US2021205208A1PendingUtilityA1

Methods of treating parkinson's disease by administration of apomorphine to an oral mucosa

66
Assignee: SUNOVION PHARMACEUTICALS INCPriority: Apr 21, 2015Filed: Feb 18, 2021Published: Jul 8, 2021
Est. expiryApr 21, 2035(~8.7 yrs left)· nominal 20-yr term from priority
Inventors:Scott David BarnhartMichael Clinton KoonsMadhu HariharanJordan DubowThierry BilbaultAnthony John Giovinazzo
A61K 47/02A61K 9/006A61K 47/36A61K 31/473A61K 47/38A61K 47/26A61P 25/16A61K 47/14A61K 47/183A61K 9/7007A61K 45/06A61K 47/10
66
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Claims

Abstract

Methods and pharmaceutical unit dosage forms for treating Parkinson's disease in a subject (e.g., an “off” episode in a subject having Parkinson's disease) are described. The pharmaceutical unit dosage forms are films having a first portion including particles containing an acid addition salt of apomorphine and a second portion containing a pH neutralizing agent. The pharmaceutical unit dosage forms can be flexible and have toughness greater than 100 g×mm. The methods can involve administering to a subject having Parkinson's disease a therapeutic dose sufficient to produce an apomorphine plasma concentrate of at least 2.64 ng/mL within 45 minutes after the administration. The subject may be identified as having low uptake, medium uptake, or high uptake of apomorphine administered via oral mucosa.

Claims

exact text as granted — not AI-modified
1 . A method of treating an “off” episode in a subject having Parkinson's disease, said method comprising:
 (a) administering an effective amount of an antiemetic; 
 (b) providing a film having a first portion comprising an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent; 
 (c) determining an effective dose of said film by uptitration of said subject; and 
 (d) sublingually administering said effective dose of said film to said subject. 
 
     
     
         2 . The method of  claim 1 , wherein, following administration to subjects, the apomorphine T max  is from 20 to 60 minutes. 
     
     
         3 . The method of  claim 1 , wherein said film maintains an apomorphine plasma concentration of at least 2.64 ng/mL for a period of at least 60 minutes. 
     
     
         4 . The method of  claim 1 , wherein said film comprises 12.5±2.5 mg of an acid addition salt of apomorphine. 
     
     
         5 . The method of  claim 1 , wherein said film comprises 17.5±2.5 mg of an acid addition salt of apomorphine. 
     
     
         6 . The method of  claim 1 , wherein said film comprises 25.0±5.0 mg of an acid addition salt of apomorphine. 
     
     
         7 . The method of  claim 1 , wherein said film comprises 35±10.0 mg of an acid addition salt of apomorphine. 
     
     
         8 - 9 . (canceled) 
     
     
         10 . The method of  claim 1 , wherein said antiemetic is administered prior to administering said film. 
     
     
         11 . The method of  claim 10 , wherein an effective amount of said antiemetic is administered to said subject for at least 2 days prior to administering said film. 
     
     
         12 . The method of  claim 1 , wherein said film has a toughness greater than or equal to 100 g×mm. 
     
     
         13 . The method of  claim 1 , wherein said second portion comprises a permeation enhancer. 
     
     
         14 . The method of  claim 1 , wherein said film comprises less than 10% (w/w) of a permeation enhancer. 
     
     
         15 . The method of  claim 1 , wherein said first portion comprises a permeation enhancer. 
     
     
         16 . The method of  claim 13 , wherein said first portion is free of a permeation enhancer. 
     
     
         17 . The method of  claim 16 , wherein each said permeation enhancer is independently menthol, an ionic surfactant, a nonionic surfactant, a polysorbate, a tocopherol derivative, a poloxamer, a monoglyceride, a diglyceride, a fatty acid, or a fatty alcohol, or a combination thereof. 
     
     
         18 . The method of  claim 17 , wherein said permeation enhancer is a mixture of menthol and glycerol monostearate. 
     
     
         19 . The method of  claim 1 , wherein said film comprises 20% (w/w) or more of a pharmaceutically acceptable high molecular weight polymer having a weight average molecular weight of 60 kDa or greater. 
     
     
         20 . The method of  claim 19 , wherein said film comprises from 20% (w/w) to 40% (w/w) of said pharmaceutically acceptable high molecular weight polymer. 
     
     
         21 . The method of  claim 19 , wherein said pharmaceutically acceptable high molecular weight polymer has a weight average molecular weight from 60 kDa to 1,000 kDa. 
     
     
         22 . The method of  claim 19 , wherein said pharmaceutically acceptable high molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 
     
     
         23 . The method of  claim 1 , wherein said film comprises 5% (w/w) or less of a pharmaceutically acceptable low molecular weight polymer having a weight average molecular weight of less than 60 kDa. 
     
     
         24 . The method of  claim 23 , wherein said film comprises from 0.01% (w/w) to 5% (w/w) of said pharmaceutically acceptable low molecular weight polymer. 
     
     
         25 . The method of  claim 23 , wherein said pharmaceutically acceptable low molecular weight polymer has a weight average molecular weight of from 5 kDa to 50 kDa. 
     
     
         26 . The method of  claim 23 , wherein said pharmaceutically acceptable low molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 
     
     
         27 . The method of  claim 26 , wherein said pharmaceutically acceptable low molecular weight polymer is hydroxypropyl cellulose. 
     
     
         28 . The method of  claim 1 , wherein said second portion is free of a pharmaceutically acceptable low molecular weight polymer. 
     
     
         29 . The method of  claim 1 , wherein said film disintegrates in aqueous media in 2 minutes or less. 
     
     
         30 . The method of  claim 1 , wherein said film disintegrates in aqueous media in 30 seconds or more. 
     
     
         31 - 60 . (canceled) 
     
     
         61 . A pharmaceutical unit dosage form that is a film comprising an acid addition salt of apomorphine and a second portion comprising a pH neutralizing agent, wherein the film comprises 20% (w/w) or more of a pharmaceutically acceptable high molecular weight polymer having a weight average molecular weight of 60 kDa or greater. 
     
     
         62 . The pharmaceutical unit dosage form of  claim 61 , wherein said film comprises from 20% (w/w) to 40% (w/w) of said pharmaceutically acceptable high molecular weight polymer. 
     
     
         63 . The pharmaceutical unit dosage form of  claim 61 , wherein said pharmaceutically acceptable high molecular weight polymer has a weight average molecular weight from 60 kDa to 1,000 kDa. 
     
     
         64 . The pharmaceutical unit dosage form of  claim 61 , wherein said pharmaceutically acceptable high molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 
     
     
         65 . The pharmaceutical unit dosage form of  claim 61 , wherein said film comprises 5% (w/w) or less of a pharmaceutically acceptable low molecular weight polymer having a weight average molecular weight of less than 60 kDa. 
     
     
         66 . The pharmaceutical unit dosage form of  claim 65 , wherein said film comprises from 0.01% (w/w) to 5% (w/w) of said pharmaceutically acceptable low molecular weight polymer. 
     
     
         67 . The pharmaceutical unit dosage form of  claim 65 , wherein said pharmaceutically acceptable low molecular weight polymer has a weight average molecular weight of from 5 kDa to 50 kDa. 
     
     
         68 . The pharmaceutical unit dosage form of  claim 65 , wherein said pharmaceutically acceptable low molecular weight polymer is carboxymethylcellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, or methyl cellulose, or a combination thereof. 
     
     
         69 . The pharmaceutical unit dosage form of  claim 65 , wherein said pharmaceutically acceptable low molecular weight polymer is hydroxypropyl cellulose. 
     
     
         70 . The pharmaceutical unit dosage form of  claim 61 , wherein said film comprises a pharmaceutically acceptable low molecular weight polymer having a weight average molecular weight of less than 60 kDa, and wherein the weight ratio of said pharmaceutically acceptable high molecular weight polymer to said pharmaceutically acceptable low molecular weight polymer in said pharmaceutical unit dosage form is within a range 4 to 5,000. 
     
     
         71 . The pharmaceutical unit dosage form of  claim 61 , wherein said second portion is free of a pharmaceutically acceptable low molecular weight polymer.

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