# US 2021/0330657 A1 · Extended release compositions comprising trihexyphenidyl

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- Number: US 2021/0330657 A1
- Document ID: US20210330657A1
- Status: Published application
- Kind: A1
- Application number: 17/272,481
- Filed: 2019-09-19
- Published: 2021-10-28
- Earliest claimed: 2018-09-21
- Assignees: Kashiv Specialty Pharmaceuticals, LLC
- Applicants: Kashiv Biosciences, LLC
- Inventors: Namdev B. Shelke; Siva Ram Kiran Vaka; Navnit H. Shah; Dipen Desai; Wantanee Phuapradit
- Web page: https://patentgrep.com/patent/US20210330657A1

## CPC

- A61K 9/2886: {having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer (of the type active core-drug layer-inactive layer A61K9/209)}
- A61K 9/5042: {Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose}
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/501: {Inorganic compounds}
- A61K 9/5047: {Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose}
- A61K 9/5078: {with drug-free core}
- A61K 9/5089: {Processes}
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 47/12: Carboxylic acids; Salts or anhydrides thereof
- A61P 25/14: for treating abnormal movements, e.g. chorea, dyskinesia
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

The present disclosure provides extended release trihexyphenidyl compositions suitable for once- or twice-daily administration. The compositions comprise a core comprising organic acid that is coated with at least one drug layer comprising trihexyphenidyl hydrochloride, and a functional coat over the drug-layered core. The extended release compositions of the disclosure provide extended release of trihexyphenidyl hydrochloride, with reduced Cmax, and a Cmin:Cmax ratio of ≥0.4, while maintaining a therapeutically effective concentration for a period of at least about 16 hours. The compositions of the disclosure improve solubility of trihexyphenidyl hydrochloride, at a pH of greater than or equal to 5, to maintain its minimum effective concentration at such pH. In certain embodiments, the compositions of the disclosure comprise an IR drug layer to provide extended release with a minimal lag time, while maintaining a therapeutically effective concentration of trihexyphenidyl hydrochloride for a period of at least about 16 hours.

## Claims

### Claim at position 1

1-20. (canceled)

### Claim 21

A pharmaceutical pellet composition comprising:
a) a core comprising an organic acid;
b) a first drug layer encompassing at least a portion of the core, wherein the first drug layer comprises trihexyphenidyl or a pharmaceutically acceptable salt thereof; and
c) a functional coat encompassing at least a portion of the drug layer,
wherein the functional coat comprises a nonionic water-insoluble polymer and a pore former,
wherein the composition provides extended release of trihexyphenidyl a pharmaceutically acceptable salt thereof, with a Cmin:Cmax ratio of ≥0.4, for a period of at least 12 hours, and
wherein the composition improves solubility of trihexyphenidyl or a pharmaceutically acceptable salt thereof at a pH of greater than or equal to 5 to maintain a therapeutic plasma concentration of trihexyphenidyl or a pharmaceutically acceptable salt thereof for at least about 12 hours.

### Claim 22 (depends on 21)

The composition of claim 21, wherein the trihexyphenidyl or a pharmaceutically acceptable salt thereof, and the organic acid are present in a weight ratio of from about 1:10 to about 1:100.

### Claim 23 (depends on 21)

The composition of claim 21, wherein the nonionic water-insoluble polymer and the pore former are present in a weight ratio from about 60:40 and about 99.5:0.5.

### Claim 24 (depends on 21)

The composition of claim 21, wherein the functional coat has a coating weight gain of from about 25% w/w to about 35% w/w, based on the total weight of the pellet without the functional coat.

### Claim 25 (depends on 21)

The composition of claim 21, wherein the therapeutic plasma concentration comprises from about 1 ng/ml to about 20 ng/ml.

### Claim 26 (depends on 21)

The composition of claim 21, wherein the core consists of one or more organic acids.

### Claim 27 (depends on 21)

The composition of claim 21, wherein the core is a nonpareil seed coated with an organic acid layer.

### Claim 28 (depends on 21)

The composition of claim 21, wherein the organic acid is selected from the group consisting of tartaric acid, citric acid, fumaric acid, succinic acid, malic acid, and combinations thereof.

### Claim 29 (depends on 21)

The composition of claim 21, wherein the first drug layer further comprises a nonionic water-soluble polymer that is methyl cellulose and/or hydroxypropyl methylcellulose.

### Claim 30 (depends on 21)

The composition of claim 21, wherein the nonionic water-insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, a polyvinyl acetate dispersion, and combinations thereof.

### Claim 31 (depends on 21)

The composition of claim 21, wherein the pore former is an enteric polymer selected from the group consisting of cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxyethyl cellulose phthalate, polyvinyl acetate phthalate, polyvinyl butyrate acetate, vinyl acetate-maleic anhydride copolymer, methacrylic acid copolymer, hydroxypropyl methylcellulose phthalate, polyvinyl acetate phthalate, cellulose acetyl phthalate, and combinations thereof.

### Claim 32 (depends on 21)

The composition of claim 21, wherein the pore former is a nonionic, water-soluble polymer comprising methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, or mixtures thereof.

### Claim 33 (depends on 21)

The composition of claim 21, wherein the pore former is a plasticizer selected from the group comprising glycerin, polyethylene glycol monomethyl ether, triethyl citrate, triacetin, polyethylene glycol, propylene glycol, sorbitol sorbitan solution, dibutyl sebacate, or mixtures thereof.

### Claim 34 (depends on 21)

The composition of claim 21, wherein the composition further comprises a second drug layer comprising trihexyphenidyl or a pharmaceutically acceptable salt thereof.

### Claim 35

A therapeutic method for treating dystonia, sialorrhea, or dyskinesia, the method comprising orally administering to a subject in need thereof an extended release trihexyphenidyl composition comprising:
a) a core comprising an organic acid;
b) a drug layer encompassing at least a portion of the core, wherein the drug layer comprises trihexyphenidyl or a pharmaceutically acceptable salt thereof; and
c) a functional coat encompassing at least a portion of the drug layer, wherein the functional coat comprises a nonionic water-insoluble polymer and a pore former,
wherein the composition is for oral administration,
wherein the composition provides extended release of trihexyphenidyl or a pharmaceutically acceptable salt thereof, with a Cmin:Cmax ratio of ≥0.4, for a period of at least about 12 hours, and
wherein the composition improves solubility of trihexyphenidyl or a pharmaceutically acceptable salt thereof at a pH of greater than or equal to about 5 to maintain a therapeutic concentration of trihexyphenidyl or a pharmaceutically acceptable salt thereof for at least about 12 hours.

### Claim 36 (depends on 35)

The method of claim 35, wherein the composition is administered once a day.

### Claim 37

A method for improving patient compliance, the method comprising orally administering to a patient in need thereof, an extended release trihexyphenidyl composition comprising,
a) a core comprising an organic acid;
b) a drug layer encompassing at least a portion of the core, wherein the drug layer comprises trihexyphenidyl or a pharmaceutically acceptable salt thereof; and
c) a functional coat encompassing at least a portion of the drug layer,
wherein the functional coat comprises a nonionic water-insoluble polymer and a pore former,
wherein the composition improves solubility of trihexyphenidyl or a pharmaceutically acceptable salt thereof at a pH of greater than or equal to about 5 to maintain a therapeutically effective concentration of trihexyphenidyl or a pharmaceutically acceptable salt thereof, for a period of at least about 12 hours, and
wherein the composition reduces side effects associated with high peak serum concentration (Cmax) and low trough-to-peak concentration ratios (Cmin:Cmax) of <0.4.

### Claim 38 (depends on 37)

The composition for the use of claim 37, wherein the side effects include drowsiness, dizziness or blurred vision, dry mouth, stomach upset, vomiting, diarrhea, constipation, and difficulty in urinating.

### Claim 39 (depends on 37)

The composition of claim 37, wherein the composition is a pellet composition suitable for dosing in capsules, sachets, or as sprinkles on food.

### Claim 40

A method of making a pharmaceutical pellet composition comprising trihexyphenidyl or a pharmaceutically acceptable salt thereof, the method comprising: coating a core comprising an organic acid with a drug layer comprising trihexyphenidyl or a pharmaceutically acceptable salt thereof to obtain a drug layered core, and coating the drug layered core with a functional coat comprising a nonionic water-insoluble polymer and a pore former,
wherein, the nonionic water-insoluble polymer is selected from the group consisting of ethyl cellulose, cellulose acetate, a polyvinyl acetate dispersion, and combinations thereof;
wherein the pore former is a nonionic water-soluble polymer, an enteric polymer, or a plasticizer; and
wherein the core consists of one or more organic acids, or is a nonpareil seed coated with an organic acid layer.