David Mastropietro

Current approaches in tamper-resistant and abuse-deterrent formulations

Context: The escalating abuse of prescription drugs has recently spawned the development of novel drug formulations resistant to various methods of tampering and misuse. Objective: The intent of this paper is to provide an overview and classification system of formulation approaches, developed to produce what most refer to as abuse-deterrent or tamper-resistant dosage forms. Methods: A comprehensive literature search was conducted within Embase™ and Medline using key words “abuse deterrentâ and “tamper resistantâ to identify relevant technologies. Only issued patents were examined using the phrase “abuse deterrent compositionâ searched through PatFT from the United States Patent and Trademark Office. Current information from press releases and product innovator websites was obtained for additional data. Results: Identified formulation approaches were organized into two categories, physical approaches and chemical approaches. Physical approaches were subcategorized into solids, gels or non-intentionals, while chemical approaches were further broken down into agonists/antagonists, aversives, or metabolics. Among issued patents specifying an abuse-deterrent method, nine diverse approaches were found. Most formulations under development combined approaches, and utilized proprietary technologies from pharmaceutical manufacturers. Conclusions: Prodrug and agonist/antagonist formulations are popular in marketed products, while solid and gel approaches are more recent additions. However, the inclusion of aversive agents or enzyme inhibitors in a product is proving to be more difficult to develop. Overall, detailed formulation and manufacturing methods still remain rather elusive to protect public health. Moreover, these innovative formulations are mostly untried in the general population and their abuse deterring effects has yet to be proven.

Drug delivery applications for superporous hydrogels.

Introduction: Considerable advances have been made to hydrogels with the development of faster swelling superporous hydrogels (SPHs). These new-generation hydrogels have large numbers of interconnected pores, giving them the capacity to absorb large amounts of water at an accelerated rate. This gives SPHs the ability to be used in a variety of novel drug delivery applications, such as gastric retention and peroral intestinal delivery of proteins and peptides. Areas covered: This review focuses on the applications of SPHs for drug transport and targeted drug therapies, as well as the characteristics and historical advancements made to SPH synthesis as it pertains to drug delivery. Manufacturing considerations and challenges that must be overcome are also discussed, such as scale-up, biocompatibility and safety. Expert opinion: Modern SPHs have high swelling and high mechanical strength making them suitable for many diverse pharmaceutical and biomedical applications. However, demonstrative preclinical animal studies still need to be confirmed in human trials, to further address safety issues and confirm therapeutic success when using SPHs as platforms for drug delivery. The focus of forthcoming applications of SPHs is likely to be in the area of oral site-specific delivery and regenerative medicine.

Abuse-deterrent formulations: Part 2: commercial products and proprietary technologies

Introduction: Increased misuse and abuse of prescription pain medications has driven extensive research and development to produce what are best known as abuse-deterrent formulations (ADFs). The ADFs are intended to prevent, impede or discourage physical and chemical tampering while still being able to provide safe and accurate delivery of an abusable medication for therapeutic benefit. Areas covered: This review primarily focuses on patents and company literature regarding the formulations, manufacturing and physiochemical properties of abuse-deterrent compositions. Also included are journal articles with relevance to the development of these novel technologies. Particular attention is given to oral dosage forms with applications found in prescription drug products, over-the-counter medications and proprietary technologies in development. Overall, the formulations of 14 drug products, 2 meth-resistant cold products and 17 pharmaceutical proprietary technologies are explored in detail. Expert opinion: Despite the introduction of a wide range of formulation and technology interventions with different deterrence potential, the progression of these technologies seems to be moving from inhibiting only one type of abuse to stopping multiple types of tampering methods. Information on inherent strengths and weaknesses of various formulations can be utilized in the development of more robust and resistant ADF in the future.

Abuse-deterrent formulations: part 1 – development of a formulation-based classification system

Introduction: Strategies have been implemented to decrease the large proportion of individuals misusing abusable prescription medications. Abuse-deterrent formulations (ADFs) have been grown to incorporate many different technologies that still lack a systematic naming and organizational nomenclature. Without a proper classification system, it has been challenging to properly identify ADFs, study and determine common traits or characteristics and simplify communication within the field. Areas covered: This article introduces a classification system for all ADF approaches and examines the physical, chemical and pharmacological characteristics of a formulation by placing them into primary, secondary and tertiary categories. Primary approaches block tampering done directly to the product. Secondary approaches work in vivo after the product is administered. Tertiary approaches use materials that discourage abuse but do not stop tampering. Part 2 of this article discusses proprietary technologies, patents and products utilizing primary approaches. Expert opinion: Drug products using opioid antagonists and aversive agents have been seen over the past few decades to discourage primarily overuse and injection. However, innovation in formulation development has introduced products capable of deterring multiple forms of tampering and abuse. Often, this is accomplished using known excipients and manufacturing methods that are repurposed to prevent crushing, extraction and syringeability.

Rheology in Pharmaceutical Formulations-A Perspective

Medications produced as semi-solids type product such as creams, ointments and lotions are based on emulsion or suspension type systems consisting of two or more incompatible materials. In order to be manufactured, these dosage forms need specific flow properties so they can be placed into a container, remain stable over time, dispensed, handled and properly applied to the affected area by patients. Rheology is therefore crucially important as it will directly affect the way a drug is formulated and developed, the quality of the raw and finished product, the drug efficacy, the way a patient adheres to the prescribed drug, and the overall healthcare cost. It can be concluded that there are inherent and independent factors that affect the flow property of a medicated material during every stage of its manufacturing all the way to its use.

Prevalence and trends of cellulosics in pharmaceutical dosage forms.

Context: Many studies have shown that cellulose derivatives (cellulosics) can provide various benefits when used in virtually all types of dosage forms. Nevertheless, the popularity of their use in approved drug products is rather unknown. Objective: This research reports the current prevalence and trends of use for 15 common cellulosics in prescription drug products. Methods: The cellulosics were powdered and microcrystalline cellulose (MCC), ethyl cellulose, hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), hypromellose (HPMC), HPMC phthalate, HPMC acetate succinate, cellulose acetate (CA), CA phthalate, sodium (Na) and calcium (Ca) carboxymethylcellulose (CMC), croscarmellose sodium (XCMCNa), methyl cellulose, and low substituted HPC. The number of brand drug products utilizing each cellulosics was determined using the online drug index Rxlist. Results: A total of 607 brand products were identified having one or more of the cellulosics as an active or inactive ingredient. An array of various dosage forms was identified and revealed HPMC and MCC to be the most utilized cellulosics in all products followed by XCMCNa and HPC. Many products contained two or more cellulosics in the formulation (42% containing two, 23% containing three, and 4% containing 4–5). The largest combination occurrence was HPMC with MCC. The use of certain cellulosics within different dosage form types was found to contain specific trends. All injectables utilized only CMCNa, and the same with all ophthalmic solutions utilizing HPMC, and otic suspensions utilizing HEC. Conclusion: Popularity and trends regarding cellulosics use may occur based on many factors including functionality, safety, availability, stability, and ease of manufacturing.

Swelling, strength, and biocompatibility of acrylate-based superporous hydrogel hybrids

A hydrogel hybrid of chemically cross-linked hydroxyethyl acrylate interpenetrated with physically cross-linked carboxymethylcellulose was prepared as a superporous structure with swelling rates ranging from a few seconds to minutes depending on the swelling medium. A new method was adopted to evaluate the swelling capacity and rate in superporous hydrogel hybrid using a modified texture analyzer. Based on the extensive data acquisition, swelling data at any time point were obtainable and fit into a Voigt viscoelastic model. Moreover, the two mechanisms by which a superporous hydrogel hybrid swells in an aqueous medium were differentiated and used to estimate the onset of the diffusion-controlled swelling, which was found to be dependent on the actual composition of the swelling medium. A correlation was found between the mechanical strength of the fully swollen hydrogels and their respective swelling force in different swelling media. The concentration of alcohol in the medium was a critical factor in the swelling characteristics and strength of these hydrogels. Two HeLa and mesenchymal stem cells derived from human umbilical cord cell lines were used to evaluate biocompatibility of the prepared hydrogels.

Reported Methods of Abuse for Common Prescription Analgesic Opioids

With the introductory of internet forums, blogs, and social networks, large numbers of individuals are connected together in ways previously deemed difficult or impossible. These outlets can be used as a means of asking questions or freely displaying personal experiences, viewpoints, and anecdotal accounts. Once posted, these questions and remarks are open for other individuals to read, comment and respond. Through these dialogues, a vast electronic database has been created which is instantly retrievable and contains new content on a daily basis. In the healthcare field, this can be beneficial to certain patients or can be used in ways leading to detrimental effects. For example, computer-mediated forums can help patients, such as those with cancer, cope with their diseases states. Likewise, webbased interventions can also help those with alcohol, tobacco, and substance use disorders. However, internet discussions can also be used by those seeking to abuse drugs, particularly those interested in recreational use of prescription opioids. Internet forums have become a source of information on how abusers can administer and defeat different prescription drug containing formulations. They can also be used as a means of estimating abusers’ preferences for certain products. The information contained in online drug abuse databases are of particular interests to those who are developing abusedeterrent formulations, since the purpose of these products is to defeat common and upcoming methods of abuse.

Drug Tampering and Abuse Deterrence

There has been a growing response from governments, industries, and academic institutions to address the worldwide incidence of prescription drug abuse. These organizations have addressed this prominent public health concern in different ways. One crucial step has been research and development into developing medications that are considerably more resistant to abuse. These novel medications prevent or discourage abuse and tampering, and consequently referred to most often as abuse-deterrent or tamper-resistant formulations. While prescription drugs used to treat insomnia, anxiety, and behavioral disorders are commonly abused, prescription opioids are most significant. Attempts to produce more rapid “high” or euphoria have resulted in various tampering techniques by abusers. Swallowing multiple dosage forms at once, either intact or crushed (chewed), is relatively considered the most common form of tampering, followed by nasal insufflation and injection. However, the prevalent route used can greatly depend on the drug or dosage form. The simultaneous use of prescription opioids with alcohol has also become a dangerous form of tampering that can lead to serious adverse effects and even death. The objective of this paper is therefore to provide a summary of the types of tampering commonly performed during abuse of prescription drugs that can be useful in developing dosage forms more resistant to multiple forms of abuse.

Routes of Opioid Abuse and its Novel Deterrent Formulations

This review aimed to investigate the abuse patterns of common prescription opioids currently on the market by collecting large-scale surveys of different abuser populations. Furthermore, we aimed to analyze the efficacy and properties of currently implemented abuse-deterrent formulations (ADF) for these compounds. Our investigation showed that while oxycodone and oxymorphone are primarily abused by oral ingestion and insufflations, respectively, their ADF products (reformulated OxyContin and Opana ER) show some encouraging results to deter their abuse. Tapentadol is not popular amongst abuser populations, its ADF are difficult to tamper with, and it does not produce significantly desirable effects in noncompliant patients when compared to other opioids. Hydromorphone is predominantly abused by injection, and any effective abuse-deterrent strategy must specifically prioritize and target this route. Current formulations have successfully conferred aversive properties onto the drug in the event of preparation for injection, yet overall rates of hydromorphone abuse remain high, suggesting that more innovative steps need to be taken. Despite novel deterrent technologies that collectively offer deterrence by insufflations, injection and co-ingestion with alcohol, more priority needs to be given to deterring the most common and accessible route of abuse, i.e., oral ingestion of multiple doses.