Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/47—Quinolines; Isoquinolines
  • A61K31/485—Morphinan derivatives, e.g. morphine, codeine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
  • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/04—Centrally acting analgesics, e.g. opioids
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P25/00—Drugs for disorders of the nervous system
  • A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
  • A61P25/36—Opioid-abuse

Definitions

• the disclosure is directed to sustained-release buprenorphine formulations that provide long-term, therapeutic levels of buprenorphine for the treatment of pain and the maintenance treatment of opioid use disorders, such as opioid dependence.
• 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.
• 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: ⁇ -, ⁇ -, and ⁇ -.
• Buprenorphine is a partial opioid agonist at the ⁇ -opioid receptor, hereafter referred to as the mu-opioid receptor, with antagonist properties at the ⁇ -receptor.
• buprenorphine at the mu-receptor has less maximal euphoric effect, and a ceiling on its respiratory depressant effects.
• buprenorphine By binding to mu-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.
• SUBUTEX® (buprenorphine; Indivior UK Limited) tablets, SUBOXONE® tablets (buprenorphine/naloxone; Indivior UK Limited), or SUBOXONE® film (buprenorphine/naloxone; Indivior UK Limited) 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.
• 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.
• the present disclosure is directed to sustained-release formulations of buprenorphine that provide, among other benefits, optimal buprenorphine dosages, therapeutic buprenorphine concentrations, and therapeutic opioid receptor occupancy for the treatment of opioid dependence.
• the disclosure provides a methodological approach to exploit all the information available, using comprehensive modeling approach to integrate and learn from the data generated in different studies the pharmacokinetic and PK/PD characteristics of sustained-release buprenorphine formulations. This learning has been subsequently applied to address relevant questions for the clinical development of sustained-release buprenorphine formulations.
• This strategy was implemented by initially defining a population pharmacokinetic model of buprenorphine and norbuprenorphine using data obtained in 36 opioid-dependent subjects who received Formulation D (as described herein) with 50 mg, 100 mg, or 200 mg of buprenorphine base.
• a population pharmacokinetic/ ⁇ ORO model was developed using data (buprenorphine pharmacokinetic and ⁇ ORO) collected in 15 heroin-dependent subjects (5 receiving buprenorphine daily tablet doses of 32 mg, 16 mg, 2 mg, or placebo and 10 receiving buprenorphine daily tablet dose of 16 mg).
• results of the buprenorphine population pharmacokinetic analysis were combined with results of the population pharmacokinetic/ ⁇ ORO analysis to estimate the expected ⁇ ORO after repeated subcutaneous injections of different doses of Formulation D administered once a month.
• blockade of hydromorphone agonist effects, withdrawal symptoms and plasma buprenorphine concentrations were correlated with ⁇ ORO.
• Norbuprenorphine is a major metabolite of buprenorphine and potent agonist of ⁇ , ⁇ , and ⁇ opioid receptors.
• norbuprenorphine is able to bind the mu-opioid receptors, it does not appreciable distribute to the CNS and would not affect the pharmacodynamic endpoints.
• the reasons why norbuprenorphine was included in the model is that it binds to peripheral mu-opioid receptors, with potential involvement in safety, and is important to the overall clinical development plan. In any case, considering that the norbuprenorphine concentrations were available, it was a reasonable strategy to evaluate these data in a comprehensive model for a better characterization and understanding of buprenorphine pharmacokinetics.
• the buprenorphine plasma exposure increased proportionally with dose.
• the established model was stable and described the data well.
• the covariate analysis was unable to detect any relevant impact of the demographic characteristics of the subjects enrolled in the trial, probably due to the limited sample size.
• the clinical efficacy of opioid medication assisted therapy for the treatment of opioid dependence is believed to result from a medication's ability to alleviate withdrawal symptoms, and bind mu-opioid receptors resulting in blockade of subjective agonist effects.
• a published clinical study suggests that the threshold for suppressing withdrawal and the blockade of agonist symptom effects is between 50-60% buprenorphine ⁇ ORO while additional benefit and clinical efficacy was observed at 70% ⁇ ORO (Greenwald et al, Biol Psychiatry, 61:101-110 (2007)).
• dose selection criterion was based on the selection of a dose appropriate to reaching and maintaining a ⁇ ORO greater than 70% after multiple doses.
• the population pharmacokinetic/ ⁇ ORO model fully characterized the relationship between buprenorphine plasma levels and ⁇ ORO.
• the relationship between buprenorphine plasma concentration and ⁇ ORO was best described by an E. model with EC 50 of 0.67 ng/mL and E max of 91%.
• the E max model showed a linear relationship between ⁇ ORO up to the desired 70% receptor occupancy and buprenorphine concentrations up to about 2 ng/mL.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a composition comprising from about 100 mg to about 400 mg buprenorphine to the humans once per month by injection to treat the opioid dependence.
• the composition comprises about 150 mg to about 400 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the composition comprises about 150 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the composition comprises about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the composition comprises about 180 mg to about 220 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the composition comprises about 200 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt. In one embodiment, the composition comprises about 250 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt. In one embodiment, the composition comprises about 280 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt. In one embodiment, the composition comprises about 300 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt. In one embodiment, the injection is a subcutaneous injection. In one embodiment, a month is from 28 days to 31 days. In one embodiment, a month is 28 days. In one embodiment, the method of treating opioid dependence suppresses opioid withdrawal signs and symptoms.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, di
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per month by injection to treat the opioid dependence; wherein the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in the human. In one embodiment, the method of administering the composition produces an average buprenorphine concentration of about 1 ng/mL to about 4.5 ng/mL in the human. In one embodiment, the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL in the human.
• the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 3.5 ng/mL in the human. In one embodiment, the method of administering the composition produces an average buprenorphine concentration of about 2 ng/mL to about 3 ng/mL in the human. In one embodiment, the method of administering the composition produces an average buprenorphine concentration of about 2 ng/mL to about 4 ng/mL in the human. In one embodiment, the method of administering the composition produces an average buprenorphine concentration of about 1.8 ng/mL to about 3.7 ng/mL in the human. In one embodiment, the injection is a subcutaneous injection.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1, 3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per month by injection to treat the opioid dependence; wherein the method of administering the composition produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• the method of administering the composition produces a mu-opioid receptor occupancy of at least 70%.
• the method of administering the composition produces a mu-opioid receptor occupancy of greater than 60% to about 90%.
• the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 85%.
• the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 80%. In one embodiment, the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 76%. In one embodiment, the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 75%.
• the injection is a subcutaneous injection. In one embodiment, a month is from 28 days to 31 days. In one embodiment, a month is 28 days. In one embodiment, the method of treating opioid dependence suppresses opioid withdrawal signs and symptoms.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, di
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per month by injection to treat the opioid dependence; wherein the composition comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in the human.
• the composition comprises about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL in the human.
• the injection is a subcutaneous injection.
• a month is from 28 days to 31 days.
• a month is 28 days.
• the method of treating opioid dependence suppresses opioid withdrawal signs and symptoms.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, di
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per month by injection to treat the opioid dependence; wherein the flowable composition comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• the composition comprises about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• the injection is a subcutaneous injection.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, di
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per month by injection to treat the opioid dependence in the human; wherein the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL, and a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL, and a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• the injection is a subcutaneous injection.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, di
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• the disclosure provides methods for treating opioid dependence in humans in need thereof by administering a buprenorphine composition to the humans once per by injection to treat the opioid dependence; wherein the flowable composition comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL, and a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• the composition comprises about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and wherein the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL, and a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• the injection is a subcutaneous injection.
• a month is from 28 days to 31 days.
• a month is 28 days.
• the method of treating opioid dependence suppresses opioid withdrawal signs and symptoms.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• the composition comprises, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %. In one embodiment, the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %. In one embodiment, the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1, 3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl
• the organic liquid is N-methyl-2-pyrrolidone.
• the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %. In one embodiment, the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof. In one embodiment, the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons. In one embodiment, the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer.
• the poly(DL-lactide-co-glycolide) copolymer is a 50:50 to 80:20 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer. In one embodiment, the poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• compositions that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone; wherein the composition: (a) comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in a human; or (d) a combination of two or more of (a), (b), and (
• compositions that comprises, consists essentially of, or consists of: (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 composition: (a) comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1)
• compositions that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone; wherein the composition: (a) comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1)
• compositions that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt; wherein the composition: (a) comprises about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in a human; or (d) a combination of two or more of
• buprenorphine refers to buprenorphine in the form of a free base and buprenorphine in the form of a pharmaceutically acceptable salt. In the formulations described herein, buprenorphine is preferably in the form of a free base.
• pharmaceutically acceptable salt refers to salts of buprenorphine that are prepared with relatively nontoxic acids or bases.
• Base addition salts can be obtained by contacting the neutral form of buprenorphine with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
• Acid addition salts can be obtained by contacting the neutral form of buprenorphine with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
• Examples of pharmaceutically acceptable acid addition salts include those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, maleic, malonic, benzoic, succinic, suberic, fumaric, lactic, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like.
• inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, or phosphorous acids and
• sustained-release buprenorphine formulation refers to any formulation comprising buprenorphine that can be administered parenterally (e.g., subcutaneous injection) and that can provide therapeutic levels of buprenorphine for at least 1 month.
• the “therapeutic levels” of buprenorphine provided by the sustained-release buprenorphine formulations are at therapeutic levels that are effective: (a) in the treatment of opioid use disorders, such as opioid dependence; (b) in suppressing opioid withdrawal signs and symptoms; and (c) in treating pain.
• one month means 28 days to 31 days. In one embodiment, one month is 28 days, 30 days, or 31 days. In one embodiment, one month is 28 days.
• the sustained-release buprenorphine formulation is a formulation described in U.S. Pat. No. 8,921,387 or U.S. Pat. No. 8,975,270, the disclosures of which are incorporated by reference herein in their entirety.
• the sustained-release buprenorphine formulation is a formulation described in US Publication No. 2013/0202658, the disclosure of which is incorporated by reference herein in its entirety.
• the sustained-release buprenorphine formulation is a formulation described in WO/2015/136253, the disclosure of which is incorporated by reference herein in its entirety.
• the sustained-release buprenorphine formulation is a formulation described in U.S. Pat. No.
• the sustained-release buprenorphine formulation is a formulation described in WO 2014/016428, the disclosure of which is incorporated by reference herein in its entirety.
• the sustained-release buprenorphine formulation is Formulation A.
• “Formulation A” is a flowable composition that comprises, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• the sustained-release buprenorphine formulation is Formulation B.
• “Formulation B” is a flowable composition that comprises, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the sustained-release buprenorphine formulation is Formulation C.
• “Formulation C” is a flowable composition that comprises, consists essentially of, or consists of: (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.
• the sustained-release buprenorphine formulation is Formulation D.
• “Formulation D” is a flowable composition that comprises, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having a carboxy terminal group and having an average molecular weight of about 9,000 Daltons to about 19,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• average molecular weight refers to the weight average molecular weight of a polymer as determined by gel permeation chromatography (also known as GPC or size exclusion chromatography (SEC)) using tetrahydrofuran (THF) as the solvent and using a molecular weight calibration curve using polystyrene standards.
• gel permeation chromatography also known as GPC or size exclusion chromatography (SEC)
• THF tetrahydrofuran
• the sustained-release buprenorphine formulation includes a flowable composition and an implant.
• the sustained-release buprenorphine formulation provides an in situ sustained release of buprenorphine.
• the flowable composition accomplishes the sustained release through its use to produce the implant.
• the implant has a low volume and provides a long term, therapeutic delivery of buprenorphine.
• the flowable composition enables subcutaneous formation of the implant in situ and causes little or no tissue necrosis.
• a flowable composition suitable for use in providing a sustained release implant is provided, a method for forming the flowable composition, a method for using the flowable composition, the biodegradable sustained release solid implant that is formed from the flowable composition, and a method of forming the biodegradable implant in situ.
• the flowable composition may preferably be used to provide a biodegradable microporous in situ implant in animals.
• the flowable composition is composed of a biodegradable thermoplastic polymer in combination with a biodegradable polar aprotic organic liquid and buprenorphine.
• the biodegradable thermoplastic polymer is substantially insoluble in aqueous medium and/or in bodily fluids, and biodegradable within the body of a patient.
• the flowable composition may be administered as a liquid or gel into tissue and forms an implant in situ.
• the implant may be formed ex vivo by combining the flowable composition with an aqueous medium.
• the thermoplastic polymer coagulates or solidifies to form the solid implant upon the dissipation, dispersement, or leaching of the organic liquid from the flowable composition when the flowable composition contacts a bodily fluid, an aqueous medium, or water.
• the coagulation or solidification entangles and entraps the buprenorphine so it becomes dispersed within the solid implant.
• the flowable composition is biocompatible and the polymer matrix of the implant does not cause substantial tissue irritation or necrosis at the implant site.
• the implant delivers a sustained level of buprenorphine to the patient.
• the flowable composition can be a liquid suitable for injection in a patient (e.g., human).
• the flowable composition is produced by combining buprenorphine, a biodegradable thermoplastic polymer, and a biocompatible polar aprotic organic liquid.
• the flowable composition can be administered by a syringe and needle to a patient in need of treatment.
• biodegradable means that the material is cleaved, oxidized, hydrolyzed, or otherwise broken down by hydrolytic, enzymatic, or another mammalian biological process for metabolism to chemical units that can be assimilated or eliminated by the mammalian body without causing toxicity or adverse biological reactions.
• the biodegradable, thermoplastic polymer may be made from a poly(DL-lactide-co-glycolide) having a carboxy terminal group.
• the thermoplastic polymer is typically formed by reaction of starting monomers containing the reactant groups that should form the backbone linking groups. For example, alcohols and carboxylic acids should form ester linking groups. Isocyanates and amines or alcohols should respectively form urea or urethane linking groups.
• the biocompatibility specifications of such starting monomers are known in the art.
• the thermoplastic polymers are substantially insoluble in aqueous media and body fluids, preferably completely insoluble in such media and fluids. They are also capable of dissolving or dispersing in selected organic liquids having a water solubility ranging from completely soluble in all proportions to water insoluble.
• the thermoplastic polymers also are biocompatible.
• the thermoplastic polymer in combination with the organic liquid provides a viscosity of the flowable composition that varies from low viscosity, similar to that of water, to a high viscosity, similar to that of a paste, depending on the molecular weight and concentration of the thermoplastic polymer.
• the biocompatible, biodegradable thermoplastic polymer is substantially soluble in the organic liquid so that solutions, dispersions, or mixtures up to about 50-60 wt. % solids can be made.
• the polymers are typically completely soluble in the organic liquid so that solutions, dispersions, or mixtures up to about 85-98 wt. % solids can be made.
• the polymers also are at least substantially insoluble in water so that less than about 0.1 g of polymer per mL of water should dissolve or disperse in water.
• the polymers are typically completely insoluble in water so that less than about 0.001 g of polymer per mL of water should dissolve or disperse in water.
• the flowable composition with a completely water miscible organic liquid should almost immediately transform to the solid implant.
• the molecular weight of the polymer can affect the rate of buprenorphine release from the implant. Under these conditions, as the molecular weight of the polymer increases, the rate of buprenorphine release from the formulation decreases. This phenomenon can be advantageously used in the formulation for the sustained release of buprenorphine. For faster release of buprenorphine, low molecular weight polymers can be chosen to provide the desired release rate. For release of buprenorphine over a relatively long period of time, a higher polymer molecular weight can be chosen. Accordingly, a sustained-release buprenorphine formulation can be produced with an optimum polymer molecular weight range for the release of buprenorphine over a selected length of time.
• the molecular weight of a polymer can be varied by any of a variety of methods.
• the choice of method is typically determined by the type of polymer composition.
• the molecular weight can be varied by controlled hydrolysis, such as in a steam autoclave.
• the degree of polymerization can be controlled, for example, by varying the number and type of reactive groups and the reaction times.
• thermoplastic polymers with higher molecular weight and higher inherent viscosity should provide an implant with a slower degradation rate and therefore a longer duration. Changes and fluctuations of the molecular weight of the thermoplastic polymer following the compounding of the formulation should result in the formation of an implant that shows a degradation rate and duration substantially different from the degradation rate and duration desired or predicted.
• the preferred thermoplastic biodegradable polymer of the flowable composition is a poly(lactic acid-co-glycolic acid).
• the composition can be used to formulate a once monthly sustained-release buprenorphine formulation.
• the biodegradable thermoplastic polyester can be a 50/50 to 95/5 poly(DL-lactide-co-glycolide) with or without a carboxy terminal group; preferably a 50/50 to 80/20 poly(DL-lactide-co-glycolide) having a carboxy terminal group; more preferably a 50/50 poly(DL-lactide-co-glycolide) having a carboxy terminal group.
• the organic liquid is highly soluble, and most preferably soluble at all concentrations in water, such as an organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof.
• an organic liquid which comprises an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof.
• the corresponding solubilities of the organic liquids in aqueous media and bodily fluids should tend to track the trends indicated by the water solubility. In bodily fluids, the solubilities of the organic liquids should tend to be higher than those in water.
• highly soluble organic liquids are used, they should diffuse from the sustained-release buprenorphine formulations over a period of seconds to hours.
• burst effect is a short-lived but rapid release of buprenorphine upon injection of the formulation immediately prior to formation of the implant, which then allows for a sustained-release of buprenorphine.
• the organic liquid When the organic liquid forms part of the flowable composition, it functions to enable easy injection of the sustained-release buprenorphine formulations into living tissue (preferably subcutaneous). It also facilitates transformation of the flowable composition to an in situ formed implant. Although it is not meant as a limitation of the invention, it is believed that the transformation of the flowable composition is the result of the dissipation of the organic liquid from the flowable composition into the surrounding bodily fluid and tissue and the infusion of bodily fluid from the surrounding tissue into the flowable composition. It is believed that during this transformation, the thermoplastic polymer and organic liquid within the flowable composition partition into regions rich and poor in polymer.
• Suitable polar aprotic organic liquid include, for example, those having an amide group, an ester group, a carbonate group, a ketone, an ether, a sulfonyl group, or a combination thereof.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprol
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, ethanol, or a mixture of two or more thereof. More preferably, the organic liquid is N-methyl-2-pyrrolidone.
• the solubility of the biodegradable thermoplastic polyesters in the various polar aprotic liquids should differ depending upon their crystallinity, their hydrophilicity, hydrogen-bonding, and molecular weight.
• the biodegradable thermoplastic polyesters should be soluble to the same extent in the same polar aprotic organic liquid, but each biodegradable thermoplastic polymer or copolymer should be soluble in its appropriate polar aprotic solvent.
• Lower molecular-weight polymers should normally dissolve more readily in the liquids than high-molecular-weight polymers.
• the concentration of a polymer dissolved in the various liquids should differ depending upon type of polymer and its molecular weight.
• the higher molecular-weight polymers should normally tend to coagulate or solidify faster than the very low- molecular-weight polymers. Moreover the higher molecular-weight polymers should tend to give higher solution viscosities than the low-molecular-weight materials.
• low-molecular-weight polylactic acid formed by the condensation of lactic acid should dissolve in N-methyl-2-pyrrolidone (NMP) to give about 73% by weight solution which still flows easily through a 23-gauge syringe needle, whereas a higher molecular-weight poly(DL-lactide) (DL-PLA) formed by the additional polymerization of DL-lactide gives the same solution viscosity when dissolved in N-methyl-2-pyrrolidone at about 50% by weight.
• the higher molecular-weight polymer solution coagulates immediately when placed into water.
• the low-molecular-weight polymer solution although more concentrated, tends to coagulate very slowly when placed into water.
• Formulation D is a compound containing 200 mg/mL buprenorphine base in a form suitable for subcutaneous injection and allowing for the release of buprenorphine at therapeutic levels for at least 28 days. Following administration of Formulation D, day-to-day compliance over the ensuing month would not be a potential issue as it is with existing products that are administered on a daily basis. Also, since Formulation D contains buprenorphine base in a sustained release delivery formulation, the safety profile and clinical efficacy of Formulation D are expected to be similar to that of sublingually administered buprenorphine (e.g., SUBUTEX®) and buprenorphine/naloxone treatments (e.g., SUBUXONE®).
• sublingually administered buprenorphine e.g., SUBUTEX®
• buprenorphine/naloxone treatments e.g., SUBUXONE®
• the primary goal of this study was to develop a model-based approach to rationally support and justify the dose and dosing regimen of Formulation D in Phase 2 and 3 trials.
• a modeling strategy was implemented to characterize the population pharmacokinetics of buprenorphine and norbuprenorphine (major metabolite of buprenorphine), and to assess the relationship between buprenorphine and ⁇ ORO.
• the relationship between plasma concentration, ⁇ ORO, withdrawal symptoms and attenuation (i.e., blockade) of hydromorphone challenge agonist effects was explored.
• Trial simulations were used for predicting the expected ⁇ ORO after repeated subcutaneous injections of different doses of Formulation D administered once monthly.
• the model-based approach aimed at determining the Formulation D dosage range that is expected to sustain a ⁇ ORO level of 70% and to establish the corresponding levels of withdrawal symptoms suppression and blockade of the effects of exogenously administered opioids.
• EDTA ethylenediaminetetraacetic acid
• LC-MS/MS tandem mass spectrometry
• Quantitation was performed using separate weighted (1/x 2 for buprenorphine and 1/x for norbuprenorphine) linear least squares regression analyses generated from fortified plasma calibration standards prepared immediately prior to each run.
• the method was validated for specificity, linearity, lower limit of quantitation, precision, accuracy, recovery and stability for a range of 0.0250 to 5.0 ng/mL for buprenorphine and 0.0200 to 4.00 ng/mL for norbuprenorphine based on the analysis of 0.500 mL of plasma.
• the overall precision for both analytes was better than 6.3%; the overall accuracy was within ⁇ 10.3%.
• the recoveries for both analytes and internal standards were above 80%.
• the established short-term and long-term stability covered the maximum sample storage time (methods unpublished).
• the first-order conditional estimation with interaction method was used for estimating the fixed and random effect parameters using a non-linear-mixed effect approach.
• Appropriateness of the model was evaluated using various goodness-of-fit criteria, including diagnostic scatter plots, likelihood-ratio-test (LRT), and measures of model stability and adequacy (successful convergence, significant digits, matrix singularity).
• LRT likelihood-ratio-test
• the results for LRT were considered statistically significant if decreases in the objective function value (OFV) of nested models were more than 3.84 (P ⁇ 0.05, 1 degree of freedom) throughout the model building process.
• the inter-individual variability (IIV) on all the model parameters was assumed log-normally distributed.
• the residual variability which was comprised of, but not limited to intra-individual variability, experimental errors, process noise and/or model misspecifications, was modeled using additive, proportional, and combined error structures.
• An outlier was defined as an aberrant observation that significantly deviates from the rest of observations in a particular individual and did not refer to a subject as an outlier.
• the proportion of outliers in a dataset should be low and such points may be excluded from the analysis given the potential for these observations to negatively impact the convergence and/or parameter estimates (i.e., which may cause a bias) (Food and Drug Administration (1999).
• Guidance for Industry Population Pharmacokinetics. http://www.fda.gov/downloads/drugs/guidances/UCM072137.pdf. Accessed 16 Dec. 2013).
• Outlier detection was based initially on visual examination of individual and pooled pharmacokinetic profiles.
• absolute conditional weighted residual
• the CWRES are weighted residuals calculated using the FOCE method and have been shown to represent a reliable estimate of the distribution of residuals (Hooker et al, Pharm Res, 24(12):2187-2197 (2007)). Given the theoretical distribution of CWRES, it is expected that 99.73% of the CWRES should lie in the interval ⁇ 3, 3; for this reason, values outside this interval were considered as outliers.
• Buprenorphine is metabolized primarily by cytochrome P450 3A4 to norbuprenorphine. Buprenorphine undergoes extensive first pass in the liver, thus it is administered sublingually with 50% to 60% bioavailability. The population pharmacokinetic model was developed to describe simultaneously the concentrations of buprenorphine and norbuprenorphine.
• a covariate model using age, sex, race, and dose was built using a step-wise process consisting of a forward and a backward selection procedure.
• the LRT was used to evaluate the significance of incorporating or removing fixed effects in the population model based on alpha levels that were set a priori.
• each covariate was individually included in the base model.
• a covariate was retained in the model if a reduction in the objective function value (OFV) was ⁇ 3.84 ( ⁇ 2 ⁇ 0.05).
• OFV objective function value
• a covariate was retained in the model if, upon removal, the OFV increased by more than 6.64 points ( ⁇ 2 ⁇ 0.001).
• a non-parametric bootstrap resampling method was used to evaluate the stability and robustness of the final pharmacokinetic model (Parke et al, Comput Meth Prog Biomed, 59:19-29 (1999)). Resampling with replacement generated 100 bootstrap data sets and the final population pharmacokinetic model was fitted repeatedly to each of the 100 bootstrap data sets. The median and 95% confidence intervals of parameters obtained from this step were compared with the final parameter estimates. In addition, a VPC was also performed. Results from the VPC were assessed using graphical comparison of the appropriate 90% prediction intervals from simulated data with overlaid observed data from the original dataset.
• the medication assisted treatment of opioid dependence is related to the opioid pharmacotherapy occupying brain mu-opioid receptors.
• the level of receptor occupancy is expected to mediate the abuse and dependence potential of opioids and to predict clinical efficacy.
• higher medication doses are hypothesized to decrease mu-opioid receptor availability (or “binding potential”) and provide agonist replacement that minimizes withdrawal symptoms and prevents the reinforcing, euphoric, and other effects of abused opioids resulting greater clinic attendance (Greenwald et al, Neuropsychopharmacology, 28:2000-2009 (2003).
• Opioid withdrawal symptoms are the body's physical response to the absence of the opioid, which include muscle aches, restless anxiety, diarrhea, abdominal cramping, nausea and vomiting.
• the experimental individual values for buprenorphine plasma concentrations, ⁇ ORO, opioid withdrawal syndrome, and opioid-like agonist effects were provided from two published clinical trials.
• 5 heroin-dependent subjects underwent buprenorphine induction from 4 mg/day on Day 1 to 16 mg/day by Day 7 and were maintained at 32 mg/day for 12 days.
• subjects were challenged with the opioid agonist hydromorphone and subjective drug effects were ascertained, and on Day 9, blood samples for the measurement of buprenorphine and norbuprenorphine were collected following buprenorphine administration.
• opioid withdrawal symptoms were measured prior to buprenorphine administration and 1, 2, 3, 6, and 12 hours afterwards.
• a positron emission tomography (PET) scan with [ 11 ]-carfentanil was administered 4 hours after buprenorphine administration to measure ⁇ ORO.
• Subjects were titrated down to the subsequent maintenance periods at buprenorphine doses of 16 mg/day for 12 days, 2 mg/day for 12 days, and to 0 mg/day for 12 days.
• subjects underwent the hydromorphone challenge, measurement of opioid withdrawal symptoms, and a PET scan (Greenwald et al, Neuropsychopharmacology, 28:2000-2009 (2003)).
• opioid agonist and withdrawal symptoms were assessed by using an Opioid Symptom Questionnaire with 16 agonist and 16 withdrawal scale items. Each item was scored from 0 (not at all) to 4 (extremely), yielding total scores ranging from 0 to 64.
• Buprenorphine attenuation (blockade) of hydromorphone agonist effects was measured by six visual analog scales (VAS) ratings including: any drug effect, high, good drug effect, bad drug effect, stimulated, and sedated (Greenwald et al, Neuropsychopharmacology, 28:2000-2009 (2003); Greenwald et al, Biol Psychiatry, 61:101-110 (2007). From both trials, whole brain imaging results were used to calculate receptor ⁇ OR availability. Percent ⁇ ORO was calculated as (100 minus mu-opioid receptor availability).
• the analysis dataset included 36 subjects for a total of 2797 observations with 66 observations below the lower limit of quantification. These values were considered as missing in the NONMEM analysis.
• the buprenorphine and norbuprenorphine measurements were simultaneously fitted using the ADVAN5 TRANS 1 routine in NONMEM.
• the absorption of Formulation D from the subcutaneous injection site was described by a dual model that was described by a first-order absorption process associated with the rapid absorption and the first observed peak; and a delayed delivery process that was described by a transit compartment absorption model to mimic the sustained-release components of Formulation D (Savic et al, J Pharmacokinet Pharmacodyn, 34:711-726 (2007).
• the disposition model was a one-compartment model with a first-order elimination, and first-order conversion to norbuprenorphine. This metabolite was subsequently distributed in a peripheral compartment and eliminated according to a first-order process.
• the new analysis dataset included 36 subjects for a total of 2,769 observations.
• the buprenorphine and norbuprenorphine concentrations were again simultaneously fitted using the ADVAN5 TRANS 1 routine in NONMEM.
• the residual error model included a combined additive (Add Err) and proportional components with a different proportional component for buprenorphine (Prop Err BUP) and for norbuprenorphine (Prop Err NorBUP). The results of this analysis were considered as the final model.
• Empirical Bayesian estimates of individual parameters and random effects were obtained from the base model in the NONMEM analysis.
• the relationships between individual model parameters and the selected covariates were evaluated graphically. Inspection of the generated plots indicated a potential impact of sex on the volume of distribution for the central norbuprenorphine compartment V 3 .
• This hypothesis was formally tested by incorporating sex as covariate of V 3 in the model.
• the resulting objective function did not show a significant change with respect to the base model.
• Equation 1 A saturable E max model with an additive error model was used for describing the relationship between buprenorphine plasma concentrations and ⁇ ORO as shown in Equation 1:
• Cp is buprenorphine plasma concentration
• EC 50 is buprenorphine plasma concentration expected to achieve 50% of the maximal ⁇ ORO (E.).
• E. maximal ⁇ ORO
• This model was developed assuming a direct relationship between plasma concentration and ⁇ ORO without equilibration delay. This model assumes that the metabolite norbuprenorphine has negligible activity with respect to brain ⁇ ORO.
• the analysis dataset ( ⁇ ORO and buprenorphine pharmacokinetic sampling) included 15 subjects with a total of 59 pharmacokinetic/ ⁇ ORO data. The modeling was performed using the FOCE-I method as implemented in the NONMEM software.
• the estimated value for E max was 91.4% (3.94) and the estimated value for EC 50 (standard error) was 0.67 (0.19) (ng/mL).
• the inter-individual variability of E max was not estimated due to the limited number of measures available in the proximity of the estimated E max value.
• the adequacy of the final model was evaluated using the visual predictive check method. Four-hundred replicates of the original dataset were simulated based on the final model, and a 90% prediction interval was computed based on the simulated datasets. The observed ⁇ ORO versus the buprenorphine concentration data were plotted on the prediction interval to visually assess the concordance between the simulated and observed data. Statistics of interest including the median were calculated from the simulated and observed data for comparison.
• Regression models were used to describe relationships between mean hydromorphone induced changes in agonist symptoms, mean withdrawal symptom scores, or mean buprenorphine plasma concentrations each with respect to the mean mu-opioid receptor availability. These data suggest that at a mean buprenorphine plasma concentration of 2 ng/mL is able to provide the desired 70% ⁇ -opioid receptor occupancy. The same conditions are associated with low reported agonist drug effects and withdrawal symptoms (scores ⁇ 2). For the treatment of opioid dependence, the positive clinical outcomes are free of withdrawal, cravings and the drug-induced highs and lows of addiction. The individuals who exhibit greater ⁇ ORO and more suppression of withdrawal symptoms experience better treatment outcomes (Greenwald et al, Imaging opioid receptors: applications to substance use disorders.
• the simulated drug concentrations of buprenorphine and norbuprenorphine after repeated subcutaneous injections of Formulation D were derived from the final model parameter estimates.
• the 400 hypothetical subjects received 4 subcutaneous injections of Formulation D containing 50 mg, 100 mg buprenorphine, 200 mg buprenorphine, or 300 mg buprenorphine doses separated by 28 days.
• the objective of this simulation was to predict buprenorphine plasma concentrations after multiple doses of Formulation D and to consequently predict the corresponding ⁇ ORO. Simulation indicated that the desired >70% receptor occupancy may be achieved after multiple doses of Formulation D containing 200 mg buprenorphine.
• PK/PD pharmacokinetic/pharmacodynamics
• a population pharmacokinetic model was developed using 36 opioid-dependent subjects who received single subcutaneous doses of Formulation D.
• Another PK/PD model was developed using ⁇ -opioid receptor occupancy data to predict efficacy of Formulation D after repeated doses. It was also assessed how buprenorphine plasma concentrations were correlated to opioid withdrawal symptoms and hydromorphone agonist blockade data from 15 heroin-dependent subjects.
• E max saturable maximum effect
• Example 3 was performed to assess Formulation D (containing 300 mg buprenorphine) blockade of hydromorphone-induced subjective and reinforcing effects, and to determine the accuracy of the modeling presented in Example 1 and 2 in a clinical setting.
• Formulation D blocked hydromorphone subjective and reinforcing effects from weeks 1-12.
• ⁇ -opioid receptors occupancy was based on a previously developed PK/PD model (Nasser et al, Clin Pharmacokinet, 2014).
• Modeling and simulation showed that a 300 mg dose of Formulation D every 28 days was appropriate for immediately achieving an effective exposure after the first SC injection and could maintain effective levels of exposure during chronic treatment. Furthermore, simulations indicated that in the unexpected event of two-week holiday the levels of ⁇ ORO remained consistently above 80% with no significant loss of drug efficacy. The results of the analysis provided quantitative criteria for effective clinical dose selection and showed that a two-week drug holiday did not result in a loss of drug efficacy.
• a method for treating opioid dependence in a human in need thereof including administering a composition including from about 100 mg to about 400 mg buprenorphine to the human once per month by injection to treat the opioid dependence.
• composition includes about 150 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• Embodiment 1 wherein the composition includes about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition includes about 180 mg to about 220 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition includes about 200 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition includes about 250 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• Embodiment 1 wherein the composition includes about 280 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition includes about 300 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per month by injection to treat the opioid dependence; wherein the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 1 ng/mL to about 4.5 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 3.5 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 2 ng/mL to about 3 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 2 ng/mL to about 4 ng/mL in the human.
• Embodiment 9 wherein the method of administering the composition produces an average buprenorphine concentration of about 1.8 ng/mL to about 3.7 ng/mL in the human.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per month by injection to treat the opioid dependence; wherein the method of administering the composition produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of at least 70%.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of greater than 60% to about 90%.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 85%.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 80%.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 76%.
• Embodiment 16 wherein the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 75%.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per month by injection to treat the opioid dependence; wherein the composition includes about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in the human.
• Embodiment 23 wherein the composition includes about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL in the human.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per month by injection to treat the opioid dependence; wherein the flowable composition includes about 100 mg to about 400 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• Embodiment 25 wherein the composition includes about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per month by injection to treat the opioid dependence in the human; wherein the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL, and a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• Embodiment 27 wherein the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL, and a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• a method for treating opioid dependence in a human in need thereof including administering a buprenorphine composition to the human once per by injection to treat the opioid dependence; wherein the flowable composition includes about 100 mg to about 400 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and the method of administering the composition produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL, and a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in the human.
• Embodiment 29 wherein the composition includes about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt; and wherein the method of administering the composition produces an average buprenorphine concentration of about 1.5 ng/mL to about 4 ng/mL, and a mu-opioid receptor occupancy of about 65% to about 80% in the human.
• the buprenorphine composition is a flowable composition that includes, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone.
• composition includes, consists essentially of, or consists of: (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.
• the buprenorphine composition is a flowable composition that includes, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone.
• the buprenorphine composition is a flowable composition that includes, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which includes an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• Embodiment 39 wherein the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 10 wt % and about 25 wt %.
• Embodiment 38 wherein the buprenorphine in the form of a free base or pharmaceutically acceptable salt is present in the flowable composition in an amount between about 15 wt % and about 20 wt %.
• Embodiment 38 wherein the organic liquid is present in the composition in an amount of about 30 wt % to about 70 wt %.
• Embodiment 38 wherein the organic liquid is present in the composition in an amount of about 40 wt % to about 60 wt %.
• Embodiment 38 wherein the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene glycol, ethanol, acetone, tetrahydrofurfuryl alcohol, dimethyl isosorbide, acetic acid, lactic acid, methyl lactate, ethyl lactate, monomethyl succinate acid, monomethyl citric acid, glycofurol, glycerol formal, isopropylidene glycol, 2,2-dimethyl-1,3-dioxolone-4-methanol, dimethylformamide, dimethylacetamide, N,N-dimethylformamide, propylene carbonate, triacetin, dimethylsulfoxide, dimethylsulfone, epsilon-caprolactone, butyrolactone, caprolactam, and a mixture of two or more thereof.
• the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, propylene glycol, polyethylene
• Embodiment 38 wherein the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, ethanol, or a mixture of two or more thereof.
• Embodiment 38 wherein the biodegradable thermoplastic polymer is present in the composition in an amount of about 10 wt % to about 60 wt %.
• Embodiment 38 wherein the biodegradable thermoplastic polymer is present in the composition in an amount of about 20 wt % to about 40 wt %.
• Embodiment 38 wherein the polymer is a polylactide, a polyglycolide, a polycaprolactone, a copolymer thereof, a terpolymer thereof, any combination thereof, or a mixture of two or more thereof.
• Embodiment 38 wherein the polymer is a poly(DL-lactide-co-glycolide) copolymer.
• Embodiment 38 wherein the polymer has an average molecular weight of about 5,000 Daltons to about 40,000 Daltons.
• Embodiment 38 wherein the polymer has an average molecular weight of about 5,000 Daltons to about 30,000 Daltons.
• Embodiment 38 wherein the polymer has an average molecular weight of about 5,000 Daltons to about 20,000 Daltons.
• Embodiment 38 wherein the polymer has an average molecular weight of about 10,000 Daltons to about 20,000 Daltons.
• poly(DL-lactide-co-glycolide) copolymer is a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight from about 5,000 Daltons to about 20,000 Daltons.
• a flowable composition that includes, consists essentially of, or consists of: (i) about 18 wt % buprenorphine in the form of the free base; (ii) about 32 wt % of a 50:50 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 25,000 Daltons; and (iii) about 50 wt % of N-methyl-2-pyrrolidone; wherein the composition includes about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt.
• a flowable composition that includes, consists essentially of, or consists of: (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 composition: (a) includes about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than
• a flowable composition that includes, consists essentially of, or consists of: (i) about 10 wt % to about 30 wt % buprenorphine in the form of the free base; (ii) about 10 wt % to about 60 wt % of a 50:50 to 95:5 poly(DL-lactide-co-glycolide) copolymer having an average molecular weight of about 5,000 Daltons to about 40,000 Daltons; and (iii) about 30 wt % to about 70 wt % of N-methyl-2-pyrrolidone; wherein the composition: (a) includes about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than
• a flowable composition that includes, consists essentially of, or consists of: (i) at least one biodegradable thermoplastic polymer; (ii) at least one organic liquid which includes an amide, an ester, a carbonate, a ketone, a lactam, an ether, a sulfonyl, or a combination thereof; and (iii) about 5 wt % to about 30 wt % of buprenorphine in the form of a free base or pharmaceutically acceptable salt; wherein the composition: (a) includes about 100 mg to about 400 mg buprenorphine in the form of a free base or a pharmaceutically acceptable salt; (b) produces an average buprenorphine concentration of about 0.5 ng/mL to about 5 ng/mL in a human; (c) produces a mu-opioid receptor occupancy (as measured by a maximum effect model of Equation 1) greater than 60% in a human; or (d) a combination of two or more of (a
• composition of any of Embodiments 58-61 wherein the composition includes about 150 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 180 mg to about 320 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 180 mg to about 220 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 200 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 250 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 280 mg to about 350 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 58-61 wherein the composition includes about 300 mg buprenorphine in the form of a free base or pharmaceutically acceptable salt.
• composition of any of Embodiments 61-68, wherein the organic liquid is N-methyl-2-pyrrolidone, 2-pyrrolidone, N,N-dimethylformamide, dimethyl sulfoxide, propylene carbonate, caprolactam, polyethylene glycol, ethanol, or a mixture of two or more thereof.

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