could be advantages for local action in the upper part of small intestine; e. g. in the treatment of peptic ulcer disease, further more improved bioavailability is expected for drug that absorbed readily upon release in the GI tract. 1.4 Physiology of Stomach: The shape of the normal stomach is generally like letter ‘J’. Sometimes the long axis may be slanting from left to right or it may be even horizontal. The junction of the esophageal mucosa with that of the stomach is abrupt. The oesophago-cardiac line of junction is irregular or zigzag and is often referred as the ‘Z’ or ‘ZZ’ line. At the pylorus, the mucous membrane of the stomach makes junction with that of duodenum. The capacity of the average stomach is about 1.12-1.7 lts. The stomach can be subdivided into three parts- the fundus, the body and the pylorus. Figure 1.3: Stomach anatomy Each of these contains a particular type of gland. The cardiac area is the zone,1 to 4 cm wide that guards the esophageal orifice, also known as cardiac Fundus Body Pylorus sphincter. The fundic area is the largest area of stomach accounting for 60-80 % of total mucosal surface, interposed between the cardiac and the pyloric areas. The lower part of the fundic area is separated from the pylorus by a sharp angle on the lesser curvature called the incisura angularis. The junction of the pyloric and fundic area is not sharply demarcated and is frequently known as transitional zone. The pylorus is limited on the left by the incisura and on the right by the pyloric sphincter. The circular fibres of pyloric sphincter guards against back flow of small intestinal contents into the stomach. The pyloric area is about 15 % of the total gastric mucosal area. It is subdivided into two parts: (a) the pyloric antrum which is short, comparatively wider, proximal chamber and (b) the pyloric canal which is narrow tubular passage about 3 cm long, ending in the pyloric sphincter (Fig.3). Histologically, stomach consists of the same four layers but with characteristic differences. The outer serous coat consists of peritoneum. The muscular coat consists of three layers: the outer longitudinal, the middle circular and the inner oblique layer. Next comes the submucous coat, and then come the layer of muscular is mucosae and a supporting stroma of connective tissue. This layer of muscle also contains of an outer longitudinal and an inner circular layer. Finally comes mucous membrane which is thrown out into the large folds called rugae when the stomach is empty and these folds tend to disappear when distended14. 1.5 Gastric Emptying: The GIT is always in a state of continuous motility. The process of gastric emptying occurs both during fasting and fed states; however, the pattern of motility differs markedly in the two states. In the fasted state, it is characterized by an interdigestive series of electrical events which cycle both through the stomach and small intestine every 2-3 h. This activity is called the interdigestive myoelectric circle or migrating myoelectric complex (MMC), which is often divided into four consecutive phases13. Figure1.4: Typical motility patterns in fasting state12 A complete cycle of these 4 phases, as illustrated in Fig. 4, has an average duration of 90-120 minutes. Any CRDDS designed to stay during the fasted state should be capable of resisting the house-keeping action of phase III, if one intends to prolong the GI retention time. The bioadhesive properties added to the GI drug delivery system must be capable of adhering to the mucosal membrane strongly enough to withstand the shear forces produced in this phase15. The gastroretentive technology of solid dosage forms is thus mainly dependent on the coincidence between dosing time and phase III MMC occurrence. Dosage forms such as tablets, capsules and particles have demonstrated a transit pattern similar to that of nutrients. These forms taken orally in the fasted state empty within 90 min. In fed state, these will have to await the MMC activity occurring at the end of digestion to be cleared from stomach in association with the Phase III cleansing contractions. It is thus the pylorus, and, more particularly, the small diameter of the gastric lumen at the gastroduodenal junction, that has remarkable function of performing the selective retention of the solid particles, depending on their size16. 1.5.1. Factors Affecting Gastric Retention 10, 12: Gastric residence time of an oral dosage form is affected by several factors. The pH of the stomach in fasting state is ~1.5 to 2.0 and in fed state is 2.0 to 4.0. A large volume of water administered with an oral dosage form raises the pH of stomach contents from 6.0 to 9.0. Stomach doesn’t get time to produce sufficient acid when the liquid empties the stomach; hence generally basic drugs have a better chance of dissolving in fed state than in a fasting state. To pass through the pyloric valve into the small intestine the particle size should be in the range of 1 to 2 mm.. In the case of elderly persons gastric emptying is slowed down. Generally females have slower gastric emptying rates than males. Stress increases gastric emptying rates while depression slows it down. Studies have revealed that gastric emptying of a dosage form in the fed state can also be influenced by its size. Small-size tablets leave the stomach during the digestive phase while the large-size tablets are emptied during the housekeeping waves. The effect of size of floating and nonfloating dosage forms on gastric emptying and concluded that the floating units remained buoyant on gastric fluids12. These are less likely to be expelled from the stomach compared with the nonfloating units, which lie in the antrum region and are propelled by the peristaltic waves. It has been demonstrated using radiolabeled technique that there is a difference between gastric emptying times of a liquid, digestible solid, and indigestible solid. It was suggested that the emptying of large (91 mm) indigestible objects from stomach was dependent upon interdigestive migrating myoelectric complex. Indigestible solids larger than the pyloric opening are propelled back and several phases of myoelectric activity take place when the pyloric opening increases in size during the housekeeping wave and allows the sweeping of the indigestible solids. Size and shape of dosage unit also affect the gastric emptying. Garg and Sharma15 reported that tetrahedron- and ring-shaped devices have a better gastric residence time as compared with other shapes. The diameter of the dosage unit is also equally important as a formulation parameter. Dosage forms having a diameter of more than 7.5 mm show a better gastric residence time compared with one having 9.9 mm. Floating units away from the gastroduodenal junction are protected from the peristaltic waves during digestive phase while the nonfloating forms which stay close to the pylorus and are subjected to propelling and retropelling waves of the digestive phase. It is also observed that of the floating and nonfloating units, the floating units had a longer gastric residence time for small and medium units while no significant difference was seen between the 2 types of large unit dosage forms. When subjects are kept in the supine position it was observed that the floating forms could only prolong their stay because of their size; otherwise the buoyancy remained no longer an advantage for gastric retention. A comparison was made to study the affect of fed and non-fed stages on gastric emptying. For this study all subjects remaining in an upright position were given a light breakfast and another similar group was fed with a succession of meals given at normal time intervals. It was concluded that as meals were given at the time when the previous digestive phase had not completed, the floating form buoyant in the stomach could retain its position for another digestive phase as it was carried by the peristaltic waves in the upper part of the stomach10. 1.6 Gastroretentive technologies (GRT) : A number of systems have been used to increase the GRT of dosage forms by employing a variety of concepts. These systems have been classified according to the basic principles of gastric retention (Fig.5). Figure 1.5: Classification of gastroretentive drug delivery system 1. Floating DDS (FDDS), with low density providing sufficient buoyancy to float over the gastric contents. 2. Bioadhesive systems, the localized retention of the system in the stomach. 3. Swelling and expanding systems, preventing transit from the gastric sphincter. 4. High density systems, remaining in the stomach for longer period of time, by sedimenting to the folds of stomach. Fig.5 illustrates the mechanistics of these systems in stomach. A number of other methods like use of passage-delaying agents and modified shape systems have also been used for gastroretention purpose. 1.6.1 Floating Drug Delivery System (FDDS) : Floating dosage form is also known as hydrodynamically balanced system (HBS). FDDS have a bulk density less than gastric fluids and so remain buoyant in the stomach without affecting the gastric emptying rate for a prolonged period of time while the system is floating on the gastric contents, the drug is released slowly at the desired rate. After release of drug, the residual system is emptied from the stomach. It is formulation of a drug (capsule or tablet) and gel forming hydrocolloids meant to remain buoyant on stomach contents. This not only prolongs GI residence time but also does so in an area of the GI tract that would maximize drug reaching its absorption site in solution and hence ready for absorption. Drug dissolution and release from the capsule retained in stomach fluids occur at the stomach, under fairly controlled condition. The retentive characteristics of the dosage form in gastric content are most significant for drugs which are insoluble in intestinal fluid, that acts locally and that exhibits sitespecific absorption16, 17. Classification of FDDS: Based on the mechanism of buoyancy, floating systems can be classified into two distinct categories viz. non-effervescent and effervescent systems. A. Non-Effervescent systems: 1. Colloidal gel barrier systems: Hydrodynamically balanced system (HBS) of this type contains drug with gel forming or swellable cellulose type hydrocolloids, polysaccharides and matrix forming polymers. They help prolonging the GI residence time and maximize drug reaching its absorption site in the solution form ready for absorption. These systems incorporate high levels (20 to 75 % w/w) of one or more gel forming highly swellable cellulose type hydrocolloids e.g. hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC) hydroxypropyl methyl cellulose (HPMC), sodium carboxy methyl cellulose (NaCMC) incorporated either in tablets or capsules. When such a system comes in contact with the gastric fluid, the hydrochloride in the system hydrates and forms a colloidal gel barrier around its surface (Fig.6). Figure1. 6: Hydrodynamically Based System (HBS) 18 The HBS must comply with following three major criteria 1. It must have sufficient structure to form cohesive gel barrier. 2. It must maintain an overall specific density lower than that of gastric contents. 3. It should dissolve slowly enough to serve as reservoir for the delivery system. Figure 1.7: Intragastric Floating Tablet Intragastric floating tablet that were hydrodynamically balanced in the stomach for an extebded period of time until all the drug- loading dose was released. Tablets were comprised of an active ingredient, 0-80 % by weight of inert material, and 20-75 % by weight of one or more hydrocolloids such as methylcellulose, hpc, hydroxypropylmethylcellulose, and sodium caboxymethylcellulose, which upon contact with gastric fluid provided a water impermeable colloid gel barrier on the surface of tablets. (as shown in fig 7) Figure 1.8: Bilayer Intra-Gastric Floating Tablet A bilayer tablet can also be prepared to contain one immediate release and other sustained release layer. (Fig.8) Immediate release layer delivers the initial dose whereas sustained release layer absorbs gastric fluid and forms a colloidal gel barrier on its surface. This results in system with bulk density lesser than that of gastric fluid and allows it to remain buoyant in the stomach for an extended period of time19. A multi-layer, flexible, sheath-like device buoyant in gastric juice showing sustained release characteristics have also been developed. The device consists of at least one dry self-supporting carrier film made up of water insoluble polymer matrix having a drug dispersed/dissolved therein, and a barrier film overlaying the carrier film. 2. Micro- porous compartment system: This technology is comprised of encapsulation of a drug reservoir inside a micro porous compartment with pores along its top and bottom surfaces. The peripheral walls of the drug reservoir compartment are completely sealed to prevent any direct contact of gastric mucosal surface with undissolved drug. In stomach, the floatation chamber containing entrapped air causes the delivery system to float over the gastric contents. Gastric fluid enters through the pores, dissolves the drug and carries the dissolved drug for continuous transport across the intestine for absorption. The micro porous compartment system is shown in (Fig.9). Figure 1.9: Floating drug delivery device with microporous membrane and floatation chamber Micro porous intra-gastric floating drug delivery device 19: Intra-gastric floating and sustained release granules of Diclofenac sodium were developed using hydroxypropyl cellulose, ethyl cellulose and calcium silicate as floating carriers which had a characteristically porous structure with numerous pores and a large individual pore volume. The coated granules acquired floating ability from the air trapped in the pores of calcium silicate when they were coated with a polymer. 3. Alginate beads: Multiple unit floating dosage forms have been developed from freeze-dried calcium alginate. Spherical beads of approximately 2.5 mm in diameter were prepared by dropping a sodium alginate solution into aqueous solution of calcium chloride, causing a precipitation of calcium alginate. These beads were then separated; snap frozen in liquid nitrogen and freeze-dried at ‘ 40”C for 24 hrs. leading to formation of porous system that maintained floating force for over 12 hrs. They were compared with non-floating solid beads of same material. The latter gave a short residence time of 1 hr., while floating beads gave a prolonged residence time of more than 5.5 hrs10. 4. Hollow Microspheres: Hollow microspheres (microballoons), loaded with ibuprofen in their outer polymer shells were prepared by novel emulsion solvent diffusion method. The ethanol: dichloromethane solution of the drug and an enteric acrylic polymer were poured into an agitated aqueous solution of PVA that was thermally controlled at 40oC. The gas phase was generated in dispersed polymer droplet by evaporation of dichloromethane and formed an internal cavity in microsphere of polymer with drug (Fig.10). Figure1. 10: Mechanism of microballoon formation by emulsion-solvent diffusion method. Figure 1.11: Microballoon These microballoons floated continuously over surface of acidic solution media that contained surfactant, for greater than 12 hrs. in vitro. The drug release was high in pH 7.2 than in pH 6.8. B. Effervescent systems: A drug delivery system can be made to float in the stomach by incorporating a floating chamber, which may be filled with vacuum, air or inert gas. The gas in floating chamber can be introduced either by volatilization of an organic solvent or by effervescent reaction between organic acids and bicarbonate salts. 1. Volatile liquid containing systems: These devices are osmotically controlled floating systems containing a hollow deformable unit that can be converted from a collapsed to an expanded position and returned to collapse position after an extended period. Figure1. 12: Gastro inflatable drug delivery device16. A deformable system consists of two chambers separated by an impermeable, pressure responsive, movable bladder. The first chamber contains the drug and the second chamber contains volatile liquid. The device inflates and the drug is continuously released from the reservoir into the gastric fluid. The device may also consist of bioerodible plug made up of PVA, polyethylene, etc. that gradually dissolves causing the inflatable chamber to release gas and collapse after a predetermined time to permit the spontaneous ejection of the inflatable system from the stomach (Fig.12). Intra-gastric, osmotically controlled drug delivery system consists of an osmotic pressure controlled drug delivery device and an inflatable floating support in bioerodible capsule. Figure 1.13: Intragastric osmotic controlled drug delivery system16. 2. Gas generating systems: These buoyant delivery systems utilize effervescent reaction between carbonate/bicarbonate salts and citric/tartaric acid to liberate CO2 which gets entrapped in the jellified hydrochloride layer of the system, thus decreasing its specific gravity and making it float over chyme. These tablets may be either single layered wherein the CO2 generating components are intimately mixed within the tablet matrix or they may be bilayer in which the gas generating components are compressed in one hydrocolloid containing layer, and the drug in outer layer for sustained release effect. Multiple unit type of floating pills (Fig.1.14) that generates CO2, have also been developed. These kinds of systems float completely within 10 minutes and remain floating over an extended period of 5-6 hrs. Figure-1.14: The multiple units floating drug delivery system using gas generation technique 1.6.1.1. Advantages of floating drug delivery system19: An FDDS offers numerous advantages over conventional DDS: 1. The gastroretensive systems are advantageous for drugs absorbed through the stomach. E.g. Ferrous salts, antacids. 2. Acidic substances like aspirin cause irritation on the stomach wall when come in contact with it. Hence HBS formulation may be useful for the administration of aspirin and other similar drugs. 3. Administration of prolongs release floating dosage forms, tablet or capsules, will result in dissolution of the drug in the gastric fluid. They H2O e) Drug d) dissolve in the gastric fluid would be available for absorption in the small intestine after emptying of the stomach contents. It is therefore expected that a drug will be fully absorbed from floating dosage forms if it remains in the solution form even at the alkaline pH of the intestine. 4. The gastroretensive systems are advantageous for drugs meant for local action in the stomach. e.g. antacids. 5. When there is a vigorous intestinal movement and a short transit time a might occur in certain type of diarrhea, poor absorption is expected. Under such circumstances it may be advantageous to keep the drug in floating condition in stomach to get a relatively better response. 6. Sustained Drug Delivery: HBS systems can remain in the stomach for long periods and hence can release the drug over a prolonged period of time. The problem of short gastric residence time encountered with an oral CR formulation hence can be overcome with these systems. These systems have a bulk density of 100 , swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover, they swell to a large size (swelling ratio of approx. 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction. Figure 1.17: High Density System 1.6.5. Superporous hydrogel: Although these are swellable systems, they differ sufficiently from the conventional types to warrant separate classification. With pore size ranging between 10 nm and 100 nm, absorption of water by conventional hydrogel is a very slow process and several hours may be needed to reach an equilibrium state during which premature evacuation of the dosage form may occur. Superporous hydrogels, average pore size >100 , swell to equilibrium size within a minute, due to rapid water uptake by capillary wetting through numerous interconnected open pores. Moreover, they swell to a large size (swelling ratio of approx. 100 or more) and are intended to have sufficient mechanical strength to withstand pressure by gastric contraction. 1.6.6. Incorporation of passage delaying food agents: The food excipients like fatty acids, e.g. salts of myristic acid change and modify the pattern of the stomach to a fed state, thereby decreasing gastric emptying rate and permitting considerable prolongation of release. The delay in the gastric emptying after meals rich in fats is largely caused by saturated fatty acids with chain length of C10-C1416, 18. 1.6.7. Modified- shape systems: These are non-disintegrating geometric shapes molded from silastic elastomer or extruded from polyethylene blends which extend the GRT depending on size, shape and flexural modulus of the drug delivery system23. Figure 1.18: Modified shape systems24 1.7 Criteria for selection of drug candidate for GRDF: ‘ Drugs that are easily absorbed from the gastrointestinal tract (GIT) and having a short half-life are eliminated quickly from the blood circulation. ‘ Absorption from upper GIT: Drugs have a particular site for maximum absorption, e.g. Ciprofloxacin, whose maximum absorption is in the stomach only. The absorption of Metformin HCL is confined to the small intestine only and the conventional sustained release dosage forms may be poorly BA since absorption appears to diminish when the dosage form pass into large intestine. ‘ Drugs insoluble in intestinal fluids (acid soluble basic drugs):e.g. Chlordiazepoxide, chlorpheniramine, cinnarizine, diltiazem. ‘ Local action is seen in the treatment of Helicobacter pylori by Amoxicillin24. ‘ The BA of drugs that get degraded in alkaline pH can be increased by formulating gastro-retentive dosage forms, e.g. Doxifluridine, which degrades in small intestine. ‘ Drug that are erratically absorbed due to variable gastric emptying time. ‘ Drug which get metabolized in the colon or having high first pass metabolism. 1.8 Floating microspheres: Floating microspheres are gastro-retentive drug delivery systems based on non-effervescent approach. Hollow microspheres are in strict sense, spherical empty particles without core. These microspheres are characteristically free flowing powders consisting of proteins or synthetic polymers, ideally having a size less than 200 micrometer. Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for controlled release of drugs 25. As the exterior surface of the dosage form dissolves, the gel layer is maintained by the hydration of the adjacent hydrocolloid layer. The air trapped by the swollen polymer lowers the density and confers buoyancy to the microspheres. However a minimal gastric content needed to allow proper achievement of buoyancy26. Hollow microspheres of Acrylic resins, Eudragit, PMAA, Polyethylene oxide, and Cellulose acetate; Polystyrene floatable shells; polycarbonate floating balloons and gelucire floating granules are the recent developments27. 1.8.1 Method of preparation for floating microspheres9, 25,27,28,29: Floating microspheres should satisfy certain criteria, they are: 1. The ability to incorporate reasonably high concentration of drug. 2. Stability of the preparation after synthesis with a clinically acceptable shelf-life. 3. Release of active agent with good control over a wide time scale. 4. It must maintain specific gravity lower than gastric content (1.004-1.01 g/cc) 5. Biocompatibility with a controllable biodegradability. 6. Susceptibility to chemical modification. Selection of excipients is an important strategic consideration for designing a dosage forms with consistence and controlled residence in the stomach. High molecular weight and less hydrophilic polymers are expected to improve floating properties of delivery system. The polymer studied for the development of such systems include cellulose acetate, chitosan, eudragit acrycoat, methocil, polyacrylate, polyvinylacetate, carbopol, agar, polyethylene oxide, and polycarbonate. Various methods are employed for the preparation of the floating microspheres is: 1. Solvent diffusion and Evaporation methods: Hollow microspheres are prepared by solvent diffusion and evaporation methods to create the hollow inner core. The polymer is dissolved in an organic solvent and the drug is either dissolved or dispersed in the polymer solution. The solution containing the drug is then emulsified into an aqueous phase containing polyvinyl alcohol to form an oil-in water emulsion. After the formation of a stable emulsion, the organic solvent is evaporated either by increasing the temperature under pressure or by continuous stirring. The solvent removal leads to polymer Precipitation at the o/w interface of the droplets, forming the cavity and thus making them hollow to impart the floating properties. 2. Solvent evaporation method: In this method drug and polymers (HPMC and Ethylcellulose) were dissolved in a mixture of ethanol and dichloromethane at room temperature (Table I). This was poured into 250 mL water containing 0.01% Tween 80 maintained at a temperature of 30’40 ”C and subsequently stirred at ranging agitation speed for 20 min to allow the volatile solvent to evaporate. The microspheres formed were filtered, washed with water and dried in vacuum. 3. Spray drying method: In Spray Drying the polymer is first dissolved in a suitable volatile organic solvent such as dichloromethane, Acetone, etc. The drug in the solid form is then dispersed in the polymer solution under high-speed homogenization. This dispersion is then atomized in a stream of hot air. The atomization leads to the formation of the small droplets or the fine mist from which the solvent, evaporate instantaneously leading the formation of the microspheres in a size range 1-100 ”m. Micro particles are separated from the hot air by means of the cyclone separator while the trace of solvent is removed by vacuum drying. One of the major advantages of process is feasibility of operation under aseptic conditions. This process is rapid and this leads to the formation of porous microparticles. Selection of excipients is an important strategic consideration for designing a dosage forms with consistence and controlled residence in the stomach. High molecular weight and less hydrophilic polymers are expected to improve floating properties of delivery system. The polymer studied for the development of such systems include cellulose acetate, chitosan, eudragit acrycoat, methocil, polyacrylate, polyvinylacetate, carbopol, agar, polyethylene oxide, and polycarbonate. Various methods are employed for the preparation of the floating microspheres is: 1.8.2 Advantages of floating microspheres24: ‘ Improves patient compliance by decreasing dosing frequency. ‘ Bioavailability enhances despite first pass effect because fluctuations in plasma drug concentration is avoided, a desirable plasma drug concentration is maintained by continuous drug release. ‘ Better therapeutic effect of short half-life drugs can be achieved. ‘ Gastric retention time is increased because of buoyancy. ‘ Drug releases in controlled manner for prolonged period. ‘ Site-specific drug delivery to stomach can be achieved. ‘ Enhanced absorption of drugs which solubilize only in stomach. ‘ Superior to single unit floating dosage forms as such microspheres releases drug uniformly and there is no risk of dose dumping. ‘ Avoidance of gastric irritation, because of sustained release effect, floatability and uniform release of drug through multiparticulate system. ‘ During the process of an gastric emptying, a proportion of the floating microspheres adheres to stomach wall (as shown in fig. 19) to provide a gastroretention and sustained drug release for drugs like PPI’s drugs which having short elimination half-life. Fig.1. 19: (A) Microspheres Float on Stomach Contents (B) &(C) Micropsheres Adheres To Stomach Wall during Gastric Emptying30 1.8.3 Disadvantages11: ‘ This requires sufficiently high levels of fluids in the stomach, for enabiling the system to float and to work efficiently. ‘ Floating microspheres are not suitable candidates for drugs with stability or solubility problem in the stomach.eg nifedipine. ‘ A drug with irritant effect on gastric mucosa also limits the applicability of floating microspheres. 1.8.4 Characterization of Floating Microspheres31, 32: Floating microspheres are characterized for micromeritic properties, surface morphology, in-vitro buoyancy, drug entrapment efficiency and in-vitro drug release. Micromeritic properties such as particle size, tapped density, compressibility index, true density and flow properties including angle of repose. The particle size is determined by optical microscopy; true density is determined by liquid displacement method; tapped density and compressibility index are calculated by measuring the change in volume using a bulk density apparatus; angle of repose is determined by fixed funnel method. The hollow nature of microspheres is confirmed by scanning electron microscopy.33, 34, 35 Floating behavior of hollow microspheres is studied in a dissolution test apparatus by spreading the microspheres on a simulated gastric fluid (pH 1.2) containing tween 80 as a surfactant; the media is stirred and a temperature of 37’C is maintained throughout the study. After specific intervals of time, both the fractions of the microspheres floating and settled are collected; the buoyancy of the floating microspheres can be calculated using the data. The in-vitro drug release studies are performed in a dissolution test apparatus using 0.1N hydrochloric acid as dissolution media. X-ray photography of hollow microspheres loaded with barium sulphate in the stomach of beagle dogs. 1.8.5 Application of floating microspheres: 1. Floating microspheres are especially effective in delivery of sparingly soluble and insoluble drugs. 2. For weakly basic drugs that are poorly soluble at an alkaline pH, hollow microspheres may avoid chance for solubility to become the rate-limiting step in release by restricting such drugs to the stomach. 3. Drugs that have poor bioavailability because of their limited absorption to the upper gastrointestinal tract can also be delivered efficiently thereby maximizing their absorption and improving the bioavailability. 4. The floating microspheres can be used as carriers for drugs with so-called absorption windows, these substances, for example antiviral, antifungal and antibiotic agents (Sulphonamides, Quinolones, Penicillins, Cephalosporins, Aminoglycosides and Tetracyclines). 5. For more effective oral use of peptide and protein drugs such as Calcitonin, Erythropoietin, Vasopressin, Insulin, low-molecular-weight Heparin, and LHRH. 6. Hollow microspheres of non-steroidal anti-inflammatory drugs are very effective for controlled release as well as it reduces the major side effect of gastric irritation; for example floating microspheres of Indomethacin are quiet beneficial for rheumatic patients. 2. AIM AND OBJECTIVE Need for the study: Oral drug delivery is the most desirable and preferred method of administering therapeutic agent for their systematic effect such as patient acceptance, convenience in administration and cost effective manufacturing process. Thus wide variety of approaches of drug delivery system has been investigated for oral application. However development process is precluded by several physiological difficulties, such as inability to restrain & localize drug delivery system within desired region of GIT tract and highly variable nature of gastric emptying process. For example relatively brief gastric emptying time can result in incomplete drug release from drug delivery devices leading to diminished efficacy of administered dose. Floating drug delivery system is noted orally applicable drug delivery system for prolongation of gastric emptying time. The bulk density of floating drug delivery system is lower than that of gastric fluid and thus it remains buoyant on stomach content for long time in the drug releasing process. Hence it is useful for obtaining sufficient bioavailability for long time and effective plasma level. Microspheres provide a constant & prolonged therapeutic effect which will reduce dosing frequency.36, 37 it was reported that microspheres prepared with proton pump inhibitor effective in reducing gastric acid level and allowing acid related disease to heal.36, 37 The aim of presented work is to develop the floating microspheres of Repaglinide by solvent evaporation method. 1. To develop the floating microspheres of Repaglinide by using Sodium alginate, HPMC K100, Sodium bicarbonate in different ratios. 2. To characterize prepared microspheres by Fourier Transform Infrared (FTIR) Spectroscopy. 3. Surface morphology of prepared microspheres can be studied by Scanning Electron Microscopy (SEM). 4. To evaluate the prepared floating microspheres for micrometric properties (particle size, bulk density, tapped density, compressibility index, hausners ratio and angle of repose), practical yield, drug incorporation efficiency, In- vitro buoyancy, In ‘vitro drug release study. 3.PLAN OF WORK 1. Literature Review 2. Selection of drug and polymers 3. Procurement of Drug and polymers 4. Construction of standard graph in 0.1 N HCL 5. Drug and excipent compatibility studies ‘ FT-IR 6. Preparation of Floating Microspheres 7. Determination of flow properties of Floating microspheres. ‘ Angle of repose ‘ Bulk density ‘ Tapped density ‘ Carr’s index ‘ Hausners ratio 8. Characterisation of Floating microspheres ‘ SEM ‘ Drug content ‘ Drug Entrapment Efficiency ‘ Percentage Yield ‘ In vitro buoyancy studies ‘ In vitro dissolution 9. Select the best formulaton 10. Application drug release kinetics of optimised formula. 6. METHODOLOGY List of Materials used: S.No List of Chemicals Manufacturing Company 1 Repaglinide Procured from Aurobindo Pharma, Provided by Sura Labs, Hyderabad 2 Sodium alginate S.D. fine chemicals Pvt. Ltd., Mumbai 3 HPMC K100 S.D. fine chemicals Pvt. Ltd., Mumbai 4 Ethanol Merk specialities Pvt Limited,Mumbai 5 Dichloromethane Merk specialiities Pvt Limited,Mumbai 6 Tween 80 Merk specialities Pvt Limited,Mumbai 7 Hydrochloric acid Merk specialities Pvt Limited,Mumbai 8 Sodium bicarbonate Merk specialities Pvt Limited,Mumbai Table 6.1: List of Materials used List of Equipments used: S.No Instruments/Equipments Manufacturer/Supplier 1 Electronic weighing balance Sartorious 2 Mechanical stirrer Remi Laboratories 3 UV-Visible spectrophotometer Lab India, India 4 Dissolution Apparatus Lab India, Lab India 5 Compound microscope Conation technologies 5 Ultrasonic cleaner Remi Laboratories 6 FT’IR Spectrometer Bruker 7 SEM JOEL Table 6.2: List of Equipments used Formulation Studies : 6.1 Preparation of 0.1N Hydrochloric acid: 8.5 ml of concentrated hydrochloric acid was diluted with distilled water and volume was made up to 1000ml with distilled water. 6.2 Preparation of calibration curve in 0.1N HCL : 10mg of Repaglinide pure drug was dissolved in 10mL of methanol (stock solution 1). 1mL of solution was taken and made up with 10mL of 0.1N HCL (100”g/ml) stock-2. From this 1mL was taken and make up with 10 mL of 0.1N HCL (10”g/ml) stock-3. The above stock-II solution was subsequently diluted with 0.1N HCL to obtain series of dilutions containing and 2, 4, 6, 8 and 10”g/mL of solution. The absorbance of the above dilutions was measured at 220 nm by using UV-Spectrophotometer taking 0.1N HCL as blank. Then a graph was plotted by taking Concentration on X-Axis and Absorbance on Y-Axis which gives a straight line Linearity of standard curve was assessed from the square of correlation coefficient (R2) which determined by least-square linear regression analysis. 6.3 Preparation of Floating Microspheres by Solvent Evaporation Method: 6.3.1 Trial and Error for determining the floating microspheres: In trial and error method, microspheres were prepared with polymer only whether to know obtaining microspheres. In another formulations different concentrations of sodium bi carbonate was added to polymer and prepared microspheres. Then compared buoyancy between those formulations which contains only polymer and another contains polymer along with sodium bicarbonate. Ratios were mentioned as in Table. By trial and Error method, It concluded that microsphere along with sodium bicarbonate was showing good buoyancy and sodium bicarbonate concentration was also optimized. Formulation Code Sodium alginate (mg) Sodium bicarbonate(mg) T1 1000 – T2 1000 100 T3 1000 200 T4 1000 300 T5 1000 400 Table 6.3 : Trial and Error formulations 6.3.2 Preparation of Floating microspheres : The floating microspheres were prepared by solvent evaporation method. Drug, Sodium alginate, HPMC K100 and Sodium bicarbonate were taken in different ratios as shown in table. Drug and excipients were dissolved in ethanol and dichloromethane (1:1). The obtaining Drug and polymer solution was poured slowly using syringe into 100 ml of water containing 5% V/V Tween 80. Preparation was stirred at 300 rpm for 1 hour. The obtained floating microspheres were filtered and dried overnight at room temperature68. Formulation code Drug (mg) Sodium alginate (mg) HPMC K 100 (mg) Sodium Bicarbonate (mg) DCM (ml) Ethanol (ml) F1 1000 1000 – 200 5 5 F2 1000 2000 – 200 5 5 F3 1000 3000 – 200 5 5 F4 1000 4000 – 200 5 5 F5 1000 1000 500 200 5 5 F6 1000 1000 1000 200 5 5 F7 1000 1000 1500 200 5 5 F8 1000 1000 2000 200 5 5 F9 1000 1000 2500 200 5 5 Table 6.4: Formulation of floating Microspheres 6.4 Characterization of Microspheres: 6.4.1 Particle size determination: Particle size of drug loaded microspheres was determined by optical microscopy by using compound microsphere . A small amount of dry microspheres was suspended in purified water (10 ml). The suspension was ultra sonicated for 5sec. a small drop of obtained suspension was placed on a clean glass slide. The slide containing microspheres was mounted on the stage of microscope and diameter of at least 200 particles was measured using calibrated micrometer. 6.4.2 Percentage Yield: The prepared floating microspheres were weighed after drying for all formulations. Then percentage yield was calculated using following formula: 6.4.3 Drug entrapment efficiency: Microspheres equivalent to Repaglinide dose were taken for evaluation. The amount of drug entrapped was estimated by crushing the microspheres. The powder was transferred to a 100 ml volumetric flask and dissolved in 10ml of methanol and the volume was made up to 100ml with 0.1N HCL. Kept it for sonication about 1 hour. Then solution was filtered through Whatmann filter paper and the absorbance was measured after suitable dilution spectrophotometrically at respective wavelength. The amount of drug entrapped in the microspheres was calculated by the following formula: 6.4.4 Micromeritic properties: The microspheres were characterized by their micromeritic properties such as Bulk density, Tapped density, Compressibility Index, Hausners ratio and Angle of repose. 6.4.4.1 Angle of repose: Angle of repose was determined using funnel method .The blend was poured through a funnel that can be raised vertically until a maximum cone height (h) is obtained. Radius of the heap (r) was measured and angle of repose (”) was calculated using the following formula. ” = tan-1 h/r S.No Angle of Repose (”) Type of Flow 1 < 20 Excellent 2 20-30 Good 3 30-34 Passable 4 > 34 Very Poor Table 6.5 : Angle of repose as an indication of flow properties 6.4.4.2 Bulk Density: Apparent bulk density (”b) was determined by pouring the powder blend into a graduated cylinder. The bulk volume (Vb) and weight of the powder (M) were determined. ”b = M / Vb 6.4.4.3 Tapped density: The measuring cylinder containing a known mass of blend (M) was tapped for a fixed time (100 tapping). The minimum volume (Vt ) occupied in the cylinder and weight of the blend was measured. The tapped density (”t) was calculated using the following formula. ”t = M / Vt 6.4.4.4 Compressibility Index or Carr’s Index: The simplest way for measurement of free flow of powder is compressibility, an indication of the ease with which a material can be induced to flow is given by compressibility index. Carr’s Index = ”b – ”t / ”b * 100 Where ”t = tapped density ”b = bulk density S.No % Compressibility Flow ability 1 5-12 Excellent 2 12-16 Good 3 18-21 Fair Passable 4 23-25 Poor 5 33-38 Very Poor 6 < 40 Very Very Poor Table 6.6: Relationship between % compressibility and flow ability 6.4.4.5 Hausners Ratio (H): Hausners ratio is an indirect index of ease of powder flow. It is calculated by the following formula: Hausner’s ratio (H) = ”t/”b Where ”t = tapped density ”b = bulk density 6.4.5 In-vitro Buoyancy: Floating microspheres (equivalent to 2 mg) were dispersed in 100ml of 0.1 N Hydrochloric acid solution (pH 1.2) to simulate gastric fluid at 37”C. The mixture was stirred with a paddle at 50 rpm and after 12 hr, the layer of buoyant microspheres (Wf) was pipetted and separated by filtration simultaneously sinking microsphere (Ws) was also separated. Both microspheres type were dried at 40”C overnight. Each weight was measured and buoyancy was determined by the weight ratio of the floating microspheres to the sum of floating and sinking microsphere46. Where Wf and Ws = the weights of the floating and settled microspheres, respectively. All the determinations were made in triplicate. 6.4.6 In vitro drug release study: The dissolution study of floating microspheres were performed over a 12 hr period using USP type I (Basket) Dissolution Testing Apparatus (Lab india) 900ml of 0.1N HCL was used as dissolution medium agitated at 100 RPM, at temperature of 37o” 0.5oC. 5 ml samples were withdrawn at required time intervals for estimating drug release. The samples were analyzed by UV Spectrophotometry at their respective wavelength. Applications of Drug Release Kinetics: The release data obtained was fitted into various mathematical models. The parameters ‘n’ and time component ‘k’, the release rate constant and ‘R’the regression coefficient were determined by Korsmeyer-Peppas equation to understand the release mechanism. To examine the release mechanism of Repaglinide from the microspheres, the release data was fitted into Peppa’s equation, Mt / M’ = Ktn Where, Mt / M’ is the fractional release of drug, ‘t’ denotes the release time, ‘K’ represents a constant incorporating structural and geometrical characteristics of the device, ‘n’ is the diffusional exponent and characterize the type of release mechanism during the release process. Release exponent (n) Drug transport mechanism Rate as a function of time 0.5 Fickian diffusion t-0.5 0.5<n 1.0 Case-II transport Zero-order release Higher than 1.0 Super Case-II transport tn-1 Table 6.7: characterisation of type of drug release mechanism If n < 0.5, the polymer relaxation does not affect the molecular transport, hence diffus-ion is Fickian. If n > 0.5, the solid transport will be non-fickian and will be relaxation controlled. Other equations to study the drug release kinetics from dosage forms A. Zero Order % R = kt This model represents an ideal release in order to achieve prolonged pharmacological action. This is applicable to dosage forms like transdermal systems, coated forms, osmotic systems, as well as Matrix tablets containing low soluble drugs. B. First Order Log (fraction unreleased) = kt/2.303 The model is applicable to hydrolysis kinetics and to study the release profiles of pharmaceutical dosage forms such as those containing water soluble drugs in porous matrices. C. Matrix (Higuchi Matrix) % R = kt 0.5 This model is applicable to systems with drug dispersed in uniform swellable polymer matrix as in case of matrix tablets with water soluble drug. D. Peppas Korsmeyer Equation This model is widely used when release mechanism is well known or when more than one type of release phenomenon could be involved. The ‘n’ values could be used to characterize different release mechanisms as: % R = kt n log % R = logk + nlogt 6.4.7 Drug and Excipient Compatability studies: FTIR – Fourier transmission infrared spectroscopy : The compatibility between the pure drug and excipients was detected by FTIR spectra obtained on Bruker FTIR Germany (Alpha T).The solid powder sample directly place on yellow crystal which was made up of ZnSe. The spectra were recorded over the wave number of 4000 to 400cm-1. 6.4.8 SEM ( Scanning Electron Microscope) Studies: The surface morphology of the layered sample was examined by using SEM(JEOL Ltd.,Japan). The small amount of powder was manually dispersed onto a carbon tab (double adhesive carbon coated tape) adhered to an aluminum stubs were coated with a thin layer (300A) of gold by employing POLARON – E 3000 sputter coater. The samples were examined by SEM with direct data capture of the images onto a computer. 7.RESULTS AND DISCUSSION 7.1 Standard graph in 0.1 N HCL (” max 220 nm): Standard graph of Repaglinide was plotted as per the procedure in experimental method and its linearity is shown in Table and Fig. The standard graph of Repaglinide showed good linearity with R2 of 0.998, which indicates that it obeys ‘Beer- Lamberts’ law. Concentration (”g/mL) Absorbance 0 0 2 0.126 4 0.238 6 0.346 8 0.452 10 0.554 . Table 7.1 : Standard graph values of Repaglinide in 0.1 N HCL Figure 7.1: Standard graph of Repaglinide in 0.1 N HCL 7.2 Characterization of microspheres: 7.2.1 Micrometric Properties: The mean size increased with increasing polymer concentration which is due to a significant increase in the viscosity, thus leading to an increased droplet size and finally a higher microspheres size. Microspheres containing Sodium alginate as polymer had a size range of 385.15”1.08 ”m to 493.24”2.43 ”m, microspheres containing HPMC K 100 exhibited a size range between 381.55”2.54 to 477.5”2.15 ”m . The particle size data is presented in Tables and displayed in Figures. The effect of drug to polymer ratio on particle size is displayed in Figure. The particle size as well as % drug entrapment efficiency of the microspheres increased with increase in the polymer concentration. The bulk density, tapped density, hausners ratio of formulation F1 to F9 containing different grades of Sodium alginate & HPMC K 100 formulation was in the range of standard Limits (as shown in table). The carr’s index of formulation F1 to F9 containing different grades of Sodium alginate & HPMC K 100 11.13”0.11 to18.18”0.33 respectively. The angle of repose of formulation F1 to F9 containing different grades of Sodium alginate & HPMC K 100 formulation was in the range Formulation Code Mean partical size(”m) Bulk density (gm/cm3) Tapped density (gm/cm3) Hauseners Ratio Carr’s Index Angle of Repose F1 473.9”2.16 0.32”0.010 0.39”0.018 1.21”0.04 11.13”0.11 28.49”1.71 F2 493.24”2.43 0.35”0.012 0.40”0.015 1.14”0.05 12.5”0.64 27.72”1.89 F3 385.15”1.08 0.40”0.007 0.47”0.014 1.17”0.03 14.8”0.24 30.88”2.78 F4 455.22”2.52 0.36”0.014 0.44”0.014 1.22”0.01 18.18”0.33 27.00”1.93 F5 381.55”2.54 0.41”0.015 0.47”0.015 1.14”0.02 12.76”0.26 26.02”1.80 F6 471.52”2.05 0.40”0.012 0.48”0.021 1.2”0.01 16.66”0.33 26.56”1.43 F7 451.84”2.07 0.39”0.018 0.45”0.022 1.15”0.03 13.33”1.5 26.80”1.68 F8 477.5”2.15 0.41”0.015 0.48”0.027 1.17”0.01 14.5”0.86 27.11”1.59 F9 481.12”2.21 0.44”0.017 0.50”0.015 1.13”0.02 12”0.35 26.56”1.68 All values represented as mean ” standard deviation (n=3) Table 7.2: Micromeritic properties of floating microspheres of Repaglinide Figure 7.2: Mean particle size of Repaglinide floatimg microspheres Floating Microspheres were subjected to micromeritic properties. The angle of repose values indicates that the floating Microspheres have good flow properties. The bulk density of all the formulations was found to be in the range of 1.59 to 1.92 (gm/mL) showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range of 1.84 to 2.36 showing the powder has good flow properties. The compressibility index of all the formulations was found to be below 18 which show that the floating Microspheres have good flow properties. All the formulations has shown the hausners ratio below 1.2 indicating the floating Microspheres have good flow properties. The mean particle size was found to be in the range of 386.81”1.23 to 463.81”2.09 micrometer. 7.3 Yield of floating microspheres: The percentage yield of floating microsphere formulation F1 to F9 was in range of 84.05”0.39 to 97.48”0.57 (as shown in table 7.3). To observe the effect of polymer concentration on the percentage yield of the floating microspheres, formulations were prepared at varying concentration of Sodium alginate & HPMC K 100 . 7.4 In-vitro buoyancy: The purpose of preparing floating microspheres was to extend the gastric residence time of a drug. The buoyancy test was carried out to investigate the floatability of the prepared microspheres. The microspheres were spread over the surface of 0.1 N HCL and the fraction of microspheres buoyant and settled down as a function of time was quantitated. The in vitro buoyancy of formulation F1 to F9, it was range from 70.42”1.36 to 95.81”2.11 respectively (as shown in table 7.3). Among all formulation F5 was found to be highest in-vitro buoyancy 95.81”2.11. The results also showed a tendency that the larger the particle size, the longer floating time. 7.5 Entrapment efficiency: The entrapment efficiency of formulation F1 to F9 was in the range of 81.62”1.72 to 95.62”2.07 (as shown in table 7.3) Among all the formulations F5 95.62”2.07. Results demonstrated that increase in concentration of polymer increased the entrapment of the drug. The drug entrapment efficiency was found to be good in all the formulation. Formulation code Percentage yield (%) In vitro buoyancy (%) Entrapment Efficiency (%) F1 86.19”0.28 74.69”0.97 81.62”1.72 F2 94.19”0.48 85.34”1.29 90.57”1.94 F3 96.87”0.54 91.87”0.62 92.59”2.01 F4 93.08”0.29 93.56”1.03 91.81”2.47 F5 97.48”0.57 95.81”2.11 95.62”2.07 F6 84.05”0.39 70.42”1.36 79.68”1.46 F7 89.17”0.43 81.57”0.84 83.74”1.67 F8 92.74”0.82 88.36”1.40 89.16”2.05 F9 94.64”0.55 90.51”1.10 91.42”1.85 All values represented as mean ” standard deviation (n=3) Table 7.3: Percentage yield, In-vitro buoyancy and Entrapment efficiency of floating Microspheres of Repaglinide Figure 7.3: comparison of yield of floating Microspheres of Repaglinide Figure 7.4: comparison of percent in-vitro buoyancy of floating Microspheres of Repaglinide Figure 7.5: Comparison of drug entrapment efficiency of floating Microspheres of Repaglinide 7.6 In Vitro drug release: TIME (hr) Cumulative % Drug Release F1 F2 F3 F4 0 0 0 0 0 1 4.83 ” 1.15 6.22 ” 1.05 8.24 ” 0.98 8.43 ” 1.24 2 9.23 ” 2.24 10.11 ” 1.12 12.14 ” 1.25 15.32 ” 1.52 3 15.65 ” 1.08 18.42 ” 1.85 23.08 ” 2.05 24.21 ” 1.47 4 22.42 ” 0.98 26.32 ” 2.04 30.64 ” 1.56 33.62 ”0.97 5 31.32 ” 1.64 33.08 ” 2.17 41.55 ” 1.81 40.12 ” 2.17 6 39.44 ” 1.55 41.15 ” 1.53 53.34 ” 2.14 48.46 ” 1.61 7 47.54 ” 1.34 50.28 ” 1.67 63.41 ” 1.74 55.38 ” 2.05 8 56.63 ” 1.27 61.33 ” 1.74 79.27 ” 2.05 65.15 ” 1.04 9 63.43 ” 1.31 73.28 ” 1.97 88.75 ” 1.34 73.26 ” 1.67 10 71.32 ” 1.55 84.36 ” 2.17 99.12 ” 2.08 84.12 ” 2.21 11 82.14 ” 2.43 95.34 ” 2.08 99.12 ” 1.45 96.34 ” 1.33 12 91.14 ” 2.11 95.34 ” 1.47 99.12 ” 1.61 96.43 ” 1.41 Table 7.4: In-Vitro drug release data of Repaglinide floating Microspheres with Sodium alginate only (F1-F4) Figure 7.6: In-Vitro drug release profile of Repaglinide Floating Microspheres (F1-F4) Time (Hrs) Cumulative % Drug Release F5 F6 F7 F8 F9 0 0 0 0 0 0 1 5.34 ” 0.98 4.07 ” 1.28 2.18 ” 1.14 3.34 ” 1.34 4.23 ” 1.11 2 12.31 ” 1.54 12.32 ” 0.98 8.56 ” 1.67 6.32 ” 1.81 9.56 ” 1.64 3 20.38 ” 2.04 21.44 ” 2.01 16.48 ” 2.15 11.52 ” 2.04 16.43 ” 1.54 4 28.45 ” 1.31 30.23 ” 1.41 23.74 ” 1.37 20.71 ” 1.41 22.71 ” 2.12 5 37.20 ” 2.15 38.86 ” 1.06 32.18 ” 1.06 28.64 ” 1.66 31.78 ” 0.95 6 44.38 ” 1.31 43.29 ” 1.75 41.28 ” 2.04 35.43 ” 1.34 38.92 ” 1.04 7 52.27 ” 1.58 51.65 ” 2.11 48.65 ” 1.62 41.45 ” 1.28 48.64 ” 2.06 8 61.46 ” 0.88 60.46 ” 1.62 56.43 ” 1.34 50.54 ” 2.14 56.38 ” 1.26 9 78.34 ” 1.04 69.45 ” 1.47 64.87 ” 2.11 58.42 ” 2.06 62.81 ” 1.40 10 82.43 ” 1.28 78.34 ” 1.09 70.34 ” 1.47 67.54 ” 1.21 70.30 ” 1.55 11 90.25 ” 2.11 85.34 ” 1.14 79.65 ” 1.32 75.43 ” 1.34 78.64 ” 1.07 12 98.65 ” 1.61 90.91 ” 2.07 88.65 ” 2.06 84.32 ” 2.01 85.48 ” 2.17 Table 7.5: In-Vitro drug release data of Repaglinide Floating Microspheres with Sodium alginate and HPMC K100 (F5-F9) Figure 7.7 : Comparison of In-Vitro drug release profile of Repaglinide Floating Microspheres (F5-F9) From the dissolution data it was evident that, formulations prepared with Sodium alginate (Alone) were revealed that formulations may not even drug release . Hence those formulations were not considered. Formulations prepared with HPMC K 100 along with Sodium alginate was shown those contain more than 90% of drug. F5 formulation was retard the maximum drug release up to 12 hrs. Hence It was considered as optimised formulation. 7.6.1 Application of drug release kinetics : Table 7.6: Data of Release Kinetics Figure 7.8: Graph of Zero order release kinetics Figure 7.9: Graph of First order release kinetics Figure 7.10: Graph of Higuchi release kinetics Figure 7.11 : Graph of Peppas release kinetics From the release kinetics data, It was evident that optimised formula was followed Peppas release kinetics. 7.7 Drug- Excipient Compatability studies: FTIR: Figure 7.12: FTIR of Repaglinide pure drug Figure 7.13: FTIR of Optimized formula (F5) From the FTIR data it was evident that the drug and excipients doses not have any interactions. Hence they were compatible. Compound name N-H stretching C-H Stretching Stretching C-O ‘C stretching Repaglinide pure drug 3365.85 1623.12 1473.24 1163.32 Optimized formulation (F5) 3369.12 1624.00 1473.93 1166.01 Table 7.7 :Interpretation results of FTIR 7.8 SEM studies: Figure 7.14: Scanning electron microphotograph of Floating microspheres of optimized formulation (F5) 8. SUMMARY Repaglinide is mainly used to treat type II diabetes mellitus. The basic idea behind devolopement of such a system is to maintain a sustained release of drug from the dosage form. In the research work an attempt was made to develop the Gastro retentive floating microspheres for sustained effect. ‘ The drug-excipient compatability studies was carried out by using FT-IR technique. Based on results, excipients were found to be compatible with Repaglinide. ‘ In preformulation study, estimation of Repaglinide was carried out by UV spectrophotometer at 220 nm using methanol as a solvent, which has good reproducibility and this method was used in enrire study. ‘ Trial and error method was used to determine the buoyancy property of Sodium bi carbonate. Formulations were prepared by using Sodium alginate, HPMC K100 as polymers, Sodium bicarbonate, solvents such as Methanol, Di Chloro methane. ‘ The prepared formulations were evaluated for particle size, drug entrapment efficiency, micrometric properties such as bulk density, tapped density, carrs index, hausners ratio, angle of repose. In vitro buoyancy drug polymer compatibility (FTIR study), scanning electron microscopy, In vitro drug release studies and drug release kinetics studies also evaluated. ‘ In order to improve the probably mechanism of drug release from the dosage form the results of In vitro dissolution studies carried out and fitted to various kinetic models. 9.CONCLUSION The present investigation was carried out on Floating microspheres of Repagilinide. Sodium alginate and HPMC K 100 were employed as polymers. By trial and Error method Sodium bicarbonate was used as gas generating agent to maintain buoyancy. Standard graph of Repagilinide was revealed that the regression value R2 is 0.998 which obeys Beer Lamberts law. Floating microspheres were subjected to micromeritic properties. The angle of repose values indicates that the floating microspheres have good flow properties. The bulk density of all the formulations was found to be in the range of Standard Limits showing that the powder has good flow properties. The tapped density of all the formulations was found to be in the range Standard Limits showing the powder has good flow properties. The compressibility index of all the formulations was found to be below 18 which show that the floating microspheres have good flow properties. All the formulations has shown the hausners ratio ranging between 0 to 1.2 indicating the floating microspheres have good flow properties. Microspheres containing Sodium alginate as polymer had a size range of 385.15”1.08 ”m to 493.24”2.43 ”m, microspheres containing HPMC K 100 exhibited a size range between 381.55”2.54 to 477.5”2.15 ”m . The percentage yield of floating microsphere formulation F1 to F9 was in range of 84.05”0.39 to 97.48”0.57 The purpose of preparing floating microspheres was to extend the gastric residence time of a drug. The in vitro buoyancy of formulation F1 to F9, it was range from 70.42”1.36 to 95.81”2.11 respectively. The entrapment efficiency of formulation F1 to F9 was in the range of 81.62”1.72 to 95.62”2.07. From the dissolution data it was evident that, formulations prepared with Sodium alginate (Alone) were revealed that formulations may not even drug release . Hence those formulations were not considered. Formulations prepared with HPMC K 100 along with Sodium alginate was shown those contain more than 90% of drug. F5 formulation was retard the maximum drug release up to 12 hrs. Hence It was considered as optimised formulation. From the release kinetics data, It was evident that optimised formula was followed Peppas release kinetics.

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Privacy Overview

Democratic lawmakers call for crack down on drug companies over system that can limit affordable options

essay on drug system

WASHINGTON – Sen. Elizabeth Warren, D-Mass., and Rep. Pramila Jayapal, D-Wash., are pushing federal regulators to "crack down" on companies they say are preventing their competitors from producing lower-cost generic drugs for Americans. 

In a letter sent to the Food and Drug Administration Thursday night and seen exclusively by USA TODAY, the progressive lawmakers urged the agency to close loopholes that discourage competition among drug companies and keep prices high for crucial medication. That can include inhalers to help with chronic lung diseases. 

Here's the system Warren and Jayapal are trying to address: The FDA keeps a list of all federally approved drugs , known as the Orange Book. The agency requires pharmaceutical companies to list in the book any valid patents they hold on drugs they created, signaling to competitors that they can’t create a generic alternative. Those alternatives often provide more affordable options for Americans.

But Warren and Jayapal have been arguing for months that major drug companies are exploiting that structure by updating listings with insignificant changes to extend the time it's protected from copycats. 

The Federal Trade Commission – the government’s consumer protection agency – has already agreed with the Democrats. It issued a new statement in September noting that improper listings may be illegal and “have likely been distorting pharmaceutical markets for decades.”

Prep for the polls: See who is running for president and compare where they stand on key issues in our Voter Guide

Prescription drugs in the United States are more than twice as expensive than they are in other large countries, according to the Department of Health and Human Services . Brand name drugs are even pricier – more than three times more expensive than in other nations.

In November, the FTC sent letters to ten drug companies warning them that they believe they are collectively listing more than 100 improper patents.

Warren and Jayapal sent letters to each of the companies following up on the FTC’s warning. Three of the ten companies did not say the flagged drugs were improper but did take them off the list, including several types of epinephrine injectors (often known by the brand name EpiPen) and inhalers.

But the other seven did not take down their listings, arguing in letters reviewed by USA TODAY that the government’s rules are murky or that their patents do qualify.

Warren in a statement urged the FDA to “crack down on this abuse.”

It’s the latest in lawmakers' inquiries into the way pharmaceutical companies impact drug pricing and availability in the United States. 

Last week, the Senate's Health, Education, Labor and Pensions Committee grilled the CEOs of three major drug companies over the cost of necessary medications. The Biden administration is also bargaining with drug companies to make 10 widely prescribed drugs cheaper for older Americans. 

The pressure from federal officials and outcry from Americans have pushed drug companies to change some pricing. In January, the industry implemented their lowest median price increase in over a decade.

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Essay on War On Drugs And Mass Incarceration

Students are often asked to write an essay on War On Drugs And Mass Incarceration in their schools and colleges. And if you’re also looking for the same, we have created 100-word, 250-word, and 500-word essays on the topic.

Let’s take a look…

100 Words Essay on War On Drugs And Mass Incarceration

War on drugs: a brief overview.

The war on drugs is a global campaign to reduce the illegal drug trade. It began in the 1970s and has led to the arrest and imprisonment of millions of people. The United States has been at the forefront of the war on drugs, and its policies have had a devastating impact on communities of color.

Mass Incarceration: A Result of the War on Drugs

The war on drugs has led to mass incarceration, the practice of imprisoning a large number of people. In the United States, the number of people in prison has increased by more than 500% since the 1970s. The vast majority of these prisoners are people of color, who are disproportionately affected by the war on drugs.

Racial Disparities in Drug Arrests and Sentencing

The war on drugs has been enforced in a racially discriminatory manner. People of color are more likely to be arrested and sentenced to prison for drug offenses than white people, even though they use and sell drugs at similar rates. These racial disparities are a result of systemic racism in the criminal justice system.

The Human Cost of Mass Incarceration

Mass incarceration has had a devastating impact on individuals, families, and communities. Incarcerated people are often separated from their loved ones, and they may lose their jobs, homes, and access to education and healthcare. Mass incarceration also contributes to poverty and crime.

250 Words Essay on War On Drugs And Mass Incarceration

War on drugs: a flawed approach.

The War on Drugs, a policy aimed at combating illegal drug use and trafficking, has had a profound impact on the United States, particularly leading to mass incarceration. This essay examines the relationship between the War on Drugs and mass incarceration, shedding light on its consequences and highlighting the need for reform.

A Surge in Arrests and Incarceration

The War on Drugs has resulted in a dramatic increase in arrests and incarcerations for drug offenses. Between 1980 and 2016, the number of people imprisoned for drug offenses in the United States grew by over 500%. This surge in arrests and incarcerations has disproportionately affected people of color, particularly African Americans, who are arrested and imprisoned for drug offenses at much higher rates than white Americans.

The Impact on Communities

Mass incarceration has had devastating consequences for communities, particularly those of color. The absence of individuals from their communities due to imprisonment has eroded social and family structures, leading to increased poverty, unemployment, and crime. The War on Drugs has also strained police-community relations, as law enforcement agencies have been tasked with enforcing drug laws that are often seen as unfair and discriminatory.

The Need for Reform

The War on Drugs has failed to achieve its stated goals of reducing drug use and trafficking. Instead, it has resulted in mass incarceration, exacerbating social and economic problems. Reform is urgently needed to address the harms caused by the War on Drugs, including ending the criminalization of drug use, investing in harm reduction programs, and addressing the underlying causes of drug abuse.

The War on Drugs has been a costly and counterproductive policy, leading to mass incarceration and devastating consequences for communities, particularly those of color. Reform is essential to end the harms caused by the War on Drugs and to create a more just and equitable society. Investment in prevention, treatment, and harm reduction programs would be far more effective than relying on punitive measures.

500 Words Essay on War On Drugs And Mass Incarceration

War on drugs: a failed policy.

The war on drugs is a global campaign against illegal drug trade and use. It has been ongoing since the early 20th century, and has resulted in the mass incarceration of people, particularly in the United States.

Origins of the War on Drugs

The war on drugs began in the early 1900s with the passage of laws prohibiting the use, sale, and possession of certain drugs, such as cocaine and heroin. These laws were largely driven by fears of the effects of these drugs on individuals and society, as well as the belief that drug use was a moral failing.

Escalation of the War on Drugs in the United States

In the United States, the war on drugs escalated significantly in the 1970s and 1980s. This was due in part to the rise of crack cocaine, a highly addictive form of cocaine that had devastating effects on communities across the country. The government responded to this crisis by passing harsh drug laws, including mandatory minimum sentences for drug offenses.

Impact of the War on Drugs on Mass Incarceration

The war on drugs led to a massive increase in the number of people incarcerated in the United States. Between 1980 and 2010, the number of people incarcerated in the United States increased from 336,000 to 2.3 million. This increase was driven largely by drug offenses. Today, the United States has the highest incarceration rate in the world, with over 2 million people behind bars.

Racial Disparities in Drug Arrests and Incarceration

The war on drugs has had a disproportionate impact on people of color. Black people are arrested for drug offenses at a rate that is over 3 times higher than the rate for white people. Black people are also more likely to be convicted of drug offenses and to receive longer sentences than white people.

Negative Consequences of Mass Incarceration

Mass incarceration has had a devastating impact on communities across the United States. It has led to the breakup of families, the loss of jobs, and the creation of a permanent underclass of people who are unable to contribute to society. Mass incarceration has also been a major driver of racial inequality in the United States.

Rethinking the War on Drugs

In recent years, there has been a growing recognition that the war on drugs has been a failure. It has not reduced drug use or drug-related crime, and it has had a devastating impact on communities and families. As a result, there has been a movement to rethink the war on drugs and to find more effective ways to address the problem of drug use.

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Drug Addiction and the Brain’s Reward System

Critically evaluate how the empirical study of the brain reward system has contributed to our understanding of addiction.

An addiction to alcohol or drugs is a multi-step process that has repercussions for the individual and society as a whole (Pinel, John, and Steven, 2017). There has been an increase in the number of people concerned about why people continue to engage in various forms of addiction despite the different social, legal, medical, and financial implications. Researchers have looked at the brain’s reward system to contribute to the scientific knowledge of addiction. This paper will critically analyze how the empirical research on the reward system in the brain has contributed to our understanding of addiction. In this paper, we will explore how an empirical study indicates a connection between addiction and brain reward, as well as describe the two essential ideas that will be covered: the Brain Reward system and addiction. At the end of the paper, a description of how the brain’s reward system helps understand addiction will be given.

According to Tomkins and Sellers (2001), drug addiction is a biopsychosocial condition characterized by the recurrent use of drugs or repetitive involvement, notwithstanding the harm produced by the behaviour. In other words, drug addicts are compulsive drug users. According to Pinel, John, and Steven (2017), people who are addicted to drugs use drugs regularly, but not all people who use drugs regularly are addicted. As highlighted, the most recent developments in scientific research have led to a better understanding of the neurological process that underlies addiction. A study by Agrawal and Lynskey (2008) investigates the extent to which genetic factors play a role in developing drug use problems. There was some evidence in the study that pointed to a moderate to high genetic connection with addiction. The findings also suggest that the environment, a person’s genetic makeup, and the relationships between the two factors are essential in understanding addiction (Blum et al., 2000).

Despite this, there is much confusion about what exactly addiction is, as Pinel, John, and Steven all point out (2017). Many believe that people addicted to drugs are caught in an endless cycle of taking drugs, experiencing withdrawal symptoms, and finding ways to cope. Despite this, the narrative about drug addiction does not square the available empirical facts. According to Pinel, John, and Steven Barnes (2017), some people may take medicines to prevent some of the withdrawal symptoms they experience.

Pinel, John, and Steven’s (2017) definition of the reward system is a collection of neural pathways and brain structures responsible for reward-related cognition, such as associative learning, incentive salience, such as a craving for a reward, and positively valenced emotions. This collection of neural pathways and brain structures is responsible for reward-related cognition. From an evolutionary point of view, Tomkins and Sellers (2001) define the brain reward circuit as the mechanism that assures survival by giving precedence to aspects such as reproduction. This is another definition of the brain reward circuit. However, according to Tomkins and Sellers (2001), substances that result in behavioural impacts differ from other compounds. Nevertheless, these compounds all have one thing in common: they are all regulated similarly by the brain’s reward system, which plays a crucial role in maintaining and initiating actions necessary for survival.

Pinel, John, and Steven (2017) note that incentives are seen as both wanted and liked. These two concepts, although seemingly equivalent, are mediated differently by the brain. Incentive salience, also known as desire, is created by the more extensive brain circuits and contains mesolimbic dopamine. In comparison, “liking” emerges from frail and smaller brain circuits that are not dependent on dopamine. Conferring to the incentive-sensitization hypothesis, drug addiction posits the excessive amplification of “wanting” without the amplification of the psychological amplification of “liking (Pinel, John, and Steven, 2017). (Pinel, John, and Steven, 2017). ” This originates from the long-lasting dopamine systems sensitive to brain sensitization.

Numerous empirical research has demonstrated the link between addiction and brain reward. The findings of Pinel, John, and Steven (2017) add to the research by proposing that the joyful sense of highness is the pull to drug usage. Highness is a feeling that results from electromagnetic stimulation in specific brain locations that are collectively referred to as the reward centre. The substantia nigra (SN), nucleus accumbens (NAc), and ventral tegmental area (VTA), all of which are located near the frontal section of the brain, are the regions in question. The neurotransmitter that is responsible for electrical stimulation is called dopamine. Early drug usage was associated with significant sensations of reward and pleasure, which encouraged users to continue using drugs. This is a factor that contributes to the neurophysiological cycle of addiction. According to Tomkins and Sellers (2001), substances of abuse exert an influence over the brain’s pathway either through a direct influence on the dopamine system of the brain or by affecting the activities of other neurotransmitters to exert a modulatory impact over the mesolimbic dopaminergic pathway. Both of these mechanisms are aimed at exerting an influence over the pathway. Based on a study conducted by Agrawal and Lynskey (2008), drug addiction may be linked to an individual’s need for novel experiences and a gene that codes for a dopaminergic receptor and contributes to the development of a reward dependent. According to Blum et al. (2000), the persistent demand for reward is a driving force behind both alcoholism and the addition of other psychoactive drugs.

In a variety of different ways, the brain’s reward system helps our comprehension of the disease of addiction. According to Pinel, John, and Steven (2017), education has traditionally been linked to both rewards and penalties. The concept of positive reinforcements originated within the framework of the operant conditioning paradigm. According to the positive reinforcement hypothesis, behavioural responses can be enhanced through the use of rewards and by the repetition of behaviour (Pinel, John, and Steven, 2017). As a result, the acute sensation that results from being intoxicated by a drug promotes a rapid and powerful learning response by connecting the drug with emotions of pleasure. As a result, the individual resorts to using drugs more frequently and in greater quantities in order to experience the same levels of pleasure and satisfaction (Blum et al., 2000).

According to the findings of the research project on brain reward and addiction, the neurotransmitter system appears to play an important part in the manifestation of drug dependency. According to Tomkins and Sellers (2001), the breakthroughs assist scientists understand the underlying cause of drug dependence, which is helpful in establishing effective treatment techniques. Additionally, the advances enable scientists to build more effective treatment tactics. After the behavior has been beginning or finished, the dopamine overflow that results from the mood-altering medications does not stop; the yearning for the reward with the drug continues to occur, which results in repetitive, compulsive use. The usage of the medicine for an extended period of time decreases the number of dopamine receptors, which is detrimental to the process of regulating the amount of dopamine that is released in the brain. Dopamine is a neurotransmitter that is responsible for rewarding and pleasurable experiences. Dopamine can also be utilized biologically to encourage life-sustaining actions such as drinking water when thirsty by providing a pleasurable sensation that is necessary for the behavior. One example of this is when dopamine is used to promote drinking water when thirsty (Agrawal & Lynskey, 2008). On the other hand, mood-altering medications and alcohol produce an artificial effect that is more intense than the benefits that come from natural sources. According to Pinel, John, and Steven (2017), the majority of drugs that are routinely misused produce a neurochemical reaction in the brain that causes an increase in the amount of dopamine that is released by neurons in the reward region of the brain. The high that one experiences can be attributed to an excess of the neurotransmitter dopamine.

Decreased brain dopamine receptors contribute to addiction in two separate ways. Pinel, John, and Steven (2017) state that impulsive conduct is caused by a lack of dopamine receptors, which in turn increases the need for drug self-medication. A study by Agrawal and Lynskey (2008) on the dopaminergic mechanism regulating nicotine’s effects found that inhibiting dopamine results in a compensatory increase in smoking rather than a decrease. Other neurotransmitter systems that can mimic the same reception include cholinergic and opioid systems (Agrawal & Lynskey, 2008). The inability to take pleasure in things that once brought you joy has also been related to a lack of dopamine receptors. Those with low self-esteem or poor impulse control are more likely to give drugs a try in an attempt to alleviate their feelings of depression. Pinel, John, and Steven (2017) found that chronic drug use reduces grey matter in the prefrontal cortex, which in turn impairs one’s ability to exercise self-control. This, in turn, has an impact on the person’s capacity for rational thought and reduction of executive function. The prefrontal cortex’s normal role, which is to manage the brain’s reward system, can be altered by chronic drug use.

A better understanding of the workings and functions of the brain’s reward system, as well as the part that dopamine receptors play, has led to advances in the treatment of compulsive behaviors and addictions (Agrawal & Lynskey, 2008). Clinicians make use of dopamine antagonists and agonists, which function similarly to skeleton keys in that they either begin analogous keys that result in a similar response to dopamine or shut down any response that was launched by dopamine. This reduces the intensity of the pleasurable responses, which in turn reduces desires, and ultimately leads to the elimination of the learning association.

There are doubts about the reliability of the study’s results. The majority of studies examining the role of dopamine in intracranial self-stimulation have been carried out on nonhuman primates. Animals participating in the clinical trial injected medications into their bodies via implanted cannulas using a drug self-administration paradigm. The animals quickly develop drug dependence after learning how to inject themselves (Agrawal & Lynskey, 2008: Pinel, John, and Steven, 2017). Animals were frequently dosed with a medication in a controlled environment to condition their preferences. It was determined how much time the drug-free animal spent in the drug compartment vs the time it spent in the visually distinguishable control container during the testing period (Pinel, John, and Steven, 2017). Individuals favored the drug group above the control group. Animal testing’s reliability is dubious because of the ever-changing nature of the brain’s complex neurological networks. Consequently, they successfully communicate and adapt to their surroundings. In addition, the human body is itself a complex system, made up of subsystems that can be understood only with a comprehensive understanding of the whole. Because of this, the use of nonhumans to research complicated human systems has a limited amount of credibility. Last but not least, the genetic makeup of humans has a role in how complex systems work, thus adjusting the starting point can affect the results.

In conclusion, the understanding of substance dependence that has been brought about by advancements in biology and neurology has allowed for the creation of an appropriate treatment strategy. In many regions of the world, drug addiction is still a major problem that has to be addressed. Tobacco, narcotic painkillers, cocaine, marijuana, and alcohol are the drugs that are used the most frequently. The earlier biopsychology research concentrated on physical dependency, which did not satisfy the treatment goals. As a consequence, scientific research into the role of the brain reward system and how it has contributed to a new understanding of addiction was developed. The dopamine system is an essential component in the addictive behavior of a person. The mesocorticolimbic pathway is home to the vast majority of the brain regions that are involved in the process of self-stimulation. In addition, research has shown that engaging in intracranial self-stimulation is connected with higher amounts of dopamine production within the mesocorticolimbic circuit. Dopamine agonists are currently being utilized in several addiction treatment protocols in order to increase intracranial self-stimulation. Dopamine antagonists, on the other hand, reduce the amount of self-stimulatory behavior.

Agrawal, A., & Lynskey, M. T. (2019). Are there genetic influences on addiction: evidence from family, adoption and twin studies. Addiction, 103(7), 1069–1081. https://doi.org/10.1111/j.1360-0443.2008.02213.x

Blum, K., Braverman, E. R., Holder, J. M., Lubar, J. F., Monastra, V. J., Miller, D., Lubar, J. O., Chen, T. J. H., & Comings, D. E. (2018). The Reward Deficiency Syndrome: A Biogenetic Model for the Diagnosis and Treatment of Impulsive, Addictive and Compulsive Behaviors. Journal of Psychoactive Drugs, 32(sup1), 1–112. https://doi.org/10.1080/02791072.2000.10736099

Tomkins, D. M., & Sellers, E. M. (2018). Addiction and the brain: the role of neurotransmitters in the cause and treatment of drug dependence. Cmaj, 164(6), 817-821. https://www.cmaj.ca/content/164/6/817.short

Wig, G. S., Barnes, S. J., & Pinel, J. P. J. (2017). Conditioning of a flavor aversion in rats by amygdala kindling. Behavioral Neuroscience, 116(2), 347–350. https://doi.org/10.1037/0735-7044.116.2.347

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Living Better

Weight-loss drugs aren't a magic bullet. lifestyle changes are key to lasting health.

Lisa Doggett

Lifestyle medicine includes helping people eat a healthier diet.

The headlines are compelling, with phrases like, " The Obesity Revolution ," and " A new 'miracle' weight-loss drug really works ." The before-and-after pictures are inspiring. People who have struggled for decades to shed pounds are finally finding an effective strategy.

The last few years saw breakthroughs in treatments for obesity, with new weight-loss medicines dominating recent news reports. The medicines, semaglutide (Ozempic, Wegovy) and tirzepatide (Mounjaro, Zepbound), work by slowing stomach-emptying and decreasing appetite. They're usually administered by weekly injection.

Clinical trials boasted success comparable to surgery. Celebrities like Oprah Winfrey shared encouraging personal stories.

The scientific literature behind the headlines is impressive as well. Those taking the medicines lose, on average, 10% to 20% of their body weight. Originally developed for Type 2 diabetes, the drugs are well known to improve control of blood sugar. In December, we also learned that in people with cardiovascular disease who are overweight or obese, semaglutide appears to reduce major adverse cardiac events by 20%.

For primary care doctors like me, who have counseled thousands of patients — often unsuccessfully — about their weight, this news is welcome. For many of those living with obesity, these medicines can feel like a game changer.

Excess body weight is tied to a range of medical problems, including diabetes, heart disease, osteoarthritis, sleep apnea and many types of cancer. It's linked to shorter life expectancy and higher rates of disability. With about 40% of U.S. adults now classified as obese — and another 30% considered overweight — many doctors and patients are embracing the new drugs as a solution.

Drugs don't address root causes of America's health crisis

Yet even as many may adopt the newest medications, we need to recognize and address their limitations, including a lack of long-term safety data and potential side effects like nausea, vomiting and, rarely, pancreatitis and gallbladder disease. Poison control centers are reporting an increase in calls due to medication overdoses, which can lead to low blood sugar and associated symptoms, like dizziness, irritability and — in severe cases — confusion and coma.

7 habits to live a healthier life, inspired by the world's longest-lived communities

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7 habits to live a healthier life, inspired by the world's longest-lived communities.

The high price of the weight-loss medicines — usually over $1,000 per month for each patient — is especially troubling in a nation that already far outspends the rest of the world in health care costs and faces major disparities in care. The cost concerns are amplified by studies showing that the drugs usually need to be taken long term to prevent weight regain.

"While these drugs are powerful and wonderful tools, they are not a panacea," said Jonathan Bonnet, a board-certified obesity, lifestyle, family and sports medicine physician who serves as program director of medical weight loss at the Palo Alto VA's Weight Management Center Clinical Resource Hub.

He is seeing positive results among his patients but recognizes cost as a significant barrier. "Treating everyone with obesity in the U.S. with medications will bankrupt the country and still not cultivate the type of health and vitality we actually want," he said.

More than half of employer insurance plans in the United States, as well as Medicare, don't cover the medicines for weight loss.

Medications also fail to address the root causes of the problem. Rates of obesity have increased substantially over the last few decades and have continued to climb since the COVID-19 pandemic. A Gallup survey released in December showed the obesity rate increased by 6 percentage points from 2019 to its current level of 38.4%. The prevalence of Type 2 diabetes — a known consequence of obesity in many individuals — increased from an estimated 10.3% of U.S. adults in the 2001-2004 time period to 13.2% in the 2017-2020 time period.

Our society's easy access to ultraprocessed, calorie-dense foods and our high levels of inactivity contribute to excessive weight gain and related health impacts. A health care system designed for "sick" care — supported by a multibillion-dollar pharmaceutical industry that stands to benefit when we fall ill — does not prioritize disease prevention.

And while we should embrace a culture of acceptance of all body types, we also can't ignore the fact that rising rates of obesity are part of a growing health crisis.

True health is not just a number on a scale

Enter lifestyle medicine . This burgeoning field focuses on prevention and treatment of chronic disease through adoption of healthy habits including a minimally processed diet rich in vegetables, fruits and whole grains; regular physical activity; restorative sleep; stress management; positive social connection; and avoidance of harmful substances.

Lifestyle medicine practitioners partner with patients to understand their core values and help them achieve goals — whether it's to lose 20 pounds, control high blood pressure or boost mood and energy.

Lifestyle medicine is cheap and low risk. Its proven benefits extend far beyond weight loss and can be lifelong. Those who make positive lifestyle decisions, including exercising, eating well and not smoking, may reduce their incidence of coronary artery disease by over 80% and Type 2 diabetes by more than 90%. They take fewer medications. They live longer and experience improved mental health and lower rates of cancer, chronic disease and disability.

And a diet that emphasizes whole, plant-based foods is also better for our planet, reducing deforestation, air and water pollution and greenhouse gas emissions related to meat and dairy production.

Lifestyle medicine and the new weight-loss medications are not mutually exclusive. In fact, the package inserts explicitly state these drugs should be prescribed in combination with increased physical activity and a reduced-calorie diet.

Yet the lifestyle piece is usually glossed over. It's not a quick fix; it requires commitment and a reexamination of personal values. It encourages us to cut back on the ultraprocessed foods we like, high in added sugars and salt, that still raise the risk of heart disease, stroke and some cancers, even in those who aren't overweight.

According to the American Heart Association, fewer than 1% of U.S. adults and adolescents engage in all practices recommended to achieve ideal cardiovascular health , which include most tenets of lifestyle medicine.

New anti-obesity medicines are an important tool. But true health is not just about a number on the scale. Widespread adoption of the principles of lifestyle medicine would reduce health care costs, reverse recent declines in U.S. life expectancy and transform lives.

To get fresh vegetables to people who need them, one city puts its soda tax to work

To get fresh vegetables to people who need them, one city puts its soda tax to work

Opportunities for change.

Because more than 82% of Americans see a health professional every year, incorporating lifestyle medicine into these visits is an obvious way to reach those who need support. But health care providers are often unprepared to offer the kind of intensive coaching that's required.

A 2017 survey indicated that 90% of cardiologists, for example, reported receiving minimal or no nutrition education during fellowship training.

Medical schools and residency programs need to teach the next generation of doctors to promote healthy behaviors — and to implement those practices in their own lives.

Time is another constraint. In my years working in community clinics, I was routinely expected to see patients in 20-minute increments, leaving almost no opportunity to address lifestyle changes in a meaningful way. I might encourage patients with heart disease to eat more fruits and vegetables, but I didn't have time to understand the underpinnings of their dietary choices, often influenced by a complex combination of culture, finances and personal preferences.

Nor could I refer patients to supportive colleagues, such as dieticians, behavioral health counselors and health coaches — my clinic didn't have them.

Doctors need time for difficult conversations to understand the drivers behind patient choices and what might motivate them to change. They need to be able to partner with other professionals who can offer support and expertise.

But even more important — and more difficult — is the need to adjust cultural norms and public policies to make it easier for individuals to adopt healthy behaviors.

For example, SNAP (Supplemental Nutrition Assistance Program), formerly known as food stamps, should be reformed to reduce taxpayer-subsidized consumption of sugar-sweetened beverages and ultraprocessed foods. Even small acts, like moving healthy foods to the front of the grocery store, can have an impact.

"Our environments are optimized for unhealthy living." Bonnet said. "Willpower will only get us so far." What we need, he told me, is to design communities that make healthy choices the default, less-expensive option.

Such communities would have more green space and walkable streets, easier access to fresh produce, plant-based entrées in restaurants and increased opportunities for face-to-face social connections. By removing the reliance on willpower and financial resources to live well, we can reduce health disparities and improve quality of life for everyone.

This story comes from Public Health Watch , a nonprofit, nonpartisan investigative news organization that focuses on threats to America's well-being.

Lisa Doggett is a columnist for Public Health Watch, a family and lifestyle medicine physician at UT Health Austin's Multiple Sclerosis and Neuroimmunology Center and senior medical director of Sagility. She is the author of a new memoir, Up the Down Escalator: Medicine, Motherhood, and Multiple Sclerosis . The views expressed in her columns do not necessarily reflect the official policies or positions of Public Health Watch, UT Health or Sagility. Doggett can be reached through her website .

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CMS Issues Additional Guidance on Program to Allow People with Medicare to Pay Out-of-Pocket Prescription Drug Costs in Monthly Payments

The Inflation Reduction Act’s Medicare Prescription Payment Plan will allow people to pay Medicare Part D out-of-pocket costs over the course of the year starting in 2025

Today, the Centers for Medicare & Medicaid Services (CMS) released the second part of draft guidance for the Medicare Prescription Payment Plan that outlines requirements for Medicare Part D plan sponsors, including outreach and education requirements, pharmacy processes, and operational considerations, for the program’s first year, 2025. The draft guidance is part of the implementation of President Biden’s prescription drug law, the Inflation Reduction Act, which will help reduce the burden of high upfront out-of-pocket prescription drug costs for seniors and people with disabilities with Medicare prescription drug coverage by allowing them to spread out costs over the year rather than requiring they pay in one lump sum.

“Too many seniors and people with disabilities can’t afford to fill their prescriptions at the pharmacy – and that is unacceptable. Thanks to President Biden’s Inflation Reduction Act, certain Medicare patients will be able to spread their costs across smaller, monthly payments,” said Health and Human Services Secretary Xavier Becerra. “In addition to adding flexibility through a payment plan, the law cuts drug costs through provisions such as caps on out-of-pocket costs and the cost of insulin, and a mandate on drug companies to pay a rebate to Medicare if they raise prices faster than inflation. We are committed to ensuring that all people – including people with Medicare – receive the care they deserve at a cost they can afford.”

“One option under the Inflation Reduction Act is the Medicare Prescription Payment Plan, a program specially designed to help people with high drug costs have more predictable costs throughout the year,” said CMS Administrator Chiquita Brooks-LaSure. “People with Medicare prescription drug coverage should look at the Medicare Prescription Payment Plan as well as our Extra Help program to see what programs are right for them. CMS is continuing to implement the many important provisions of the Inflation Reduction Act on time to help older Americans and people with disabilities afford the care they need.”

Today’s draft guidance provides information on outreach, education, and communications requirements to ensure that people with Medicare Part D, particularly those who are most likely to benefit from this program, are aware of the Medicare Prescription Payment Plan. The guidance complements CMS’ forthcoming national education and outreach efforts to engage interested parties, including pharmacies, providers, and beneficiary advocates, on program implementation and ensure that they have the support and materials needed to communicate effectively on the program.

“Older Americans and people with disabilities who have experienced sticker shock from high prescription drug prices will have the option in 2025 to spread out-of-pocket costs out over the year, rather than paying all at once,” said Meena Seshamani, MD, PhD, CMS Deputy Administrator and Director of the Center for Medicare. “This specifically helps alleviate cash flow issues for people who face high out-of-pocket costs early in the year that may prevent these individuals from taking a drug that could keep them healthy. The draft guidance we have released is a blueprint to help operationalize this program to ensure both health care organizations and people with Medicare are empowered and educated. That way, people in Medicare can make the best choices for their health and financial needs.”

The Medicare Prescription Payment Plan, which goes into effect in 2025, is part of the Inflation Reduction Act’s suite of provisions aimed at lowering prescription drug and health care costs. Other provisions of the law are already helping to lower costs for people with Medicare. On January 1, 2024, the law expanded eligibility for the Low-Income Subsidy program (LIS or “Extra Help”) under Medicare Part D. Nearly 300,000 people with low and modest incomes currently enrolled are now benefitting from the program’s expansion, and 3 million people are eligible for the program but not yet enrolled. In addition, as of January 1, 2024, for some people enrolled in Medicare Part D who have very high drug costs, for the first time, their out-of-pocket costs will be capped at about $3,300 to $3,800 for most people. The Medicare Prescription Payment Plan complements these provisions by allowing individuals to spread their spending over the year rather than paying the total out-of-pocket cost upfront.

CMS is seeking comments from the public on today’s draft part two guidance. The comment period is open for 30 days. Comments received by March 16, 2024 will be considered during development of the final guidance. Comments should be sent to [email protected] with the following subject line: “Medicare Prescription Payment Plan Guidance – Part Two.”

The draft part two guidance builds on the previously released draft part one guidance and fact sheet (released on August 21, 2023). Final part one guidance is forthcoming.

For the draft part two guidance, please visit:  https://www.cms.gov/files/document/medicare-prescription-payment-plan-draft-part-two-guidance.pdf

For the fact sheet on the draft part two guidance, please visit: https://www.cms.gov/files/document/fact-sheet-medicare-prescription-payment-plan-draft-two-guidance.pdf

For an implementation timeline for the Medicare Prescription Payment Plan, please visit:  https://www.cms.gov/files/document/medicare-prescription-payment-plan-timeline.pdf

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Design of a Drug Court System Essay

Introduction.

The concept, principle and practice of Drug Court across the United States provide a paradigm shift from the traditional process of imposing penalties and jail sentences on offenders. More studies have proven the effectiveness of drug courts in reducing offender recidivism and also in reducing the costs of maintaining penal institutions for offenders.

The popularity of drug courts has been primarily due to reports by studies and researchers that there have been reductions in recidivism by offenders. Empirical evidence points to the successes of drug courts across many counties in the United States.

Judges play a significant role in the implementation of drug courts, while offenders are also held accountable for their actions in following the programs and sanctions imposed upon them. Offenders have to comply with the rules and processes of the Drug Court.

Offenders have a strong incentive in being members of the Drug Court in that they have the prospect of avoiding being in jail for as long as they abide by the rules and cooperate in the success of the program. The Drug Court serves as a program to divert offenders from the traditional way of incarceration or being admitted in a correctional facility. (Goldkamp qtd. in Sanford and Arrigo 251)

The Drug Court System has also been used in administering juvenile justice. In a study by the Department of Justice, it was found that in 1999, juvenile offenders accounted for 11% of drug use offenders (U.S. Department of Justice Office of Juvenile Justice and Delinquency Prevention, 2001 qtd. in Sanford and Arrigo 251).

Juvenile drug courts have also been introduced in line with the concept of adult drug courts due to the increasing successes of drug courts. Empirical evidence also shows significant successes of juvenile drug courts. (Hiller et al. 1)

Proposing a Drug Court is by the current number of drug addicts in the community. Currently, there are more drug addicts than it was 3-5 years ago when our children used to roam around the neighborhood without the parents having to think about them.

Upon consultation with the various sectors and agencies involved in the criminal justice promotion, the following is a detailed plan of a Drug Court for the community.

The Drug Court Management Team

Members of the Drug Court Management Team have a big role to play in this practice. Their findings and inputs are the basis for the judge’s decision of the Drug Court and regarding the status of the offender. All in all, they shape the proceedings of the Drug Court program.

The Drug Court Team will be composed of the prosecuting attorney and defense attorney, treatment providers who will come from the Community Rehabilitation Center, the probation officer, and the local law enforcement unit. (Huddleston and Marlowe 7)

Duties and Responsibilities of the Drug Court

  • With the Judge as Presiding Officer, the Drug Court shall hold regular status hearings, and this must be with the attendance of the prosecutor, defense counsel, treatment providers and other members of the Drug Court.
  • During the first few months of the Drug Court, status hearings shall be done frequently, at least on a bi-weekly basis.
  • Random drug testing shall also be done twice a week.
  • Rewards should be provided by the Management Team to offenders who are making good progress in their treatment and performance.

The Participants

Eligible participants are drug and alcohol dependents. Drug addicts will be screened by the Management Team. Mostly, recommendations will come and will be subsequently accepted after screening from law enforcement and treatment providers.

Participants will be required to submit themselves for drug and alcohol testing regularly, but the process will be randomly done by the Management Team, particularly the treatment providers.

The judge plays an important role in the Drug Court and is a pivotal figure in the drug court management team. His/her decision will be unprecedented in contemporary criminal justice proceedings. The judge shall have the dual role as ‘formal and informal activist in the drug court model’ (Sanford and Arrigo 249).

The judge shall have the full authority to see that programs are enforced. Without the judge’s able leadership and authority, the Drug Court’s effectiveness and power will be lost.

The judge can impose penalties and rewards depending on the progress of the participants. Rewards may be in the form of ‘reduced supervision’, gifts, or modification of treatment.

The Process

Funding for this program of a Drug Court will come from state coffers and from judicial funding. This program drug court program will also be used as a court for juvenile offenses and problem-solving court. Juvenile offenses are drug-related crimes that involved burglary and simple theft.

The existing Department of Justice process for drug court formation will be applied in this respect, including the unique structure, guidelines, and the use of judicial resources. The local government shall help in providing resources for this implementation. The duration of this Drug Court Team will last for one year or upon recommendation of the Team and as the need arises.

The Drug Court will bring together the efforts of the various community-based services and agencies involved in treating and rehabilitating the participants. Rather than the adversarial method of reforming offenders, the Court will aim to treat and rehabilitate participants and reduce the percentage of recidivism. Offenders will have the incentive of not being in jail for the duration of the program and as long as they do not violate the rules set forth by the judge and the Management Team.

The judge will assume a central leadership role and will have the discretion over the cases submitted under supervision and study by the Management Team (Goldkamp qtd. in Sanford and Arrigo 248). The participant or offender will be held responsible for his actions and will promptly report or make himself available during judicial status hearings, drug screening tests, and other schedules provided by the team such as counseling and treatment.

There will be sanctions whenever the offender cannot comply with the standards and conditions imposed by the Drug Court.

The Drug Court Management Team, which is composed of the judiciary, courtroom workgroup, and service providers, shall provide the necessary means to make the proceedings of the Court effective. The composition of the team that includes probation officers, treatment providers, and other nonjudicial members, is a departure from normal court and adjudication proceedings.

The Drug Court shall have the ability to shape the outcomes of the processes by providing programs, procedures, and goals that would meet the requirements for effective implementation. The principle to be followed in the processes is to create a courtroom workgroup that will be composed of the representatives of the community-based service agencies including treatment providers and probation officers.

The drug court management team will provide the basis for a final decision to be delivered by the judge who is the final decision authority. In other words, the team’s feedback, information, screening and test results on offenders will be the judge’s basis for the decision. (Olson et al., qtd. in Sanford and Arrigo 248)

Judicial status hearings are another important part of the Court proceeding. It is assumed, and further supported by studies of the past (Sanford and Arrigo), that constant status hearing will result in the detection and infractions so that sanctions can be instituted upon the offenders. A study conducted in Portland and Las Vegas drug court systems by Goldkamp et al. (qtd. in Sanford and Arrigo 249), found that sanctions, drug court appearances, and treatment were important in the successful implementation of drug court programs.

Treatment will be an integral part of the Drug Court model and the offender will be held accountable for the progress of the treatment.

The Drug Treatment Services

Drug treatment services are an important part of the process, in fact, a central component of the Drug Court program. Service providers and rehabilitation centers will determine if an offender deserves treatment and if so needed, necessary procedures should be undertaken to benefit the offender.

Drug treatment will be administered depending upon the individual needs of the offender.

The judge will have the absolute power to impose sanctions based upon findings by the Drug Court Management Team. The members of the team including the probation officer, treatment service provider, and judicial court members will regularly report any violation of the offender. Sanctions will depend on the degree of violation and this can be brief jail detention, community service, or other light punishment that will be decided by the judge. If the offender becomes a recidivist, heavier penalties, such as jail detention, will be imposed.

Works Cited

Hiller, Matthew et al. A Multisite Description of Juvenile Drug Courts: Program Models and During-Program Outcomes. International Journal of Offender Therapy and Comparative Criminology, Web.

Huddleston, West and Marlowe, Douglas. Painting the Current Picture: A National Report on Drug Courts and Other Problem-Solving Court Programs in the United States. National Drug Court Institute, Bureau of Justice Assistance, U.S. Department of Justice , 2011.

Sanford, J. Scott and Arrigo, Bruce A. Lifting the Cover on Drug Courts: Evaluation Findings and Policy Concerns . International Journal of Offender Therapy and Comparative Criminology, 2005.

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1. IvyPanda . "Design of a Drug Court System." April 24, 2022. https://ivypanda.com/essays/design-of-a-drug-court-system/.

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  5. Essay About Drugs

    Essay About Drugs Sort By: Page 1 of 50 - About 500 essays The Drug Of Drugs And Drugs Many times these drugs affect the brain and in result, cause the addiction to occur. More and more there are people coming into the hospital from a heroin overdose, are released from the hospital, go back out, and inject the drug.

  6. Drug Abuse Effects on Health and Nervous System

    Drug Abuse Effects on Health and Nervous System Exclusively available on IvyPanda Updated: Nov 20th, 2023 Table of Contents Introduction According to the data provided by the US Department of Health and Human Services, in 2019, almost 30 percent of Americans older than 12 years illicitly used drugs (14).

  7. Health Care Systems and Substance Use Disorders

    Integrating services for primary care, mental health, and substance use-related problems together produces the best outcomes and provides the most effective approach for supporting whole-person health and wellness. 3. This chapter describes the key components of health care systems; historical reasons substance use and its consequences have ...

  8. Essay on Drugs: Definition, Classification and Moral Implication

    Essay on Drugs: Definition, Classification and Moral Implication Article Shared by ADVERTISEMENTS: A drug (French-Drogue a dry herb) is defined as "any chemical agent which affects living protoplasm and is intended for use in the treatment, prevention or diagnosis of disease."

  9. Drug delivery systems: An updated review

    A novel colon-specific drug delivery system based on a polysaccharide, guar gum was evaluated in healthy human male volunteers, with gamma scintigraphic study using technetium 99m-DTPA as tracer. It was seen that some amount of tracer present on the surface of the tablets was released in stomach and small intestine and the bulk of the tracer ...

  10. Drug Abuse as an Ethical Issue

    Drug Abuse as an Ethical Issue Essay. Exclusively available on IvyPanda. Updated: Dec 23rd, 2023. Theories explaining how life should be lived are defied by the addicts, they device their new ways of living which are inconsistent with the societal rules and norms. Drugs change an individual's ego making him/her to have desires and aspirations ...

  11. Essay: Drug administration and Drug Delivery Systems

    1. INTRODUCTION The oral route of drug administration is the most important method of administering drugs for systemic effects. The parentral route is not routinely used or not possible to self-administration of medication. The topical route of administration has only recently been employed to deliver drugs to the body for systemic effects.

  12. Essay on Drugs for Students

    Students are often asked to write an essay on Drugs in their schools and colleges. And if you're also looking for the same, we have created 100-word, 250-word, and 500-word essays on the topic. ... risky use, and finally, dependence and addiction. The brain's reward system is hijacked, creating a powerful drive to continue using the drug ...

  13. Democratic lawmakers call for crack down on drug companies over system

    Here's the system Warren and Jayapal are trying to address: The FDA keeps a list of all federally approved drugs, known as the Orange Book. The agency requires pharmaceutical companies to list in ...

  14. Does Portugal Have The Answer To Stopping Drug Overdose Deaths?

    Drug consumers line up outside of the SAOM van for a methadone cocktail and supplies in the city center of Porto, Portugal last spring. There are very few overdose deaths in the country where drug ...

  15. Essay on War On Drugs And Mass Incarceration for Students

    The war on drugs led to a massive increase in the number of people incarcerated in the United States. Between 1980 and 2010, the number of people incarcerated in the United States increased from 336,000 to 2.3 million. This increase was driven largely by drug offenses. Today, the United States has the highest incarceration rate in the world ...

  16. Drug Smuggling as a System of Distributing Drugs Essay

    Introduction. Drug smuggling, also referred to as drug trafficking refers to a system of distributing drugs either across a country or a number of them. Drug prohibition which has varied across nations contributed to the illegalization of drugs, whose usage and distribution were otherwise legal. For example, although the usage of opium brought ...

  17. Criminal Justice System Essay

    599 Words. 3 Pages. Open Document. hort Essay. "All wrong." That is how the nation's top drug official sums up the way America has waged the war on drugs for more than 40 yearsi. . The battleground of choice has been the criminal justice system as tough-on-crime politicians assumed the harshest punishment would produce the best results.

  18. Drugs in the Prison System Essay

    4 Works Cited Open Document Drugs in the Prison System This research paper will consist of an analysis of the use and abuse of illicit drugs within the prison systems on a global basis.

  19. Drug Addiction and the Brain's Reward System

    According to Tomkins and Sellers (2001), drug addiction is a biopsychosocial condition characterized by the recurrent use of drugs or repetitive involvement, notwithstanding the harm produced by the behaviour. In other words, drug addicts are compulsive drug users.

  20. Opinion: Weight-loss drugs like Ozempic can't fix America's ...

    A doctor argues that the current focus on fighting obesity with drugs like Ozempic ignores the bigger picture: We need a medical system and society that support healthy life habits.

  21. Essay On Drug Delivery System

    Essay On Drug Delivery System Essay On Drug Delivery System 954 Words4 Pages Transdermal drug delivery is an enthusiastic and demanding area. During the last few years, drug delivery technology has been changing into the fashion in which they are required to elicit pharmacological action by the utilization of old drug molecules.

  22. Essay on Drugs

    Introduction Drug are addictive in nature. Its addiction is seen as a serious brain disorder. Despite its adverse effects, it is considered as compulsive usage of drugs. Drug addiction is defined as a state where a person is unable to control his urge to use drugs. Besides being chronic, it also has a relapsing nature. 250 Words Essay on Drugs

  23. Drug Abuse And The Criminal Justice System Essay

    Drug Abuse And The Criminal Justice System Essay Better Essays 1085 Words 5 Pages Open Document Case Review Although Michael was in fact convicted of burglary, he also tested positive for heroin and marijuana. Michael is an adult male 50 years of age, he has a history of prior convictions such as, • Driving under the influence • Disorderly conduct

  24. PDF 2024 National Money Laundering Risk Assessment (NMLRA)

    a growing concern for U.S. law enforcement. Drug traffickers are also turning to professional money launderers to launder their ill-gotten proceeds. In particular, drug traffickers use Chinese Money Laundering Organizations (CMLOs),91 which employ an informal value transfer system (IVTS) to move

  25. Ecuador's drug kingpin José Adolfo 'Fito' Macías lived 'like a king

    Ecuador's prison system has turned into the headquarters for criminal groups that have amassed foot soldiers and influence across the country, say experts. In less than a decade, organized crime ...

  26. New Parkinson's drug Produodopa to be available on NHS

    The drugs work by helping the brain transmit messages to nerves that control movement. ... How the plague rewired our immune system. Future. NHS trust facing new forecast deficit of £117m.

  27. CMS Issues Additional Guidance on Program to Allow People with Medicare

    The draft guidance is part of the implementation of President Biden's prescription drug law, the Inflation Reduction Act, which will help reduce the burden of high upfront out-of-pocket prescription drug costs for seniors and people with disabilities with Medicare prescription drug coverage by allowing them to spread out costs over the year ...

  28. Design of a Drug Court System

    The Drug Court serves as a program to divert offenders from the traditional way of incarceration or being admitted in a correctional facility. (Goldkamp qtd. in Sanford and Arrigo 251) The Drug Court System has also been used in administering juvenile justice. In a study by the Department of Justice, it was found that in 1999, juvenile ...

  29. Drug And The Drug Court System Essay

    Drug And The Drug Court System Essay 1788 Words 8 Pages "A drug court is a special court given responsibility to handle cases involving substance-abusing offenders through comprehensive supervision, drug testing, treatment services and immediate sanctions and incentives" ("what are drug courts?").