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US-20260124147-A1 - THERAPEUTIC METHODS AND COMPOSITIONS FOR TREATING MOVEMENT DISORDERS

US20260124147A1US 20260124147 A1US20260124147 A1US 20260124147A1US-20260124147-A1

Abstract

The invention provides therapeutic methods, pharmaceutical compositions, and unit dose formulations for treating movement disorders, such as using a muscarinic acetylcholine receptor inhibitor in combination with a muscarinic acetylcholine receptor activator to treat the movement disorder, such as dystonia. In some aspects, the invention provides a method of treating a movement disorder in a patient, where the method comprises administering to a patient in need thereof (i) a muscarinic acetylcholine receptor inhibitor in an amount effective to treat the movement disorder and (ii) a muscarinic acetylcholine receptor activator in an amount effective to reduce the frequency and/or magnitude of at least one side effect of the muscarinic acetylcholine receptor inhibitor, to thereby treat the movement disorder.

Inventors

  • Bernard Mayer RAVINA
  • Maria G. BECONI-BARKER
  • Judith Dunn
  • Mark Rogge
  • Danielle SUPPLEE

Assignees

  • Vima Therapeutics, Inc.

Dates

Publication Date
20260507
Application Date
20251031

Claims (20)

  1. 1 - 95 . (canceled)
  2. 96 . A pharmaceutical composition comprising: a. about 2.8% by weight (R)-trihexyphenidyl (R-THP) or a pharmaceutically acceptable salt thereof, b. about 10% by weight hydroxpropyl methylcellulose 100SR; c. about 30% by weight hydroxpropyl methylcellulose 15,000SR; d. about 10% by weight microcrystalline cellulose; e. about 44% by weight dicalcium phosphate anhydrous; f. about 2.2% by weight lactose; and g. about 1% by weight magnesium stearate.
  3. 97 - 120 . (canceled)
  4. 121 . A pharmaceutical composition comprising: a. about 15.25% by weight bethanechol (BTC) or a pharmaceutically acceptable salt thereof; b. about 10% by weight hydroxpropyl methylcellulose 100SR; c. about 30% by weight hydroxpropyl methylcellulose 15,000SR; d. about 20% by weight microcrystalline cellulose; e. about 23.75% by weight dicalcium phosphate anhydrous; and f. about 1% by weight magnesium stearate.
  5. 122 - 131 . (canceled)
  6. 132 . A pharmaceutical composition comprising a sustained release (R)-trihexyphenidyl (R-THP) component and a sustained release bethanechol (BTC) component, wherein the sustained release R-THP component comprises: a. about 2.8% by weight R-THP or a pharmaceutically acceptable salt thereof, b. about 10% by weight hydroxpropyl methylcellulose 100SR; c. about 30% by weight hydroxpropyl methylcellulose 15,000SR; d. about 10% by weight microcrystalline cellulose; e. about 44% by weight dicalcium phosphate anhydrous; f. about 2.2% by weight lactose; and g. about 1% by weight magnesium stearate; wherein the sustained release BTC component comprises: a. about 15.25% by weight BTC or a pharmaceutically acceptable salt thereof, b. about 10% by weight hydroxpropyl methylcellulose 100SR; c. about 30% by weight hydroxpropyl methylcellulose 15,000SR; d. about 20% by weight microcrystalline cellulose; e. about 23.75% by weight dicalcium phosphate anhydrous; and f. about 1% by weight magnesium stearate.
  7. 133 - 216 . (canceled)
  8. 217 . The pharmaceutical composition of claim 96 , wherein the pharmaceutical composition is administered to a patient with a movement disorder selected from dystonia, primary dystonia, secondary dystonia, tardive dystonia, drug-induced dystonia, cerebral palsy-associated dystonia, focal dystonia, cervical dystonia, blepharospasm, hand dystonia, writer's cramp, musician's dystonia, leg dystonia, foot dystonia, idiopathic in origin, a genetic dystonia, Multiple System Atrophy, Progressive Supranuclear Palsy, tremor, Parkinson's disease, tremor in Parkinson's disease, drug-induced Parkinsonism, Huntington's disease, or dementia with Lewy Bodies.
  9. 218 . The pharmaceutical composition of claim 96 , wherein the pharmaceutical composition is administered to a patient with dystonia.
  10. 219 . The pharmaceutical composition of claim 96 , wherein the pharmaceutical composition is administered to a patient with tremor in Parkinson's disease.
  11. 220 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition is a bilayer tablet.
  12. 221 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition comprises the R-THP and the BTC in a weight ratio of R-THP to BTC of about 1:5.
  13. 222 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition provides a plasma C(minimum) concentration of the R-THP of greater than or equal to about 25 ng/ml after administration of the pharmaceutical composition.
  14. 223 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition provides a plasma concentration rate of rise of the R-THP is less than or equal to about 10 ng/ml/hr after administration of the pharmaceutical composition.
  15. 224 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition provides an area under the curve (AUC) plasma concentration of the R-THP is about 800 to about 1200 ng*hr/ml after administration of the pharmaceutical composition.
  16. 225 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition provides after administration of the pharmaceutical composition: a. a plasma C(minimum) concentration of the R-THP of greater than or equal to about 25 ng/ml; b. a plasma concentration rate of rise of the R-THP is less than or equal to about 10 ng/ml/hr; and c. an area under the curve (AUC) plasma concentration of the R-THP is about 800 to about 1200 ng*hr/ml.
  17. 226 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition is administered to a patient with a movement disorder selected from dystonia, primary dystonia, secondary dystonia, tardive dystonia, drug-induced dystonia, cerebral palsy-associated dystonia, focal dystonia, cervical dystonia, blepharospasm, hand dystonia, writer's cramp, musician's dystonia, leg dystonia, foot dystonia, idiopathic in origin, a genetic dystonia, Multiple System Atrophy, Progressive Supranuclear Palsy, tremor, Parkinson's disease, tremor in Parkinson's disease, drug-induced Parkinsonism, Huntington's disease, or dementia with Lewy Bodies.
  18. 227 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition is administered to a patient with dystonia.
  19. 228 . The pharmaceutical composition of claim 132 , wherein the pharmaceutical composition is administered to a patient with tremor in Parkinson's disease.
  20. 229 . The pharmaceutical composition of claim 132 , wherein the magnitude or severity of at least one side effect of the R-THP or a pharmaceutically acceptable salt thereof is reduced in the patient compared to a patient administered an immediate release formulation of trihexyphenidyl or a pharmaceutically acceptable salt thereof alone.

Description

CROSS REFERENCE TO RELATED APPLICATIONS The present application claims the priority benefit of U.S. Provisional Application No. 63/813,518, filed May 28, 2025, and U.S. Provisional Application No. 63/715,318, filed Nov. 1, 2024, which are each hereby incorporated by reference in their entirety. FIELD OF THE INVENTION The invention provides therapeutic methods, pharmaceutical compositions, and unit dose formulations for treating movement disorders, such as using a muscarinic acetylcholine receptor inhibitor in combination with a muscarinic acetylcholine receptor activator to treat dystonia. BACKGROUND Movement disorders impact a substantial number of patients. One such movement disorder, dystonia, is a neurological movement disorder characterized by involuntary (unintended) muscle contractions that cause slow repetitive movements or abnormal postures that can sometimes be painful. The condition can affect one part of the body (focal dystonia), two or more adjacent parts (segmental dystonia), or multiple parts of the body (general dystonia) including the trunk. The muscle spasms can range from mild to severe. Dystonia can be described as primary or secondary. Primary dystonia is when the dystonia is the sole neurological condition experienced by a subject. Secondary dystonia is when the dystonia is caused by outside factors and can be attributed to a specific cause such as exposure to certain medications, toxins, infections, stroke, spinal cord injury, head injury, or peripheral injury. Dystonia is reported to be associated with over activity of cholinergic interneurons (Chls) that provide acetylcholine (Ach) to medium spiny neurons (MSNs). Overactivity of cholinergic interneurons produces more acetylcholine for signaling to medium spiny neurons and other neuronal populations leading to dystonia. Treatment options currently available for patients with dystonia do not provide adequate therapeutic benefit for all patients and/or have significant adverse side effects. Trihexyphenidyl-HCl (THP), a phenyl propylamine, is an anticholinergic agent that was first approved by the FDA in 1949. THP is a synthetic antispasmodic drug that is widely used in the treatment of patients with parkinsonism, including primary or idiopathic Parkinson's disease, secondary symptomatic parkinsonism (postencephalitic, arteriosclerotic, infection-induced, tumor-induced, trauma-induced, and drug-induced), and involuntary movements due to side effects of certain psychiatric drugs. See, for example, Cheung et al. in “Pharmacokinetic evaluation of a sustained release formulation of trihexyphenidyl in healthy volunteers” J Pharm. Sci. (1988) 77(9):748-50. THP is approved by the FDA as an adjunct in the treatment of parkinsonism and for the control of extrapyramidal disorders caused by central nervous system drugs such as dibenzoxazepines, phenothiazines, thioxanthenes, and butyrophenones. THP is widely used off-label for treating certain types of dystonia. However, there are major problems associated with using THP to treat dystonia and Parkinsonism, including that it causes significant adverse side effects at the dosage typically used to treat dystonia and current reports describe frequent administration of THP; each of the foregoing contribute to poor patient compliance with THP therapy and concomitant poor therapeutic outcomes. Accordingly, the need exists for new therapeutic methods and pharmaceutical compositions for treating movement disorders, including dystonia. The present invention addresses the foregoing needs and provides other related advantages. SUMMARY The invention provides therapeutic methods, pharmaceutical compositions, and unit dose formulations for treating movement disorders, such as using a muscarinic acetylcholine receptor inhibitor in combination with a muscarinic acetylcholine receptor activator to treat dystonia. In particular, one aspect of the invention provides a method of treating a movement disorder in a patient, where the method comprises administering to a patient in need thereof (i) a muscarinic acetylcholine receptor inhibitor in an amount effective to treat the movement disorder and (ii) a muscarinic acetylcholine receptor activator in an amount effective to reduce the frequency and/or magnitude of at least one side effect of the muscarinic acetylcholine receptor inhibitor, to thereby treat the movement disorder. The muscarinic acetylcholine receptor inhibitor may be, for example, trihexyphenidyl or a pharmaceutically acceptable salt thereof. The muscarinic acetylcholine receptor activator may be, for example, bethanechol or a pharmaceutically acceptable salt thereof. Use of the muscarinic acetylcholine receptor inhibitor in combination with the muscarinic acetylcholine receptor activator reduces the frequency and/or magnitude of at least one side effect of the muscarinic acetylcholine receptor inhibitor, and also provides the further benefit of permitting a higher dose of muscarinic acetylcholine recept