Novel Abuse Deterrent Formulations

• ExxPharma Therapeutics LLC

Introduction

Advances in pain control therapies over the last decade have led to the discovery of breakthrough drug products that provide patients with a wider range of highly effective medications. Compliant use of these medications allows many patients to carry out relatively normal daily functions. Unfortunately, along with the continuing growth of the prescription medication market, drug abuse, misuse and diversion have led to growing health and socioeconomic problems for the United States as reflected in the increased number of treatment admissions, emergency room visits and overdose deaths. The United States National Institute of Drug Abuse has reported that, in 2015 alone, antipain prescription opioid drug products were a cause of suffering to an estimated 2 million people in the United States. For instance, between 2002 and 2012, hospital admission related to opioid medicines more than quadrupled; similarly, overdose deaths linked to these medicines increased almost four-fold between 2000 to 2014. Every day, more than 90 Americans die due to opioid overdosing.¹ According to the Center for Disease Control and Prevention, the total “economic burden” of prescription opioid misuse in the United States, including the costs of healthcare, lost productivity, addiction treatment, and criminal justice involvement is estimated to be $78.5 billion a year.² In addition to the detrimental effects of overdose, an increase in the incidence of infant opioid dependency due to the use of these medicines by mothers during pregnancy, as well as the spread of infectious diseases, such as HIV and HVC, attributed to the misuse of opioids have been reported.¹

Abuse Deterrent Formulations

As part of the multifaceted efforts to help combat the opioid epidemic, the U.S. Food and Drug Administration (FDA) has been encouraging pharmaceutical companies to develop opioid oral solid formulations with abuse-deterrent properties, using tamper-resistant dosage forms that prevent instantaneous drug release when the product is manipulated.³ To that effect, the FDA has issued guidelines that assist development of abuse deterrent formulations by identifying three categories of studies that need to be carried out to establish the abuse deterrent potential of technologies:^4,5

1. Laboratory-based in vitro manipulation and extraction studies (Category 1)
2. Pharmacokinetic studies (Category 2)
3. Clinical abuse potential studies (Category 3)

In some cases, data from all three categories may not be necessary; however, they are essential in establishing unequivocally the abuse potential of a product.

While all solid dosage forms have been subject to abuse, extended release products have been particularly attractive to the abuser due to the high drug content incorporated in these dosage forms  with the intent of ensuring prolonged pain relief when used as prescribed. When these dosage forms are tampered with and administered through one of the common routes, they often lead to an instant release of the drug, which, in turn, provides abusers with the euphoria that they desperately desire.

Therefore, the objective behind the FDA guidelines is to help develop effective abuse deterrent formulations that thwart the deliberate attempt by abusers to extract a significant amount of opioid drugs that generate euphoria when administered using one of many routes of abuse. These routes of abuse vary from product to product as depicted in the estimated prevalence of drug abuse of some products shown in Table 1.

Table 1. imated Prevalence of Route of Abuse

Therefore, evaluation of the abuse potential of opioid oral solid dosage forms should take into consideration all common routes of abuse, including: (1) oral ingestion, where the dosage form is chewed to destroy the release controlling matrix and deliver high doses of therapeutic agent into the gastrointestinal tract when swallowed with or without co-ingestion of alcohol; (2) intravenous injection, which involves extraction of the drug substance from the dosage form using an appropriate solvent, followed by injection of the extracted drug directly into the blood stream; (3) nasal snorting, where the dosage form is crushed, milled, or ground into a fine powder and administered intra-nasally to facilitate rapid drug absorption through the lining of the nasal passages; (4) smoking, where the therapeutic agent is vaporized for inhalation by subjecting the dosage form to heat at elevated temperatures; and (5) swallowing of multiple tablets, where a large number of tablets are ingested simultaneously to generate euphoria.

One of the main approaches that are used to reduce or prevent drug abuse is the development of tamper-resistant dosage forms which resist chewing, cutting, crushing, milling, extraction and concomitant ingestion of tablets with or without alcohol. Evaluating the effectiveness of the abuse deterrent formulations is somewhat subjective, and, to minimize subjectivity, dosage form manipulation and extraction studies on the to-be-marketed formulation have to be done using tools that mimic the processes by which abusers manipulate the dosage forms (Category 1). The results should provide sufficient information to fully characterize the product’s tamperresistant properties, including the degree of effort required to bypass or defeat those properties. Ingestion of multiple tablets, the most prevalent route of administration for drug abuse is beyond the scope of this paper, and will not be discussed.

To meet the challenge, many pharmaceutical companies have been conducting intensive research to develop an “ideal” abuse deterrent formulation. On its part, ExxPharma has developed a patented abuse deterrent technology (Sync-Loc™), that utilizes an innovative formulation and process design which employ multiple barriers of tamper-resistance in a solid oral dosage form. Consequently, many products with abuse deterrent technologies have been developed and submitted to the FDA for approval. To-date, FDA has approved ten abuse deterrent opioid formulations that purportedly reduce or prevent drug abuse, out of which nine of them are extended release products. However, as of April 30, 2017, only five products are available in the U.S. market.

SyncLoc™ Abuse Deterrent Formulation

Sync-Loc™ employs a synchronized abuse deterrent technology that relies on physical, mechanical and chemical barriers to prevent dosage form tampering, including chewing, crushing, extraction and volatilization, thereby potentially preventing abuse by ingestion, insufflation, injection and inhalation. The technology generates tablets and multiparticulates, and drug release is modulated through a hybrid mechanism comprising erosion, desorption and diffusion. The abuse deterrent potential of the Sync-Loc™ technology has been evaluated using laboratory-based in vitro manipulation and extraction studies (Category 1), and is discussed below.

Abuse by ingestion following dosage form manipulation

Chewing is one of the dosage form tampering methods that abusers utilize prior to ingestion. Abusers chew tablets to destroy the tablet matrices, circumvent the extended release mechanism of the tablets and achieve instantaneous drug release. When ingested, the manipulated dosage form releases the drug immediately leading to a spike in the concentration of the drug in blood, thereby illiciting euphoric response. It is generally believed that chewing an extended release opioid dosage form is an important step towards addiction, followed by intranasal and intravenous routes of abuse. An effective abuse deterrent formulation should, therefore, be able to make it difficult, if not impossible, to chew the dosage form and release all of the drug instantly when ingested.

Sync-Loc™ tablets are extremely hard and very difficult to chew. It was demonstrated that the tablets do not break even when a 500N force is applied. Hardness and plasticity are imparted onto the dosage form through a combination of thermal processing and the incorporation of uniquely blended water-soluble and water-insoluble polymers and other pharmaceutical additives in the formulation. As a result, the dosage form does not easily get plasticized in the presence of saliva during chewing unlike many other abuse deterrent technologies. Instead the surface of the dosage form hydrates, forms a thin viscous gel layer and slowly erodes, while keeping the core hard and dry with limited liquid penetration. Therefore, hydration of the tablets with saliva followed by chewing is not expected to lead to instantaneous drug release irrespective of the bite force applied since the tablets remain intact and do not disintegrate as was demonstrated when the tablets were loaded separately in a pill crusher, wetted with artificial saliva, and then rubbed by applying considerable force for an extended period of time. The tablets did not break; instead, they only eroded from the surface over time (Figure 1).

Figure 1. Chewing

Crushing is another method that is used by drug abusers to manipulate the dosage form prior to ingestion. To achieve euphoria, the dosage form is crushed to increase surface area and speed up drug dissolution, and potentially absorption, when taken orally with water or alcohol. The most commonly used tools to crush dosage forms include mortar and pestle, and hammer.

Sync-Loc™ tablets are extremely difficult to crush using common tools such as pill crusher, and mortar and pestle; they maintain their shape even after many attempts are made to crush them (Figure 2A & B). However, the tablets can be deformed and broken down into pieces of plastic mass after repeated hammering with a lot of force (Figure 2C). The pieces of plastic mass are not expected to release the drug instantly upon ingestion by the abuser due to surface area considerations and potential gel formation.

Figure 2. Crushing

Abuse by insufflation following dosage form manipulation

Drugs are commonly abused by insufflation, a route of abuse which requires the dosage form to be ground into fine powders using conventional tools like coffee grinder. The abuser snorts the powdered drug through the nose, a route of administration often referred to as nasal insufflation. Nasally insufflated drugs get transported straight into the bloodstream via blood vessels in the nasal cavity to elicit euphoric response.

Sync-Loc™ tablets resist grinding using commonly used tools and hence do not generate fine powders that are suitable for snorting. Grinding using a coffee grinder only produces coarse and hard particles that are not amenable to snorting (Figure 3). Even if the finer particles were to be separated and snorted, the drug would not be available for absorption through the lining of the nasal cavity due to the entrapment of the drug within the rigid matrix of the particles. It is likely that the particles obtained are so hard and sand-like that, not only would they irritate the nassal cavity when snorted, but they also would form a very viscous gel when they come in contact with nasal fluids, thereby limiting drug availability for absorption through the nasal cavity.

Figure 3. Milling

Abuse by injection following dosage form manipulation

Abuse by injection usually involves extraction of intact or mechanically manipulated (e.g., crushed, milled) drug products in small volumes of water followed by injection using a syringe. Abuse by injection from manipulated dosage forms depends upon extractability of the drug and syringeability. That is, the amount of drug available for injection is determined by the drug concentration in the extraction medium, such as water (extractability), the volume that can be drawn into a syringe, and the volume that can be expelled from the syringe’s needle (syringeability). A tamper-resistant dosage form should, therefore, be able to resist crushing as well as extraction of the drug using common solvents and prevent subsequent injection using a syringe.

Sync-Loc™ tablets resist crushing using conventional tools, and, when they come in contact with aqueous media, generate thin viscous gel layers on the surface of the hard and dry cores, the thickness of which is dictated by the type of extraction solvent employed. Both with hydrated intact and crushed tablets, the entrapped drug present at the solvated gel layer does not diffuse out into the extraction medium due to its poor mobility within the uniquely formulated gel layer and hence would not be readily available for extraction. Even if the thin gel layer were to erode and releases the entrapped drug into the extraction medium, the drug is tightly bound to one of the formulation components to impede extraction. (Table 2).

Table 2. Extraction

To determine syringeability of Sync-Loc™, tablets were milled using a coffee grinder. The milled particles were placed on a spoon, and a small volume of distilled water was added on top of the particles to wet the mass and form a gel. Attempts were then made to withdraw drug-loaded liquid from the viscous gel using a syringe as practiced by drug abusers. The viscous mass was not syringable (Figure 4). The highly viscous nature of the formulation coupled with the entrapped drug makes syringability very difficult.

Figure 4. Syringeability

Abuse by inhalation following dosage form manipulation

Abuse by inhalation (smoking) is one of the most common mode of abuse. For example, 57–92% of individuals reportedly abuse extended release oxycodone by inhalation. Abuse by smoking involves subjecting the intact, crushed or milled drug product to elevated temperatures in order to vaporize the drug substance for inhalation purposes. During inhalation, drugs are transported into the body’s circulation system faster than during ingestion because the inhaled smoke travels into the lungs from which it quickly diffuses into the bloodstream. A tamper-resistant dosage form should therefore be able to prevent preferential vaporization of the drug substance from intact or milled tablets.

Vaporization of the drug substance from Sync-Loc™ tablets is not expected to occur when the tablets are heated at elevated temperatures due to the dense and hard structure of the dosage form, entrapment of the drug by one of the formulation components and immobilization of the entrapped drug within the dosage form through a unique composition and processing technique. Heating the dosage form using a cigarette lighter or candle, methods that abusers commonly use to vaporize the drug, does not bring about any change to the texture or weight of the dosage form. The entrapped drug in the dosage form has much lower vapor pressure than that of the free drug, and would require much higher heat energy to liberate the free drug from the dosage form assuming that the formulation components are thermally stable when exposed to elevated temperatures. However, it was discovered that heating the dosage form at high temperatures using, for example, an acetylene torch, leads to decomposition and charring of formulation components, which potentially liberate toxic fumes that the abuser wouldn’t be able to tolerate.

Conclusion

Based on the in vitro manipulation and extraction studies, it was found out that Sync-Loc™ tablets are resistant to all modes of tampering and hence has the potential to prevent or reduce all modes of abuse including ingestion, injection, insufflation and smoking. The technology is applicable to the development of abuse deterrent oral solid dosage forms of a wide range of abuse prone drug substances.

References

1. N. I. Drug Abuse (2016, August). Misuse of Prescription Drugs. Retrieved from National Inistitute of Drug Abuse: https://www.drugabuse.gov/publications/research-reports/ misuse-prescription-drugs/how-can-prescription-drug-misuse-be-prevented
2. N. I. Drug Abuse (2017), Opioid Crisis, www.drugabuse.gov/drugs-abuse/opioids/ opioid-crisis
3. FDA. (2017, April 21). FDA Facts: Abuse-Deterrent Opioid Medications. Retrieved from U.S. Food and Drug Administration: https://www.fda.gov/newsevents/newsroom/factsheets/ ucm514939.htm
4. (CDER), U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. (2016, May). General Principles for Evaluating the Abuse Deterrence of Generic Solid Oral Opioid Drug Products - Guidance for Industry. Retrieved from FDA: https://www.fda.gov/downloads/Drugs/ GuidanceComplianceRegulatoryInformation/Guidances/UCM492172.pdf
5. (CDER), U. D. (2015, April). Abuse-Deterrent Opioids — Evaluation and Labeling. Retrieved from www.fda.gov: https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ UCM334743.pdf
6. Kyle Simon, Stacey L. Worthy, Michael C. Barnes and Benjamin Tarbell, Abuse-deterrent formulations: transitioning the pharmaceutical market to improve public health and safety, Ther Adv Drug Saf 2015, Vol. 6(2) 67–79
7. Michael Mezher, (June 13, 2017), FDA to Take Closer Look at Abuse-Deterrent Opioids, Regulatory Affairs professional Society, http://www.raps.org/Regulatory-Focus/ News/2017/06/13/27895/FDA-to-Take-Closer-Look-at-Abuse-Deterrent-Opioids/
8. Institute for clinical and economic review (May 2017) Abuse Deterrent Formulations of Opioids: Effectiveness and Value – Draft evidence report, https://icer-review.org/wp content/uploads/2016/08/NECEPAC_ADF_Draft_Report_05.05.17.pdf
9. Maciej Gasier, Mary Bond, Richard Malamut, Routes of abuse of prescription opioid analgesics: a review and assessment of the potential impact of abuse-deterrent formulations, Journal Postgraduate Medicine, Volume 128, 2016 -Issue 1
10. Institute for clinical and economic review (May 2017) Abuse Deterrent Formulations of Opioids: Effectiveness and Value – Draft evidence report, https://icer-review.org/wp content/uploads/2016/08/NECEPAC_ADF_Draft_Report_05.05.17.pdf

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