FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)

1. Title of the invention.- NOVEL FORMULATIONS OF GALANTAMINE

2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company.
(c) ADDRESS : Alembic Campus, Alembic Road, '
Vadodara - 390 003, Gujarat, India.

2. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention

Field of Invention
The present invention relates to extended release solid dosage forms of acetylcholinesterase inhibitors. In particular the present invention relates to extended release matrix solid dosage forms of galantamine.
Background of the invention
Galantamine, chemically described as (4aS,6R,8aS)-4a,5,9,10,11,12-hexahydro-3-methoxy-11-methyl-6H-benzofuro[3a,3,2-ef][2]benzazepin-6-ol hydrobromide, is a reversible, competitive acetylcholinesterase inhibitor. It is isolated from the bulbs of Caucasian snowdrops of galanthus genus. It is known to be effective for the treatment of mild to moderate dementia of the Alzheimer's type. But, therapy with galantamine can be considered optimal only when effective plasma levels are reached when required. In addition, peak values (Cmax) should be as low and level as possible so as to reduce the incidence and severity of possible side effects. Accordingly, an extended release formulation fulfils these requirements. Extended release formulations are also preferred over the immediate release formulations as they reduce the frequency of dosing thereby increasing patient compliance.
Extended release formulations for galantamine are marketed in the United States under the brand name of Razadyne® available as extended release capsules and in Europe as Reminyl® available as prolonged release capsules containing pellets. US 7,160,559 discloses controlled release particles of galantamine where galantamine and a water soluble film forming polymer are coated on inert spheres, followed by a release rate controlling membrane coating comprising a water insoluble polymer and optionally a plasticizer, and a topcoat with galantamine and water-soluble polymer and wherein the formulation is capable of releasing in USP buffer pH 6.8 at 37°C in a paddle apparatus operating at 50 rpm, from 20 to 40% of the total amount of galantamine hydrobromide in 1 hour, and more than 80% of the total amount of galantamine hydrobromide in 10 hours. EP 1140105 discloses particles of galantamine comprising a water soluble excipient and optionally other excipients, and which are coated by a release rate controlling membrane coating.


However, the production of coated pellets is an expensive and lengthy process and involves the use of specialized equipment like extruders, spheronizers and rotor granulators.
There is still a need to formulate an economic and robust extended release solid dosage form for galantamine. The inventors have now been able to prepare an economic and robust extended release matrix solid dosage form of galantamine.
Object of the invention
An object of the invention is to formulate an extended release matrix solid dosage form of galantamine with a desired release profile.
Summary of the invention
The present invention relates to formulation of an extended release matrix solid dosage form of galantamine with a desired release profile.
Detailed description of the invention
The present invention discloses an extended release matrix solid dosage form of galantamine.
The term "extended release" can be used interchangeably with prolonged release and means release of the active agent over an extended period of time so that plasma concentrations of active agent are maintained at a therapeutic level to provide therapeutic benefits for an extended period of time.
The term "matrix" refers to any dosage form where the active ingredient and the release controlling agent are interdispersed optionally along with other excipients.
The term "galantamine" encompasses galantamine and its pharmaceutically acceptable salts, hydrates and solvates thereof.
The extended release matrix solid dosage form can be in the form of any solid dosage form known in the art and can be for example, tablets, pellets, spheroids, particles and the like. The term "tablet" includes without limitation, tablets, pills, minitablets and the like. The term 'particle' includes particles, granules, crystals, agglomerates and the like.


The term "minitablet" as used herein refers to any tablet with an overall weight in their uncoated form of from about 10-50 mg. The minitablets are preferably cylindrical in shape having a convex upper face and a convex lower face having diameters ranging between 2-4 mm.
The desired release profile of galantamine from the extended release matrix dosage forms of the present invention is regulated by a release controlling agent. The release controlling agent may be hydrophilic or hydrophobic. The hydrophilic release controlling agents may include but are not limited to cellulose derivatives such as hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, ethylcellulose and the like, noncellulose derivatives which include, but are not limited to guar gum, galactomannans, agar, alginates, polyvinylpyrrolidone, polyvinylacetate, acrylic polymers and the like and mixtures thereof. The hydrophobic release controlling agents include but are not limited to glycerides such as for example mono-, di- or triglycerides: stearin, palmitin, laurin, myristin, hydrogenated castor or cottonseed oils, glyceryl palmitostearate, glyceryl behenate and the like, fatty acids and alcohols such as for example stearic, palmitic or lauric acids, stearyl, cetyl or cetosteryl alcohols and the like and waxes such as for example white wax, bees wax, carnauba wax and the like.
The amount of release controlling agent required to get the desired release profile depends upon the nature and extent of the release controlling agent.
In another embodiment of the present invention, the extended release matrix solid dosage form may further be coated with one or more coatings which may or may not control release of the drug.
In an interesting embodiment, the one or more coating(s) responsible for controlling the release of the drug comprise of one or more excipients selected from the same group of excipients which are enumerated above as release controlling agents optionally with additives useful for film formation.


In a preferred embodiment, the extended release matrix solid dosage form is in the form of tablets one or more of which may optionally be filled in a hard capsule which may be comprised of gelatin, hydroxypropyl methyl cellulose and the like.
In a still preferred embodiment of the present invention, the extended release matrix tablets comprise of a hydrophobic release controlling agent.
In a still more preferred embodiment of the present invention, the hydrophobic release controlling agent is glyceryl behenate. Glyceryl behenate is a mixture of glyceryl esters of behenic acid and monobehenate having a melting point range of 69-74°C.
The extended release matrix solid dosage form of the present invention, in addition, also contains other excipients necessary for formulation of the dosage form. For example, for tablets, these excipients include fillers or diluents, binders, lubricants, glidants and the like.
Examples of diluents include, but are not limited to calcium salts such as calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate and the like; cellulose derivatives such as microcrystalline cellulose, silicified microcrystalline cellulose and the like; saccharides such as lactose, sucrose, starch, pregelatinized starch, mannitol, sorbitol, lactitol, dextrose, fructose and the like, and mixtures thereof.
Examples of binders include, but are not limited to starches, cellulose and cellulose derivatives such as hydroxypropyl methylcellulose, hydroxypropyl cellulose and the like, saccharides such as lactose, sugar alcohols and the like, polyvinyl pyrrolidone, polyethylene glycol, copovidone, polyvinyl alcohol, gelatin, gum arabic, pullulan, agar, tragacanth, sodium alginate and the like.
Examples of lubricants include, but are not limited to talc, stearates such as magnesium stearate, calcium stearate, stearic acid, glyceryl behenate, canola oil, hydrogenated vegetable oil, magnesium oxide, mineral oil, poloxamer, polyethylene glycols, sodium lauryl sulfate, sodium stearyl fumarate and the like.


Examples of glidants include, but are not limited to talc, starches, stearic acid, anhydrous colloidal silica and magnesium trisilicate.
It should be appreciated that there is considerable overlap between all the above-listed matrix forming agents and other additives of the core and the coat, in common usage, since a given agent is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, for example, some of the release controlling agents of the present invention, may, also be used to, impart other properties to the final dosage form. The above-listed agents should be taken as merely exemplary, and not limiting, of the types of additives that can be included in composition s of the present invention.
One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation and without any undue burden. The amount of each type of additive employed may vary within ranges conventional in the art. Thus for example, the amount of glidant may vary within a range of from 0.1 to 10% by weight, the amount of binder may vary within a range of from about 1 to 15% by weight, the amount of filler or diluent may vary within a range of from 5 to 40% by weight whereas the amount of lubricant may vary within a range of from 0.1 to 5.0% by weight. The ranges mentioned here should be taken as exemplary and not limiting of the ranges of additives that can be included in compositions of the present invention.
In a preferred embodiment of the invention, the tablets comprise microcrystalline cellulose as a diluent, magnesium stearate as glidant and glyceryl behenate as a matrix release controlling agent.
The extended release matrix solid dosage form of the present invention may be prepared by any of the techniques well known to the person of skill in the art. For example, the tablets of the present invention can be prepared by any of the tabletting techniques known to a person skilled in the art such as wet granulation, dry granulation, direct compression, melt granulation and the like.


In a preferred embodiment, the present invention employs melt granulation technique for the preparation of the tablets.
The melt granulation technique involves mixing all the intragranular excipients with the drug and melting the mixture in a jacketed rapid mixer granulator (RMG). The melted blend is then allowed to cool, dried if required, lubricated and compressed (preferably using multi-tip punches) to get the tablets.
A more complete understanding can be obtained by reference to the following example which is described only for purposes of illustration and is not intended to limit the scope of the invention.
Example 1

Ingredients Quantity (mg/tablet)
Galantamine hydrobromide equivalent to Galantamine base 5.126
Microcrystalline cellulose (Avicel® PH-101) 10.874
Glyceryl behenate (Compritol® 888 ATO) 18.000
Magnesium stearate 1.000
Total weight in mg 35.000
Manufacturing Process
Galantamine hydrobromide was weighed and mixed with the required quantity of microcrystalline cellulose and glyceryl behenate which were previously sifted through a suitable sieve. This mixture was melt granulated in a jacketed rapid mixer granulator. The melted blend was dried at room temperature and sifted through a suitable sieve. The blend was then lubricated with magnesium stearate (previously sifted through a suitable sieve) and compressed using 4mm round shaped multi-tip punches. These tablets, two tablets for the 8 mg, were then filled into hard gelatin capsules. Similarly four tablets for the 16 mg and eight tablets for the 32 mg strengths can be filled into hard gelatin capsules.


Dissolution study of the prepared capsules was carried out in type II apparatus (paddle with sinkers) using 900 ml of 50mM phosphate buffer of pH 6.5 as medium at a speed of 50 rpm and at 37±0.5°C temperature.
The following table shows the comparative dissolution data of the cited example and that of Reminyl® (Shire Laboratories).

Time (hrs) % Drug release (Reminyl®) % Drug release (Example 1)
1 27.0 24.0
24 I 41.0 40.0
61.0 65.0
6 75.0 81.0
8 83.0 91.0
10 12 89.0 97.0
93.0 100.0
Claim
1. An extended release matrix solid dosage form comprising galantamine.