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US-12616686-B2 - Donepezil oral films

US12616686B2US 12616686 B2US12616686 B2US 12616686B2US-12616686-B2

Abstract

The present invention provides an oral dispersible film for donepezil hydrochloride. The film is a bilayer structure containing a drug layer containing 45-75% w/w donepezil hydrochloride and a backing layer without donepezil hydrochloride. The present oral film retains donepezil hydrochloride in a crystal form and minimizes impurity generation. The oral film contains a selected hydrophobic material to improve the drug stability and minimize the drug solubility.

Inventors

  • Zhoue Gao
  • Jing Yin
  • Zhichao Lin
  • Yanyan Wang
  • Avinash Singh
  • Rongbin Ling

Assignees

  • XIAMEN LP PHARMACEUTICAL CO., LTD.

Dates

Publication Date
20260505
Application Date
20230718
Priority Date
20230707

Claims (14)

  1. 1 . An oral donepezil film, comprising: (a) a drug layer comprising 45-75% w/w of donepezil or a pharmaceutical acceptable salt thereof, in a crystalline form, 5-30% w/w of a first film-forming material, a first plasticizer, and 2-12% w/w of a first hydrophobic material of titanium dioxide or magnesium aluminum silicate; and (b) a backing layer comprising 60-95% w/w of a second film-forming material, a second plasticizer, 2-12% w/w of a second hydrophobic material of titanium dioxide or magnesium aluminum silicate; wherein the first and second film-forming materials are independently selected from the group consisting of: hypromellose (HPMC), hydroxypropyl cellulose (HPC), xanthan gum, chitosan, carboxymethylcellulose, sodium alginate, copovidone, polyvinylpyrrolidone (PVP), or any combination thereof.
  2. 2 . The oral film of claim 1 , wherein the drug layer comprises 10-25% w/w of the first film-forming material.
  3. 3 . The oral film of claim 1 , wherein the first film-forming material is HPMC or HPC.
  4. 4 . The oral film of claim 1 , wherein the second film-forming material is HPMC, HPC, PVP, or any combination thereof.
  5. 5 . The oral film of claim 1 , wherein the first and the second plasticizer are independently triethyl citrate, glycerin, or polyethylene glycol 400.
  6. 6 . The oral film of claim 1 , wherein the drug layer comprises 2-10% w/w of the first plasticizer, and the backing layer comprises 1.5-9% w/w of the second plasticizer.
  7. 7 . The oral film of claim 1 , wherein the drug layer and the backing layer further comprises a sweetening agent and/or a flavoring agent.
  8. 8 . The oral film of claim 7 , wherein the flavoring agent is menthol.
  9. 9 . The oral film of claim 1 , wherein the drug layer comprises 45-75% w/w of donepezil hydrochloride, 10-25% w/w of HPMC or HPC, 2-10% w/w of triethyl citrate, glycerin, or polyethylene glycol 400, and 2-12% w/w of titanium dioxide or magnesium aluminum silicate, and the backing layer comprises 70-90% w/w of HPMC or HPC, 1.5-9% w/w of triethyl citrate, glycerin, or polyethylene glycol 400, and 2-10% w/w of titanium dioxide or magnesium aluminum silicate.
  10. 10 . A process for preparing the oral film of claim 1 , comprising the steps of: (a) mixing the second film-forming material, the second hydrophobic material, the second plasticizer in 30-70% w/w ethanol to prepare a backing layer suspension; (b) coating the backing layer suspension on a substrate and drying the suspension to form a backing layer film; (c) mixing donepezil hydrochloride, the first film-forming material, the first hydrophobic material, a first plasticizer in 70-95% w/w ethanol to form a drug suspension; (d) coating the drug suspension on the backing layer film and drying the drug suspension to form a bilayer film on the substrate, wherein the bilayer film comprises a drug layer film and the backing layer film; and (e) removing the bilayer film from the substrate to form a bilayer donepezil hydrochloride oral film.
  11. 11 . The oral donepezil film of claim 1 , wherein the first hydrophobic material and the second hydrophobic material are titanium dioxide.
  12. 12 . The oral donepezil film of claim 1 , wherein the first hydrophobic material and the second hydrophobic material are magnesium aluminum silicate.
  13. 13 . The oral donepezil film of claim 9 , wherein the drug layer comprises 2-12% w/w of titanium dioxide and the backing layer comprises 2-10% w/w of titanium dioxide.
  14. 14 . The oral donepezil film of claim 9 , wherein the drug layer comprises 2-12% w/w of magnesium aluminum silicate and the backing layer comprises 2-10% w/w of magnesium aluminum silicate.

Description

This application claims the priority of Chinese Application No. 202310829734.X, filed Jul. 7, 2023; which is incorporated herein by reference in its entirety. FIELD OF INVENTION The present invention provides a bilayer oral film for delivering donepezil hydrochloride in the oral cavity. The bilayer oral film is a stable film and masks an unpleasant taste of drug. BACKGROUND OF THE INVENTION Donepezil hydrochloride, chemical name 1-benzyl-4-((5,6-dimethoxy-1-indanon)-2-yl)methylpiperidine hydrochloride, sold under the brand name Aricept among others, is used in treating a variety of disorders, including dementia and attention deficit disorder. In particular, donepezil hydrochloride is used as a pharmaceutically active agent for treating dementia of the Alzheimer's type. Efficacy has been demonstrated in patients with mild, moderate, and severe Alzheimer's disease. There are various types of dosage formulations of donepezil hydrochloride available for oral administration. Within those preparations, tablets and capsules are widely available but they are disadvantageous for patients having difficulties in taking tablets and capsules. Liquid formulations are disadvantageous due to instability and inaccurate dispensing. Several formulations with different drug delivery systems are available in the market. ODT (orally dispersible tablet) is one of those formulations. However, the problems are that ODT generally does not completely or consistently disintegrated in a short time due to smaller surface area and thus it frequently requires water after dose. ODTs are fragile and can break during transport. Geriatric and pediatric patients have difficulty chewing or swallowing solid dosage forms. Therefore, many children and elderly people are reluctant to take these solid dosage forms due to fear of asphyxiation. Psychiatric patients may refuse medication or develop behaviors such as failure to swallow pills and/or expulsion of pills. There exists a need for a new donepezil hydrochloride formulation in which the drug is stable under common storage conditions, and the formulation provides an acceptable taste in the oral cavity. DETAILED DESCRIPTION OF THE INVENTION Definitions “An oral film”, as used herein, refers to a film or strip used in a drug delivery system to deliver a drug. When an oral film is placed in the mouth or on the tongue, it disintegrates or dissolves by the saliva within a few seconds to deliver its content. “A pharmaceutically acceptable salt,” as used herein, is a salt that retains the desired biological activity of the parent compound and does not impart undesired toxicological effects. “About” when used in this application, refers to +10% of the recited value. “Donepezil oral film” or “oral donepezil film”, as used herein, refers to an oral film comprising an active ingredient donepezil, or a pharmaceutical acceptable salt thereof such as hydrochloride. Unless otherwise specified, % used in this application refers to weight by weight %. The inventors have discovered an oral film suitable for oral delivery of donepezil with similar therapeutic efficacy to that of the presently available reference listed drug (RLD) ARICEPT® tablet. The donepezil oral film of the present invention is essentially uniform in thickness, color, and without bubbles. The active ingredient donepezil in the present oral film is in an anhydrous crystalline form which has a slow dissolution rate in the oral cavity, and thus reducing the bitterness produced by the dissolved drug. The present application provides a pharmaceutical composition comprising donepezil or a pharmaceutical acceptable salt thereof in an oral film, which is rapidly dispersible and is suitable for oral administration of donepezil or a pharmaceutical acceptable salt thereof such as donepezil hydrochloride. Oral dispersible films have many advantages over other solid dosage forms, including a better flexibility of the film, and increased efficacy of an active principal ingredient (API). Due to the large surface area, oral films can be dissolved and disintegrated with a small amount of saliva. The oral dispersible film is useful for the patients who are bedridden, active working, or traveling. Oral dispersible films offer advantages for treating geriatric patients, pediatric patients, and patients with psychiatric disorders. The donepezil hydrochloride oral film of the present invention is stable under common storage conditions. The film provides a good taste, and it is essentially uniform in thickness, color, and without bubbles. The donepezil oral film of the present invention makes it acceptable to administer the active ingredient by an oral route. The present invention provides a bilayer oral donepezil film comprising a drug layer and a backing layer. The drug layer comprises about 45-75% w/w of donepezil, or a pharmaceutically acceptable salt thereof, in a crystalline form, about 5-30% w/w of a first film-forming material, about 2-10% w/w of a first plas