# US 11,433,058 B2 · Non-pulsatile prolonged-release betahistine oral solid compositions

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- Number: US 11,433,058 B2
- Document ID: US11433058B2
- Status: Granted
- Kind: B2
- Application number: 16/632,500
- Filed: 2018-07-16
- Published: 2021-06-03
- Granted: 2022-09-06
- Earliest claimed: 2017-07-20
- Assignees: Intas Pharmaceuticals Ltd.
- Applicants: Intas Pharmaceuticals Ltd.
- Inventors: Himanshukumar Dasharathlal Patel; Vinod Purushottam Dube; Venkataramana Naidu; Sunil Shantwan Borude
- Web page: https://patentgrep.com/patent/US11433058B2

## CPC

- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 9/2009: {Inorganic compounds}
- A61K 9/2013: {Organic compounds, e.g. phospholipids, fats}
- A61K 9/2027: {obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates}
- A61K 9/205: {Polysaccharides, e.g. alginate, gums; Cyclodextrin}
- A61K 9/2054: {Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose}
- A61K 9/2072: {characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms (A61K9/0004, A61K9/0056, A61K9/0065 take precedence)}
- A61K 9/2095: {Tabletting processes}
- 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)

## Abstract

An oral solid non-pulsatile 24 hours prolonged-release composition including an amount of betahistine, or of a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride, together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits a dissolution profile according to which: up to 30% by weight of betahistine is dissolved in 1 hour; from 35% to 45% by weight of betahistine is dissolved in 2 hours; from 46% to 60% by weight of betahistine is dissolved in 4 hours; from 61% to 80% by weight of betahistine is dissolved in 8 hours; from 81% to 97% by weight of betahistine is dissolved in 16 hours; and from 98% to 100% by weight of betahistine is dissolved in 24 hours. It also relates to the treatment of a vestibular disease or condition, more particularly in the treatment of Ménière's disease.

## Claims

### Claim 1

A non-pulsatile 24 hours prolonged-release oral solid composition comprising an amount of betahistine, or of a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride, together with one or more pharmaceutically acceptable excipients or carriers, wherein the composition exhibits a dissolution profile according to which:
up to 30% by weight of betahistine is dissolved in 1 hour;
from 35% to 45% by weight of betahistine is dissolved in 2 hours;
from 46% to 60% by weight of betahistine is dissolved in 4 hours;
from 61% to 80% by weight of betahistine is dissolved in 8 hours;
from 81% to 97% by weight of betahistine is dissolved in 16 hours; and
from 98% to 100% by weight of betahistine is dissolved in 24 hours
wherein the dissolution profile is measured using a USP type I apparatus (basket), placing the composition in 900 mL of phosphate buffer having pH 6.8, at 37° C. and 100 rpm,
wherein the pharmaceutically acceptable excipients or carriers comprise one or more hydrophilic matrix forming agents, and
wherein the hydrophilic matrix forming agent is a mixture of hydroxypropylmethylcellulose and carrageenan.

### Claim 2 (depends on 1)

The composition according to claim 1, which comprises betahistine dihydrochloride salt.

### Claim 3 (depends on 1)

The composition according to claim 1, wherein after an oral single-dose administration of the composition under fed conditions, betahistine or a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride exhibits a maximum plasma concentration (Cmax) of from 400 ng/ml to 700 ng/ml expressed as plasma concentration of its 2-pyridylacetic acid metabolite.

### Claim 4 (depends on 1)

The composition according to claim 1, wherein after an oral single-dose administration of the composition under fed conditions, betahistine, or a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride exhibits a time to maximum plasma concentration (Tmax) of from 5 h to 7 h expressed as plasma concentration of its 2-pyridylacetic acid metabolite.

### Claim 5 (depends on 1)

The composition according to claim 1, wherein after an oral single-dose administration of the composition under fed conditions, betahistine, or a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride exhibits an area under the time/plasma concentration curve from time 0 to 24 hours (AUC (0-24)) of from 5000 ng·h/ml to 10000 ng·h/ml expressed as plasma concentration of its 2-pyridylacetic acid metabolite.

### Claim 6 (depends on 1)

The composition according to claim 1, wherein the weight ratio between the hydroxypropylmethylcellulose and carrageenan is from 3:1 to 12:1.

### Claim 7 (depends on 1)

The composition according to claim 1, which comprises:
an amount of betahistine, or of a pharmaceutically acceptable salt thereof, equivalent to 48 mg of betahistine dihydrochloride;
from 20 to 85% by weight of hydrophilic matrix forming agent is a mixture of hydroxypropylmethylcellulose and carrageenan;
from 20 to 40% by weight of one or more diluents;
from 0.1 to 15% by weight of one or more stabilizers;
from 0.1 to 15% by weight of one or more binders;
from 0.1 to 10% by weight of one or more glidants;
and from 0.1 to 10% by weight of one or more lubricants;
being the sum of the ingredients 100% by weight.

### Claim 8 (depends on 1)

A process for the preparation of the composition as defined in claim 1, which comprises:
(a) preparing a solution of betahistine or a pharmaceutically acceptable salt thereof in a polar solvent selected from the group (C1-C4)alkyl-CO—(C1-C4)alkyl, (C1-C4)alky)-COO—(C1-C4)alkyl, water and mixture thereof:
(b) sifting and mixing one or more diluents, one or more stabilizers and optionally one or more binders to obtain a mixture;
(c) granulating the mixture of step (b) by the addition of the solution of step (a) to obtain wet granules;
(d) drying the wet granules obtained in step (c) to obtain dried granules;
(e) mixing the dried granules obtained in step (d) with one or more hydrophilic matrix forming agents to obtain a mixture,
(f) blending the mixture obtained in step (e) with one or more of the excipients or carriers selected from the group consisting of glidant and lubricant to obtain a mixture;
(g) compressing the mixture obtained in step (f) to form tablets, and
(h) coating the tablets obtained in step (g).

### Claim 9 (depends on 1)

The composition according to claim 1, wherein the one or more hydrophilic matrix forming agents are in an amount from 35% to 65%, by weight of the total weight of the composition.

### Claim 10 (depends on 1)

The composition according to claim 1, wherein the one or more hydrophilic matrix forming agents are in an amount from 40% to 60%, by weight of the total weight of the composition.

### Claim 11 (depends on 1)

The composition according to claim 1, wherein the one or more hydrophilic matrix forming agents are in an amount from 45% to 55%, by weight of the total weight of the composition.

### Claim 12 (depends on 1)

The composition according to claim 1, wherein the one or more hydrophilic matrix forming agents are in an amount from 50% to 55%, by weight of the total weight of the composition.