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EP-3735239-B1 - ORAL CANNABINOID RECEPTOR MODULATOR FORMULATIONS

EP3735239B1EP 3735239 B1EP3735239 B1EP 3735239B1EP-3735239-B1

Inventors

  • FOSS, JOSEPH
  • ATTALA, MOHAMED NAGUIB

Dates

Publication Date
20260506
Application Date
20190107

Claims (10)

  1. A pharmaceutical composition comprising a spray dried dispersion suitable for oral administration, the spray dried dispersion comprising a compound having the formula: or a salt thereof, and hydroxypropyl methylcellulose acetate succinate subtype M (HPMCAS-M), wherein the ratio of the compound to HPMCAS-M in the spray dried dispersion is 1:3 by weight.
  2. Composition according to claim 1 for use in the treatment of a cannabinoid receptor-mediated disease.
  3. Composition according to claim 1 for use in the treatment of neuropathic pain.
  4. Composition according to claim 1 for use in the treatment of addiction.
  5. Composition according to claim 1 for use in enhancing learning, cognition and/or memory, regulating cell growth, providing neuroprotection.
  6. Composition according to claim 1 for use in the treatment of cancer.
  7. Composition according to claim 1 for use in the treatment of melanoma, lymphoma or glioma.
  8. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition further comprises one or more excipients.
  9. The pharmaceutical composition of claim 1, wherein the pharmaceutical composition is a tablet or capsule.
  10. The pharmaceutical composition of claim 9, wherein when the pharmaceutical composition is a tablet it further comprises one or more excipients selected from a binder, a lubricant, a diluent, a surface active agent or a dispersing agent, and/or when the pharmaceutical composition is a push fit capsule it further comprises one or more excipients selected from a filler, a binder, a lubricant, and/or a stabilizer.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of U.S. Patent Application No. 15/862,721, filed January 5, 2018. BACKGROUND CB1 and CB2 are two cannabinoid receptors that belong to the GPCR family and have very different functions and distribution. While no x-ray structure is available for these receptors, various models have been described on the basis of the x-ray structure of rhodopsin, a GPCR belonging protein responsible of the light sensitivity in vision. Matsuda LA, Lolait SJ, Brownstein MJ, Young AC, Bonner TI, Structure of a CannabinoidReceptor and Functional Expression of the Cloned cDNA, Nature 1990, 346:561-4. CB1 is abundantly expressed in the central nervous system and is most dense in the basal ganglia, cerebellum, hippocampus, and cortex and in the peripheral nervous system, it is expressed in such sites as the testis, eye, urinary bladder, and adipocytes. CB2 is mainly expressed in the immune tissues, in cells such as those in the thymus, marrow, spleen, pancreas, and in glioma and skin tumor cells. It was recently demonstrated that CB2 receptors and their gene transcripts are widely distributed in the brain. A third cannabinoid receptor seems to be present as some chemical analogues exhibit cannabinoid biological activity without activating CB1 and CB2. Di Marzo V, Bifulco M, De Petrocellis L, The Endocannabinoid System and Its Therapeutic Exploitation, Nat Rev Drug Discov 2004, 3:771-84. Solubility is important for any oral solid dosage form of cannabinoid receptor modulating compounds, as the compounds must be released, dissolved in aqueous gastrointestinal media, traverse the endothelial barrier, and bypass various metabolic enzymes to reach systemic circulation and deliver a therapeutic effect. If the cannabinoid receptor modulating compound does not dissolve, it will be wasted, passing through the gastrointestinal tract without serving its intended pharmacological purpose. The development of effective oral dosage forms for poorly soluble compounds such as cannabinoid receptor agonists and antagonists therefore represents a significant challenge. Bioavailability is a subcategory of absorption and is the fraction of an administered dose of unchanged drug that reaches the systemic circulation, one of the principal pharmacokinetic properties of drugs. By definition, when a medication is administered intravenously, its bioavailability is 100%. However, when a medication is administered via other routes (such as orally), its bioavailability generally decreases, due to incomplete absorption and first-pass metabolism. Many cannabinoid receptor agonists are hydrophobic, and suffer from poor bioavailability when administered orally. Accordingly, there remains a need for improved formulations for oral administration of hydrophobic cannabinoid receptor agonists. WO2009/012221 discloses heterocyclic modulators of cannabinoid receptors, their use in pharmaceutical compositions, methods of using them and their synthesis. SUMMARY OF THE INVENTION Novel oral formulations for benzofuran compounds that modulate CB1 and CB2 have been found. These formulations can be used to prepare pharmaceutical compositions having improved oral bioavailability, and using the pharmaceutical compositions in methods of treatment of cannabinoid receptor-mediated diseases. In a first aspect there is provided a pharmaceutical composition comprising a spray dried dispersion suitable for oral administration, the spray dried dispersion comprising a compound having the formula: or a salt thereof, and hydroxypropyl methylcellulose acetate succinate subtype M (HPMCAS-M), wherein the ratio of the compound to HPMCAS-M in the spray dried dispersion is 1:3 by weight. The benzofuran compound presented herein possesses useful cannabinoid receptor modulating activity, and may be used in the treatment or prophylaxis of a disease or condition in which a cannabinoid receptor plays an active role. Thus, in broad aspect, pharmaceutical compositions are provided comprising a compound optionally together with a pharmaceutically acceptable carrier, as well as methods of making and using the compositions. A pharmaceutical composition for use in methods for modulating cannabinoid receptors are also provided. A pharmaceutical composition for use in methods for treating a cannabinoid receptor-mediated disorder such as neuropathic pain or addiction in a patient in need of such treatment is presented herein. BRIEF DESCRIPTION OF THE FIGURES The foregoing summary as well as the following detailed description of the preferred embodiment of the invention will be better understood when read in conjunction with the appended drawings. It should be understood, however, that the invention is not limited to the precise arrangements and instrumentalities shown herein. For a more complete understanding of the present invention, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with