Issue:October 2012

DRUG DELIVERY – OraGuard(TM): A Tampering-Deterrent & Alcohol-Resistant Extended-Release Technology


BIOGRAPHY

INTRODUCTION

In US, abuse, misuse, and diversion of prescription opioids are a growing problem. Americans are the world’s largest consumer of opioid products with 80% of the world’s supply of opioids and 99% of the hydrocodone being dispensed in the US.1 From 1998 to 2007, the US saw a steep increase in the number of prescriptions for opioids through US outpatient retail pharmacies. For hydrocodone, the increase was 172% from 2.68 to 7.28 billion units dispensed. For oxycodone, the increase was 314% from 725 million to 3 billion units dispensed.2

Data from the National Survey on Drug Use and Health (NSDUH) shows that an increasing number of individuals aged 12 or older have abused illicit and/or prescription drugs.

-In 2010, an estimated 3 million people used an illicit drug for the first time within the past 12 months of this survey interview.3

-Almost 22.6 million Americans had used an illicit drug (marijuana/hashish, cocaine, heroin, hallucinogens, inhalants, or prescription-type psychotherapeutics used nonmedically) during the month prior to the survey interview.3

-In 2009-2010 of those who used pain relievers non-medically 55% got the drug from a friend or a relative for free. Other sources were through a prescription from doctor, from a drug dealer, or by purchasing them on the internet.3

Also among abusers, there is a major underestimation of the risk associated with casual illicit prescription drug use. Almost one third of teens (grade 7 to 12) do not believe there is a great risk in abusing prescription medicine, and 30% believe prescription pain relievers are not addictive.4

According to Drug Abuse Warning Network, in 2007, the estimated economic cost of illicit drug use to society was more than $193 billion. There were approximately 2 million emergency room visits related to non-medical use in 2009. The healthcare costs for non-homicide emergency department visits related to drug use are estimated to be $161 million annually, and the hospital admissions (including treatment for illicit drug use) would be an additional $5.5 billion.5 This data demonstrates the burden on the healthcare system and shows the extent to which the prescription drug problem is prevalent in the US that demands action from healthcare providers, manufacturers, and law makers.

Several initiatives are ongoing or have been proposed to address the growing abuse of opioids, such as:

-Designing novel formulations and drug delivery systems intended to deter casual abusers from tampering with the drug product.
-Continuing advancement in the design and evaluation of epidemiological studies to address changing patterns of abuse.
-Training of healthcare providers on responsible opioid prescription practices
-Requiring manufacturers through the Opioid Risk Evaluation and Mitigation Strategy (REMS) to develop effective educational materials for healthcare providers and patients on proper prescribing and disposal of opioid pain relievers.
-Providing guidance to pharmaceutical industry on the development of abuse-deterrent drug formulations and on post-market assessment of their performance.

Pharmaceutical manufacturers have attempted several tamper-deterrent mechanisms in order to limit the abuse potential of an opioid formulation. The interest in developing tamper-deterrent formulations increased with the passage of the Food and Drug Administration Amendments Act of 2007, which provided the FDA with the authority to require drug sponsors to submit and implement Risk Evaluation and Mitigation Strategy (REMS). In February 2009, the FDA sent letters to 15 manufacturers of 24 currently approved opioid products indicating their products require REMS.7 Later that year, the FDA published its Guidance for Industry, reflecting the agency’s general views on the format and content of REMS.8 In January 2010, the FDA published guidance on Assessment of Abuse Potential of Drugs that recommends including an abuse potential assessment as a section for the NDA or supplement. This section contains all pertinent preclinical, pharmacological, chemistry, biochemical, human laboratory, and clinical studies, drug formulation data, and proposal for appropriate scheduling.6 The FDA Draft Guidance concurs that tamper-deterrent formulations are expected to provide incremental improvement in combating abusers’ tampering techniques.

ABUSE DETERRENT MECHANISMS

The selection of tamper-deterrent features is generally based on the following questions: Who is going to abuse these formulations? and what forms of tampering are abusers likely to employ? Most people who are tampering with formulations are casual abusers. Some of the common forms of tampering are crushing, chewing, snorting, smoking, and injection. These tampering methods can lead to exposure to large amounts of drug, which increase the euphoric affect that abusers desire. This is especially true for extended-release formulations that can contain up to a full day’s dose in one tablet or capsule. The increased exposure may also cause adverse effects, such as sedation or clouded mentation, nausea, vomiting, constipation, respiratory depression, or even death.

The best approach to address prescription opioid abuse would be to develop molecules that can alleviate pain but have no or minor euphoric and physical dependence effects. Thus far, no molecules with these attributes have been successfully identified. Therefore, to tackle the problem of opioid abuse, pharmaceutical manufacturers are focusing on the development of tamper-deterrent formulations for existing molecules.

The tamper-deterrent mechanism may involve providing a physical barrier to reduce the chance that an opioid formulation can be altered by physical or chemical manipulation. Physical barriers can be in the form of a thick and strong coat on a drug-loaded core.9 The core can be in the form of small particles, tablets, or capsules. Or the drug can be distributed through a matrix that can be made of fat or wax, gelling polymers, or plastic polymers.10-14 In all cases, the excipients are selected to impart crushing and solvent resistance (owing to their physico-chemical properties and how they are used within the dosage form). Another approach relies on simply making very strong tablets that are hard to break with commonly available utensils, such as spoons, cigarette lighters, porcelain mugs, etc.

One of the abuse-deterrent mechanisms involves administering an opioid as a prodrug, which is converted to its active form via hepatic metabolism after ingestion.15 This delays the time to reach maximum concentration. Also, when ingested in large quantities, it may saturate the metabolic system and consequently the biotransformation to the active form may be limited thus reducing the euphoria. Some tamper-deterrent formulations may contain an opioid antagonist in combination with opioid agonist, such as naloxone and buprenorphine or oxycodone and naltrexone; the antagonist is released along with agonist when the dosage form is tampered, which significantly reduces the rapid euphoric effects of the opioid.

Aversion agents have also been utilized as deterrent mechanisms. With this mechanism, the opioid product may be incorporated along with aversive agents, such as niacin and capsaicin, which are released along with the opioid when the dosage form is tampered. Niacin, if taken in excessive dose, produces warmth, flushing, and other uncomfortable symptoms. Capsaicin, if crushed and snorted or dissolved and injected, would cause a severe burning that would deter abusers from tampering the product.15

An additional feature that a tamperdeterrent formulation may offer is its resistance to accidental alcohol-induced dose dumping. Extended-release pharmaceutical formulation of opioids and other drugs with narrow therapeutic window and/or potential pharmacological interaction with alcohol are expected to offer resistance against alcohol-induced dose dumping. Extended-release opioid formulations that rely on an alcoholsusceptible mechanism to extend the drug release carry the risk of dumping its entire dose of opioid when co-ingested with alcohol that can lead to serious and potentially fatal adverse reactions. Such phenomenon was highlighted by the voluntary withdrawal of the extendedrelease hydromorphone product from the US market in 2005.16

In order to protect against tampering and accidental alcohol-induced dose dumping, CIMA LABS developed the OraGuardTM tamper deterrent and alcohol resistant, extended release drug delivery platform.

ORAGUARD(TM) TECHNOLOGY

The OraGuard technology developed by CIMA LABS is an extended-release, tamper-deterrent and anti-alcohol-induced dose-dumping platform. The formulations developed using OraGuard technology provide overlapping resistance against various tampering methods, such as crushing and ingestion, chewing, small-volume extraction for IV injection, and snorting (Figure 1).

The OraGuard technology is a multistep process in which the drug is granulated with high load of polymers (Figure 2). These polymers are specifically selected for their water and alcohol solubility. Then the granules are coated with a strong film-forming polymer and compressed with gel-forming polymers. Due to these polymers and the tablet composition, the final formulation has tamper-deterrent characteristics and is resistant to intentional and unintentional dose dumping in the presence of alcohol.

RESISTANCE OF ORAGUARD(TM) FORMULATIONS TO ORAL AND IV TAMPERING

One of the common tampering methods used by abusers is to crush the dosage forms to release the drug, which could then be ingested orally. Optionally, the abusers could crush the dosage form and then use solvents, such as boiling water in order to extract the drug from the dosage form and then inject for the euphoric effects. OraGuard formulations impart resistance to these physical forms of tampering as evident further in Figure 3 and Figure 4. Figure 3 compares the extraction efficiency of an OraGuard extended-release formulation to a commercial oxycodone product when subjected to the common methods of physical tampering. Extraction efficiency is defined as the percent oxycodone released from an OraGuard formulation when subjected to common methods of physical tampering. It is important to note that the commercial oxycodone product used in this study was later reformulated by its manufacturer to impart tampering-deterrent features. In this study, the OraGuard tablets and the commercial oxycodone tablets were crushed to fine powder using pestle and mortar, and the release profile of resulting powder was determined using standard dissolution apparatus/media. As seen in Figure 3, the OraGuard formulation prevented the complete extraction of oxycodone even though the OraGuard tablets were subjected to higher number of crushing strokes, whereas the commercial oxycodone formulation released ~90% oxycodone within 5 minutes. Figure 4 compares the simulated IV tampering of OraGuard formulations to a commercial oxycodone formulation. This commercial oxycodone product was later reformulated by its manufacturer to impart tampering-deterrent features. In this study, the OraGuard prototypes and the commercial oxycodone formulations were crushed with a pill crusher followed by extraction by boiling in water for 5 minutes. The three OraGuard prototype formulations were resistant to complete extraction (≤ 5% drug released) by this tampering method, whereas >70% drug was released from the commercial oxycodone formulation.

RESISTANCE OF ORAGUARD(TM) FORMULATIONS TO ALCOHOL-INDUCED DOSE DUMPING

The OraGuard formulation prevents any notable dose dumping with the coingestion of up to 40% alcohol, as evident with a OraGuard extended-release hydromorphone formulation.

Figure 5 displays the pharmacokinetic profiles of three OraGuard extended-release hydromorphone formulations with different coat levels and granule formulation. The formulations were intended for once-daily dosing. A randomized crossover study was conducted to assess the effect of coingestion of 4%, 20%, and 40% alcohol on the pharmacokinetics of OraGuard hydromorphone formulation in healthy subjects. The results are shown in Figure 6. The OraGuard formulation prevented any notable dose dumping with the co-ingestion of up to 40% alcohol.

OraGuard’s resistance against alcoholinduced dose dumping is applicable to other drugs beyond those that carry abuse potential. As described previously, extended-release formulations for drugs with narrow therapeutic windows or drugs with pharmacological interaction with alcohol must carry resistance against alcohol-induced dose dumping. Figures 7 and 8 display the in vitro release profiles in 0.1N HCl as well as 0.1N HCl in presence of 40% v/v ethanol for OraGuard formulations of metoprolol succinate and venlafaxine hydrochloride. Both the OraGuard formulations are less susceptible to dose dumping in the presence of alcohol compared to commercially available metoprolol succinate and venlafaxine hydrochloride formulations.

SUMMARY

The growing non-medical use of opioids is a major challenge for lawmakers, doctors, and pharmaceutical companies. One way to address this challenge is to limit the abuse by offering tamper-deterrent characteristics to opioid products. OraGuard technology is a tamper-deterrent and alcohol-resistant extended-release formulation platform for opioids. It is also adaptable to a wide variety of other molecules. The platform is designed to provide resistance against common abusers’ techniques, including crushing, chewing, small-volume extraction for IV injection, and snorting. OraGuard opioid formulations have been extensively evaluated for their tamper-deterrent features using a battery of in vitro simulated tampering techniques, multiple pharmacokinetic studies, an abuse likeability study, and safety and efficacy studies. All of the excipients used in OraGuard formulations are compendial, and the processes use standard equipment that has been successfully scaled up to commercial equipment. The first commercial product based on OraGuard technology is expected to be available in 2014

REFERENCES

1. Website visited: http://www.ioam.org/statistics.html
2. Webster L, et al. Current status and evolving role of abuse-deterrent opioids in managing patients with chronic pain. J Opioid Manag. 2011;7(3):235-245.
3. Website visited: http://www.samhsa.gov/data/NSDUH/2k10ResultsRev/NSDUHresultsRev2010.htm
4. Website visited: http://www.drugfree.org/wpcontent/uploads/2011/04/PATS-Teens-Full-Report-FINAL.pdf
5. Website visited: http://www.justice.gov/archive/ndic/pubs44/44849/44849p.pdf
6. Website visited: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM198650.pdf
7. Website visited: http://www.fda.gov/Drugs/DrugSafety/InformationbyDrugClass/ucm187975.htm
8. Website visited: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm184128.pdf
9. Habib W, Hamed E, Moe D, inventors;CIMA LABS Inc., assignees. Abuse Resistant Drug Formulation. United States Patent No. 20080069891. March 2008.
10. Hirsh J, Kibanov AM, Swager TM, et al. inventors; Collegium Pharmaceutical, Inc., assignee. Abuse-Deterrent Pharmaceutical ompositions of Opioids and Other Drugs. United States Patent No. 7,399,488. July 2008.
11. Morrison YV, inventor. Abuse Resistant Capsules. United States Patent No. 2009123386. May 2009.
12. Kumar V, Dixon D, Tewari D,Wadgaonkar DB, inventors; Acura Pharmaceuticals Inc., assignee. Methods and Compositions for Deterring Abuse of Opioid Containing Dosage Forms. United States Patent No. 7,510,726. March 2009.
13. Bastin RJ, Lithgow BH, inventors;Aventis Pharma Limited, assignee. Abuse Resistant Tablets. United States Patent No. 6,309,668. October 2001
14. Mannion RO, Mckenna WH, O’Donnell EP, et al. inventors; EURO-CELTIQUE S.A., assignee. Alcohol Resistant Dosage Forms. United States Patent No. 20070259045. November 2007.
15. Katz N, Abuse-deterrent opioid formulations: are they a pipe dream? Current Rheumatol Repor. 2008;10:11-18.
16. Website visited: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/2005/ucm108460.htm

Dr. Dinesh K. Haswani is the Group Leader R&D Formulations, at CIMA Labs. His primary focus is developing modified-release, tamperdeterrent, orally disintegrating, buccal and immediate-release solid dosage forms using novel technologies. Dr. Haswani joined CIMA Labs in 2009 and is mainly responsible for formulation development, scale-up, as well as supporting regulatory fillings, intellectual property, and technology transfer activities. Prior to joining CIMA Labs, he was part of the product development group at Patheon Inc., and Spherics Pharmaceuticals Inc. He has numerous articles, patents, and abstracts published to his credit. He earned his PhD in Pharmaceutical Sciences from College of Pharmacy, Mercer University, Atlanta and his BS in Pharmacy from Prin. K.M. Kundnani College of Pharmacy, Mumbai, India.

John C. Nagel is the Senior Director of Business Development at CIMA. He joined CIMA in 2007. He began his career as a Venture Manger at Hoechst AG, the parent company of Aventis Pharmaceuticals. After Aventis, he spent 8 years in the Bay Area working for a number of biotech start-up companies, including Maxygen, Genencor, and IntraBiotics. Mr. Nagel earned his BA in Biology and his MBA from the University of Tennessee.

Dr. Derek Moe is the Vice President of Drug Delivery Technologies at CIMA. Dr. Moe came to CIMA in 2001 from the formulation group at Pfizer Global Research and Development in La Jolla, CA (previously Agouron). He began his career as a formulator at Syntex, Inc. in Palo Alto, CA. He earned his PhD in Pharmaceutics from the University of Minnesota and his BA in Chemistry and Math from St. Olaf College.

Dr. Ehab Hamed started as a Formulation Scientist at CIMA Labs 10 years ago and is currently the Director of the Formulations Department at CIMA. In this role, he is responsible for all internal and partnered new drug product formulation development, including prototype design, CTM manufacturing, process scale-up to pilot and commercial scale, as well as commercial products transfer between sites. He also provides technical leadership role in IP strategy/litigation, technology/product valuation, and regulatory filings. He has numerous patent applications, book chapters, and published articles to his credit. He is a pharmacist by training and earned his PhD in Industrial Pharmacy from the University of Cincinnati.