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US-12622904-B2 - Buprenorphine dosing regimens

US12622904B2US 12622904 B2US12622904 B2US 12622904B2US-12622904-B2

Abstract

The disclosure provides a dosage regimen using sustained-release buprenorphine formulations to produce therapeutic levels of buprenorphine in patients for the treatment of pain or opioid use disorders.

Inventors

  • Azmi NASSER
  • Celine M. Laffont
  • Christian A. HEIDBREDER

Assignees

  • INDIVIOR UK LIMITED

Dates

Publication Date
20260512
Application Date
20250320

Claims (9)

  1. 1 . A method of treating moderate to severe opioid use disorder in an opioid-dependent human, the method comprising: (a) administering to said opioid-dependent human, by subcutaneous injection once per month for a period of one to three months, a first composition comprising: (i) about 14 wt % to about 22 wt % buprenorphine in the form of the free base; (ii) about 22 wt % to about 42 wt % of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt % to about 60 wt % of N-methyl-2-pyrrolidone; and (b) administering to said opioid-dependent human, by subcutaneous injection once per month beginning one month after the last dose of the first composition, a second composition comprising: (i) about 14 wt % to about 22 wt % buprenorphine in the form of the free base; (ii) about 22 wt % to about 42 wt % of a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 30,000 Daltons; and (iii) about 40 wt % to about 60 wt % of N-methyl-2-pyrrolidone, wherein the amount of buprenorphine in (a)(i) is greater than the amount of buprenorphine in (b)(i).
  2. 2 . The method according to claim 1 , wherein the amount of buprenorphine in (a)(i) is about 250 mg to about 350 mg.
  3. 3 . The method according to claim 2 , wherein the amount of buprenorphine in (b)(i) is about 80 mg to about 120 mg.
  4. 4 . The method according to claim 1 , wherein the amount of buprenorphine in (b)(i) is about 80 mg to about 120 mg.
  5. 5 . The method according to claim 1 , wherein the amount of buprenorphine in (b)(i) is about 300 mg.
  6. 6 . The method according to claim 1 , wherein the amount of buprenorphine in (b)(i) is 300 mg.
  7. 7 . The method according to claim 1 , wherein the amount of buprenorphine in (b)(i) is about 100 mg.
  8. 8 . The method according to claim 2 , wherein the amount of buprenorphine in (b)(i) is about 100 mg.
  9. 9 . The method according to claim 2 , wherein the amount of buprenorphine in (b)(i) is about 300 mg.

Description

CROSS-REFERENCES TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/985,253 filed Nov. 11, 2022, which is a continuation of U.S. application Ser. No. 17/217,914 filed Mar. 30, 2021, now U.S. Pat. No. 11,839,611, which is a continuation of U.S. application Ser. No. 15/523,986, a National Stage of PCT/IB2015/002269 filed Nov. 6, 2015, now U.S. Pat. No. 11,000,520, which claims priority to U.S. Application No. 62/076,854 filed Nov. 7, 2014, U.S. Application No. 62/100,391 filed Jan. 6, 2015; U.S. Application No. 62/112,546 filed Feb. 5, 2015, and U.S. Application No. 62/199,778 filed Jul. 31, 2015, the disclosures of all of which are incorporated by reference herein in their entirety. BACKGROUND The disclosure is directed to dosing regimens for sustained-release buprenorphine formulations that provide sustained therapeutic levels of buprenorphine and μ-opioid receptor occupancy for the treatment of pain and opioid use disorders. Opioid addiction is a neurobehavioral syndrome characterized by the repeated, compulsive seeking and use of an opioid despite adverse social, psychological, and/or physical consequences. Opioid addiction is a problem with high costs to individuals, families, and society. The use of prescription opioids has tremendously increased in the past decade in the United States (from 174 million in 2000 to 257 million in 2009) due to the widespread availability and variety of prescription opioid products, and changes in treatment paradigms. Opioid abuse, addiction, overdose, and other health and social consequences of opioid misuse are taking a rapidly growing toll on individuals and institutions in the United States. It is estimated that 2.2 to 2.4 million individuals initiate non-medical use of opioids in the United States each year and non-medical opioid use now exceeds use of many conventional street drugs, including cocaine and heroin. Overdose deaths from prescription drugs have exceeded those from street drugs since 2002 and have surpassed traffic accidents as a cause of accidental death. In 2011, over 1,252,500 of 2.5 million emergency department (ED) visits associated with drug abuse or addiction involved illicit drugs, including 258,482 ED visits related to heroin and about 420,040 ED visits related to narcotic pain relievers. Opioid receptors are located in both the central nervous system (CNS) and the periphery. In the CNS, they are found in high concentrations in the limbic system and the spinal cord. The natural ligands for the opioid receptors are a group of neuropeptides known as endorphins. Opioid analgesics mimic the action of these natural ligands, but have a more prolonged action as they are not subject to rapid local metabolism. Three major opioid receptor subclasses have been identified: μ-, κ-, and δ-. Buprenorphine is a partial opioid agonist at the μ-opioid receptor, with antagonist properties at the κ-receptor. In contrast to a full agonist, buprenorphine at the μ-receptor has less maximal euphoric effect, and a ceiling on its respiratory depressant effects. By binding to μ-opioid receptors in the brain, buprenorphine reduces craving for opioids and opiate withdrawal symptoms, minimizing the need of opioid-dependent patients to use illicit opiate drugs. For the maintenance treatment of opioid dependence, SUBUTEX® (buprenorphine; Indivior PLC), SUBOXONE® tablets (buprenorphine/naloxone; Indivior PLC), or SUBOXONE® film (buprenorphine/naloxone; Indivior PLC) may be given as a single daily dose ranging from 4 to 24 mg per day, with the recommended dosage being 16 mg buprenorphine per day. A major issue in the pharmacological treatment of opioid dependence is the high rate of non-adherence. Currently, there is no approved parenterally-administered, sustained-release buprenorphine product indicated for the treatment of opioid dependence. Such a product could offer advantages over existing buprenorphine pharmacotherapy by improving patient compliance and reducing diversion, abuse, and unintended exposure, particularly regarding children. To this end, the present disclosure is directed to dosing regimens for sustained-release formulations of buprenorphine that provide, among other benefits, optimal buprenorphine dosages, therapeutic buprenorphine concentrations, and therapeutic μ-opioid receptor occupancy for the treatment of opioid dependence or pain. SUMMARY The disclosure provides dosing regimens for treating opioid dependence or pain in a human in need thereof including the steps of: (a) administering a first composition including a dose of buprenorphine to the human once per month by injection for one month, two months, or three months; and thereafter (b) administering a second composition including a dose of buprenorphine to the human once per month by injection beginning with the second month, third month, or fourth month of administration, respectively, and for each month thereafter; to treat the opioid dependence or pain; wherei