Neuro Innovators: Reformulating Pain Therapy Products Into Potential Blockbusters
By Michael D. Becker, SVP of finance and corporate development, Relmada Therapeutics
In recent years, several older opioid drugs have been reformulated and reintroduced to the market with great commercial success due to their ability to address significant unmet medical needs in the marketplace.
One example is the class of short-acting opioids (SAOs), which were first introduced in the early 1900s and are considered appropriate treatment for different forms of transient pain such as acute, breakthrough, or chronic intermittent pain, which do not require long-lasting analgesia. Commonly prescribed SAOs include immediate-release (IR) morphine, hydromorphone, oxymorphone, codeine, fentanyl, hydrocodone, and oxycodone.
Recognizing that some patients require long-lasting analgesia, extended-release (ER), sustained-release (SR), or controlled-release (CR) formulations of SAOs including oxycodone, oxymorphone, fentanyl, and morphine have been developed to temporally extend the release of the drug into the bloodstream. These changes in formulation led to the development of long-acting opioids (LAOs) capable of producing an analgesic effect that generally lasts eight to 72 hours. Such advances in opioid formulations made them appropriate for treating chronic pain, which affects an estimated 75 million people in the United States and is the nation's leading cause of disability.
Oxycodone Reformulation
According to Purdue Pharma, oxycodone is an SAO that was introduced in the U.S. in the late 1930s and is now used in more than 50 different drug formulations manufactured by over 30 companies.
In 2000, annual U.S. OxyContin prescriptions reached 5.6 billion, and reports of OxyContin abuse and diversion rose rapidly. Abusers of the drug discovered they could circumvent the controlled-release function by crushing the pills and administering the resulting powder via oral, inhaled, or injected routes to take advantage of the high drug content in long-acting formulations. This created a new medical need and another major formulation challenge – tamper and abuse resistance.
Approved in 2010, Purdue Pharma replaced the original OxyContin formulation with a new version intended to minimize the risk of abuse, misuse, and diversion by various routes of administration (e.g., inhalation and intravenous injection). The reformulated pills were much harder, making them difficult to break apart. In addition, they didn’t burst into powder when crushed and didn’t dissolve in water.
Fentanyl Reformulation
Other examples of opioid reformulation include products based on the strong opioid fentanyl. Fentanyl is a potent, synthetic opioid analgesic with a rapid onset and short duration of action mainly due to its high lipid solubility. When ingested orally, however, fentanyl undergoes extensive first-pass metabolism, with only 20 percent escaping hepatic metabolism and entering systemic circulation. Due to this poor oral bioavailability, alternative formulations of fentanyl were explored with great success.
Fentanyl transdermal patches (Durogesic DTrans, Duragesic, Matrifen) were designed to slowly release fentanyl through the skin into the bloodstream over 48 to 72 hours. In addition, solid formulations on a stick in the form of a lollipop and/or lozenges that dissolve slowly in the mouth were also designed to provide transmucosal absorption and release fentanyl quickly into the system. However, one challenge with these lozenge formulations is that it can take 10 to 15 minutes for a patient to use one complete lozenge and those with a dry mouth (a common side effect of cancer therapy) cannot use this route. This led to the development of additional fentanyl preparations, including buccal tablets and patches, nasal sprays, and inhalers.
Recent Efforts In Opioid Reformulation
Today, several companies have been working to develop both formulations and manufacturing capabilities to improve the performance of pain medications in areas such as abuse deterrence and patient compliance. In recent years, companies including Mallinckrodt, Teva, Purdue, Collegium Pharma, Egalet Corp, KemPharm, Elite Pharmaceuticals, Relmada Therapeutics, and others, have made significant progress in advancing new formulations of various opioids, including morphine, hydrocodone, oxycodone, and levorphanol. For example, Relmada is currently at work on an oral formulation of levorphanol known as REL-1015 using a proprietary technology that supports normal drug release via oral administration while deterring recreational usage via inhalation or injection.
Other companies are paving entirely new ground as it relates to manufacturing. For instance, Egalet is pioneering the use of an injection molding technology first used in the manufacture of medical devices, including implants and diagnostics, to create a matrix and shell that makes it difficult to crush or grind oral tablets, thereby enhancing their abuse-deterrent properties.
However, advancing new formulations also comes with its own set of challenges, which have led some drug makers to hold back the release of their product or withdraw their product from the market. Pfizer’s Embeda, which is a combination of extended-release morphine sulfate with naltrexone HCl (a mu-opioid antagonist), was first approved in August 2009 but was voluntarily withdrawn from the market in March 2011 due to stability concerns in the manufacturing process. The FDA confirmed these issues were resolved with its approval of a manufacturing supplement in November 2013.
In 2004, the FDA approved an extended-release formulation of hydromorphone (Palladone, Purdue Pharma). However, within six months of Palladone’s release onto the market, overdoses associated with alcohol use were reported. Palladone was withdrawn from the market in July 2005.
Many recent examples of reformulation indicate that it is possible to significantly improve efficacy, safety and convenience in opioids in the years ahead, improving outcomes for millions of patients while also reducing or potentially eliminating the risk of abuse in the use of these products. The track record of success thus far is inspiring researchers and manufacturers to target an entirely new generation of opioids with inherent advantages based on new chemistries as well as more advanced delivery mechanisms (see Table 1).
As the current pipeline of late-stage pain therapy programs advances however, industry observers will need to watch carefully to see whether production of extended release or abuse deterrent pain products continues to face unique challenges from both a formulation and manufacturing perspective.
Table 1: Select Neuro Innovator Companies And Opioid Reformulation Programs Currently In Clinical Development
About the Author:
Michael Becker joined Relmada in November 2014. Mr. Becker brings more than 20 years of experience as a C-level industry executive and Wall Street securities analyst. Most recently, he was founder and president of the consulting firm MDB Communications LLC. Mr. Becker previously served as president, CEO, and member of the board of directors for publicly traded biotechnology companies, including commercial-stage Cytogen Corporation (acquired by EUSA Pharma). He held positions of increasing responsibility prior to being appointed president and CEO of Cytogen in 2002, including VP of business development, industry and investor relations, and CEO of AxCell Biosciences, a subsidiary of Cytogen.
References:
FDA Anesthetic and Life Support Drugs and Drug Safety and Risk, Management Advisory Committees, November 13 & 14, 2008.
Prescription Painkillers: History, Pharmacology, and Treatment By Marvin D. Seppala, Mark E. Rose
Mayo Clin Proc. 2009 Jul; 84(7): 602–612. A Comparison of Long- and Short-Acting Opioids for the Treatment of Chronic Noncancer Pain: Tailoring Therapy to Meet Patient Needs. Charles E. Argoff, MD and Daniel I. Silvershein, MD
Case Reports in Medicine. Volume 2011 (2011), Article ID 495938. Management of an Oral Ingestion of Transdermal Fentanyl Patches: A Case Report and Literature Review. Andrew C. Faust, Ralph Terpolilli, and Darrel W. Hughes