US 2010.0260834A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0260834 A1 Hirsh et al. (43) Pub. Date: Oct. 14, 2010 (54) ABUSE-DETERRENT DRUG A69/48 (2006.01) FORMULATIONS A6IP 25/04 (2006.01) (75) Inventors: Jane C. Hirsh, Wellesley, MA (52) U.S. Cl. ......... 424/451; 514/282; 424/490; 424/498: (US); Alison B. Fleming, 424/491; 424/493 Mansfield, MA (US); Roman V. Rariy, Philadelphia, PA (US); (57) ABSTRACT Alexander M. Klibanov, Boston, MA (US) An abuse-deterrent pharmaceutical composition has been developed to reduce the likelihood of improper administra Correspondence Address: tion of drugs, especially drugs such as opiods. In the preferred Pabst Patent Group LLP embodiment, the drug is modified to increase its lipophilicity 1545 PEACHTREE STREET NE, SUITE 320 by forming a salt between the drug and one or more fatty acids ATLANTA, GA 30309 (US) wherein the concentration of the one or more fatty acids is one to 15 times the molar amount of the active agent, preferably (73) Assignee: Collegium Pharmaceutical, Inc. two to ten times the molar amount of the active agent. In one embodiment the modified drug is homogeneously dispersed (21) Appl. No.: 12/823,628 within microparticles composed of a material that is either slowly soluble or not soluble in water. In some embodiments (22) Filed: Jun. 25, 2010 the drug containing microparticles or drug particles are coated with one or more coating layers, where at least one Related U.S. Application Data coating is water insoluble and preferably organic solvent (63) Continuation of application No. 1 1/149.867, filed on insoluble. The abuse-deterrent composition prevents the Jun. 10, 2005, now Pat. No. 7,771,707. immediate release of a Substantial portion of drag, even if the physical integrity of the formulation is compromised (for (60) Provisional application No. 60/579,191, filed on Jun. example, by chopping with a blade or crushing) and the 12, 2004. resulting material is placed in water, Snorted, or Swallowed. However, when administered as directed, the drug is slowly Publication Classification released from the composition as the composition is broken (51) Int. C. down or dissolved gradually within the GI tract by a combi A 6LX 9/50 (2006.01) nation of enzymatic degradation, Surfactant action of bile A6 IK 3/485 (2006.01) acids, and mechanical erosion. Patent Application Publication Oct. 14, 2010 Sheet 1 of 2 US 2010/0260834 A1 6/7/p9.//7s09/// Ç//3//D3S03/9/ S////// |OHNO Sunou21ÁqpasD3|94%,O6:436IDL• Patent Application Publication Oct. 14, 2010 Sheet 2 of 2 US 2010/0260834 A1 Sorted by Decending Fatty Acid MW (OLO<r.fr)(\]?• I?------ EGOET |-ZZZZZZZZZZZZZZZZZNo.=NNNNNNNNNNNNNNNNNNNNNNN |ZZZZZZZZZZZZZZZZZNNNNNNNNNNNNNNNN 444444444444444ZZZZZZZZ C)OC)OOOO l:9I‘OIHVELS l:GL'OILIWTV'd 2:GI‘OLSIHAW 2:G:['OIMJnºT 2 STEROTExL-I-III-leae, K BEES WAX N CAMAUBA O NO ADDITIONAL WAX A/6. 2 US 2010/0260834 A1 Oct. 14, 2010 ABUSE-DETERRENT DRUG 0005. In recent years, there have been numerous reports of FORMULATIONS Oxycodone diversion and abuse in several states. For example, DEA's Office of Diversion Control reported 700 CROSS-REFERENCE TO RELATED OxyContin R thefts in the U.S. between January 2000 and APPLICATIONS June 2001. Some of these reported cases have been associated with serious consequences including death. 0001. This application claims priority under 35 U.S.C. 0006. Oxycodone is a controlled substance in Schedule II S119 to U.S. Provisional Application No. 60/579,191, filed of the Controlled Substances Act (CSA), which is adminis Jun. 12, 2004 entitled “Abuse-Deterrent Drug Formulations'. tered by the Drug Enforcement Administration (DEA). Despite the fact that Schedule II provides the maximum FIELD OF THE INVENTION amount of control possible under the CSA for approved drug 0002 The present invention is generally in the field of products, in practice, it is difficult for law enforcement agen pharmaceutical compositions, specifically compositions cies to control the diversion or misuse of legitimate prescrip tions. Although abuse, misuse, and diversion are potential designed to reduce the potential for improper administration problems for all opioids, including Oxycodone, opioids are a of drugs that are Subject to abuse. very important part of the medical arsenal for the manage ment of pain when used appropriately under the careful Super BACKGROUND OF THE INVENTION vision of a physician. 0003 Oxycodone, morphine, and other opioid analgesics 0007 Currently available formulations for such drugs are are therapeutically useful and effective medications, e.g., as designed for oral administration but do not include mecha pain killers, when administered orally. Unfortunately, they nisms to prevent or retard improper methods of administra also pose a severe threat for willful abuse due to their ability tion Such as chewing, injection and Snorting. This represents to alter mood and/or cause a sense of euphoria. Currently a serious problem given the large number of legitimate pre available Sustained release formulations of such drugs, which scriptions written in the U.S.; for example, the medical use of contain a relatively large amount of drug intended to be opioids within the U.S. increased 400% from 1996 to 2000. released from the formulation over an extended period of The problems with abuse are significant and longstanding, time, are particularly attractive to abusers since the Sustained and efforts to design new abuse-resistant or abuse-deterrent release coating can be destroyed by crushing or grinding the formulations have been largely unsuccessful. U.S. Pat. Nos. formulation. The crushed material no longer controls the 3,980,766, 4,070,494 and 6,309,668 describe formulations release of drug. Depending on the drug, abusers can then (1) designed to prevent the injection of compositions meant for snort the material, (2) swallow the material or (3) dissolve the oral administration. U.S. Pat. No. 3,980,766 describes the material in water and Subsequently inject it intravenously. incorporation of an ingestible solid which causes a rapid The dose of drug contained in the formulation is thus increase in Viscosity upon concentration of an aqueous solu absorbed immediately through the nasal or GI mucosa (for tion thereof. U.S. Pat. No. 4,070,494 describes the incorpo Snorting or Swallowing, respectively) or is administered sys ration of a non-toxic, water gelable material in an amount temically in a bolus via the circulatory system (for IV injec Sufficient to render the drug resistant to aqueous extraction. tion). These abuse methods result in the rapid bioavailability U.S. Pat. No. 6,309,668 describes a tablet for oral adminis of relatively high doses of drug, giving the abuser a "high”. tration containing two or more layers comprising one or more Since relatively simple methods (crushing, grinding, chewing drugs and one or more gelling agents within separate layers of and/or dissolution in water) can be used to transform Such the tablet. The resulting tablet forms a gel when combined formulations into an abusable form, they provide virtually no with the volume of water necessary to dissolve the drug; this deterrent to a potential abuser. formulation thus reduces the extractability of the drug from 0004 For example, the FDA recently strengthened the the tablet. It should be noted that although these compositions warnings and precautions sections in the labeling of OxyCon preclude abuse by injection, this approach fails to prevent tin R (oxycodone HC1 controlled-release) tablets, a narcotic abuse by crushing and Swallowing or Snorting the formula drug approved for the treatment of moderate to severe pain, tion, which are commonly reported methods of abuse associ because of continuing reports of abuse and diversion. Oxy ated with OxyContin R. ContinR contains oxycodone HCl (available in 10, 20, 40 and 0008 U.S. Pat. Nos. 3,773.955 and 3,966,940 describe 80 mg strengths), an opioid agonist with an addiction poten formulations containing a combination of opioid agonists and tial similar to that of morphine. Opioid agonists are Sub antagonists, in which the antagonist does not block the thera stances that act by attaching to specific proteins called opioid peutic effect when the admixture is administered orally, but receptors, which are found in the brain, spinal cord, and which does not produce analgesia, euphoria or physical gastrointestinal tract. When these drugs attach to certain dependence when administered parenterally by an abuser. opioid receptors in the brain and spinal cord they can effec U.S. Pat. No. 4,457.933 describes a method for decreasing tively block the transmission of pain messages to the brain. both the oral and parenteral abuse potential of strong analge OxyContin R is supplied in a controlled-release dosage form sic agents by combining an analgesic dose of the analgesic and is intended to provide up to 12 hours of relief from agent with an antagonist in specific, relatively narrow ratios. moderate to severe pain. The warning specifically states that U.S. Pat. Nos. 6,277,384, 6,375,957 and 6,475,494 describe the tablet must be taken whole and only by mouth. When the oral dosage forms including a combination of an orally active tablet is chewed or crushed and its contents are swallowed, opioidagonist and an orally active opioidantagonist in a ratio Snorted into the nostrils or dissolved and Subsequently that, when delivered orally, is analgesically effective but that injected intravenously, the controlled release mechanism is is aversive in a physically dependent subject. While such a destroyed and a potentially lethal dose of oxycodone formulation may be successful in deterring abuse, it also has becomes bioavailable. the potential to produce adverse effects in legitimate patients. US 2010/0260834 A1 Oct.