FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -- "STABILIZATION OF BUPROPION HYDROCHLORIDE"
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Campus, Alembic Road, Vadodara-390 003,
Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

FIELD OF THE INVENTION
The present invention relates to stable bupropion hydrochloride in general. In
particular, the present invention relates to stable bupropion hydrochloride compositions comprising pharmaceutically acceptable stabilizers like dextrins, polyacids or a mixture of these.
BACKGROUND OF THE INVENTION
Bupropion hydrochloride is a well-known antidepressant. It is chemically known as
(±)-2-(tert-butylamino)-3'-chloropropiophenone hydrochloride. (SeeU.S.3, 819,
706 and 3,885,046 and the Merck Index, Eleventh Edition, entry No. 1488). Bupropion hydrochloride, as such a stable molecule by itself, starts degrading once it is mixed with excipients. While the instant release tablets currently sold are quite suitable and degradation of bupropion hydrochloride is successfully prevented, the method of manufacturing the same is less than desirable based on cost as well as process conditions. Methods of. stabilization are disclosed in Orange Book patents claimed for bupropion hydrochloride sustained release formulation, US 5,358,970, US 5,731,000 and US 5,763,493 which is marketed in the United States as ZYBAN® by Glaxo-Smithkline.
However, there is still a need for improved stabilizers for bupropion hydrochloride. It has now been surprisingly observed that dextrins, polyacids or mixtures of these can be used as stabilizers for bupropion hydrochloride.
OBJECT OF THE INVENTION
An object of the present invention is to provide a stable pharmaceutical composition comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer where the stabilizer used is a dextrin, a polyacid derivative or a mixture of both so as retard the rate of degradation of bupropion hydrochloride so as to lower the levels of impurities in the said composition.
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SUMMARY OF THE INVENTION
The present invention relates to pharmaceutical compositions comprising bupropion hydrochloride and a pharmaceutically acceptable stabilizer where the stabilizer used is a dextrin, a polyacid derivative or a mixture of both.
DETAILED DESCRIPTION OF THE INVENTION
This present invention is particularly directed to a new and improved stable composition of the antidepressant bupropion hydrochloride which comprises pharmaceutically acceptable stabilizers such as dextrins, polyacids or mixtures of these. These stabilizers retard decomposition of bupropion thereby reducing the level of impurities in pharmaceutical compositions comprising these excipients and bupropion.
Bupropion hydrochloride degrades rapidly when it is admixed with any pharmaceutical excipients Formulating a stable bupropion hydrochloride pharmaceutical composition is therefore a big challenge for the formulation scientist. The compositions formulated may not be stable under normal conditions of storage owing to various mechanisms namely oxidation, hydrolysis etc. This may result in higher levels of impurities than that are normally acceptable. Suitable stabilizers may be included to retard the rate of degradation so as to lower the levels of impurities. In the present invention, novel stable compositions of bupropion hydrochloride are disclosed.
Stabilizers used in the present invention are, but not limited to dextrins, polyacids and mixtures of dextrins and polyacids. In a preferred embodiment, maltodextrin, polycarbophil or a mixture of both are used as stabilizers.
Maltodextrin belongs to the class of dextrins, which have the same general formula as starch but a smaller and less complex molecule. They are polysaccharides and are
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produced as intermediate products in hydrolysis of starch by heat, by acids, and by
enzymes.
Polycarbophil is a polyacid and is a polymer of acrylic acid cross linked with divinyl
glycol whose molecular weight ranges from 700000 to 3-4 billion.
The amount of the stabilizer which should be used to achieve the results desired, for stabilization of bupropion hydrochloride in pharmaceutical compositions, is about 0.1% to 50% and more preferably 0.5% to 10% of the total weight of the composition. In a preferred embodiment, polycarbophil is used within the range of 0.1% upto 2.5% and maltodextrin is used within the range of 0.1% upto 10% of the total weight of the composition. In a preferred embodiment, a mixture of polyacid and dextrin is used in a ratio of 0.1:9.9 to 9.9:0.1. In a still preferred embodiment, a mixture of polycarbophil and maltodextrin is used in a ratio of 0.1:9.9 to 9.9:0.1.
The composition of bupropion hydrochloride with the stabilizer may be any of the compositions such as. but not limited to solid dosage forms, liquids, semisolids etc and may be administered through known routes of administration, for e.g., oral, parenteral, topical routes.
Solid dosage forms may include, but are not limited to tablets, pellets, capsules, pills, powders, granules, cachets, suppositories etc. Liquid dosage forms may include, but are not limited to elixirs, tinctures, suspensions, syrups, and emulsions. Semi-solids may be, but are not limited to pastes, creams, lotions etc.
In a preferred embodiment, the composition used in the present invention is a tablet administered through oral route. The tablet may either be an immediate release or an extended release tablet which can further be coated or uncoated. Immediate release refers to a composition which releases active agent substantially immediately upon contact with gastric juices and will result in substantially complete dissolution within about 1 hour. Extended release refers to a pharmaceutical composition which releases one or more active pharmaceutical agents over a prolonged period of time, in this
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case over a period of more than 1 hour. In yet another preferred embodiment, the tablet is an extended release tablet.
A solid oral dosage form according to the invention may optionally comprise additives commonly used in solid dosage formulations. These include but are not limited to disintegrants, fillers or diluents, binders, lubricants, glidants, surfactants, spheronizing aids and the like. As disintegrants one can particularly mention as examples calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, crosslinked polyvinyl pyrrolidone. sodium starch glycolate, alginic acid, sodium alginate and guar gum, crosslinked carboxy methylcellulose and the like. Examples of fillers or diluents include but are not limited to calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, silicified microcrystalline cellulose, cellulose powdered, fructose, kaolin, lactitol, starch, starch pregelatinized, sucrose, confectioner's sugar, compressible sugar, dextrose, lactose, mannitol, sorbitol, sucrose and the like, or mixtures thereof. Examples of binders include , but are not limited to starches, microcrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropylmethyl cellulose, methyl cellulose, polyvinylpyrrolidone, gelatin, gum arabic. ethyl cellulose, copovidone. polyvinyl alcohol, pullulan, agar, tragacanth, sodium alginate and the like, or mixtures thereof. Examples of lubricants and glidants include, but are not limited to silicon dioxide, colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, sodium stearyl fumarate, talc, polyethylene glycol 4000-8000, hydrogenated castor oil, magnesium trisilicate, sucrose esters of fatty acids, microcrystalline wax, yellow beeswax, white beeswax and the like, or mixtures thereof. An example of spheronization aid can be, but not limited to microcrystalline cellulose. Examples of surfactants include, but are not limited to sodium lauryl sulphate, sorbates and the like.
When formulated as a capsule, the capsule can be a hard or soft gelatin capsule, a starch capsule, or a cellulosic capsule. Such dosage forms can further be coated with,
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for example, a seal coating, an enteric coating, an extended release coating, or a targeted delayed release coating. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents which include, but are not limited to sorbitol syrup, methyl cellulose or hydrogenated edible fats, emulsifying agents which include , but are not limited to lecithin or acacia, non-aqueous vehicles which include, but are not limited to almond oil, oily esters or ethyl alcohol and preservatives which include, but are not limited to methyl or propyl p-hydroxybenzoates or sorbic acid. The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions 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, e.g., 0.1 to 5% by weight; the amount of binder may vary within a range of from about 1 to 45%
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by weight, e.g. 20 to 30% by weight; the amount of disintegrant may vary within a range of from 1 to 20% by weight, e.g. 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 are not limiting of the ranges of additives that can be included in compositions of the present invention. Compositions can be prepared by methods well known to persons skilled in the art. For example, liquids like solutions and suspensions may be prepared by simple blending, whereas emulsions are usually prepared by homogenization techniques.
In a preferred embodiment, tablets are prepared by any of the granulation methods known in the art, e.g., dry granulation, wet granulation and direct compression. In a still preferred embodiment, the tablets are prepared by wet nonaqueous granulation. In a preferred embodiment, the non-aqueous wet granulation is carried out using a fluid bed processor.
The tablets prepared are then subjected to accelerated stability studies to evaluate the impurity profile. Accelerated stability studies are studies designed to increase the rate of chemical degradation or physical change of a drug substance or drug product by using exaggerated storage conditions as part of the formal stability studies. Data from these studies, in addition to long term stability studies, can be used to assess longer term chemical effects at non-accelerated conditions and to evaluate the effect of short term excursions outside the label storage conditions such as might occur during shipping. Results from accelerated testing studies are not always predictive of physical changes.
The following examples are few representatives of the invention and are in no way construed as being limited to the invention.
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Example 1
Ingredient Weight(mg)
Bupropion hydrochloride 150
Mannitol (Pearlitol SD200) 10
Povidone (K90D) 4
Colloidal silicon dioxide (Aerosil R972) 1
Talc 1
Colloidal silicon dioxide (Aerosil R972) 1
Sodium stearyl fumarate (Pruv) 3
Total 170
The drug, mannitol and colloidal silicon dioxide were admixed. Povidone was dissolved in the granulating solvent and the blend was granulated with the povidone solution. The granules were lubricated with talc, colloidal silicon dioxide and sodium stearyl fumarate. The lubricated granules were compressed using 8mm round, standard concave punches.
Example 2
Ingredient Weight(mg)
Bupropion hydrochloride 150
Mannitol (Pearlitol SD200) 10
Polycarbophil (Noveon AA1) 4
Colloidal silicon dioxide (Aerosil) 1
Talc 1
Colloidal silicon dioxide (Aerosil) 1
Sodium stearyl fumarate (Pruv) 3
Total 170
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The drug, mannitol and colloidal silicon dioxide were admixed. Polycarbophil was dispersed in the granulating solvent. The powder blend was granulated with the polycarbophil dispersion. The granules were lubricated with talc, colloidal silicon dioxide and sodium stearyl fumarate. The lubricated granules were compressed using 8mm round, standard concave punches.
Tablets of examples 1 and 2 were coated with a novel coating composition which is
disclosed in our copending provisional application number and which is
incorporated herewith in its entirety as a reference.
Composition of first coat

S.No. Ingredient Percent Composition
1 Ethyl cellulose (7cps) 40
2 Polyethylene glycol (Polyglykol 6000P) 40
3 Lactose monohydrate 20
4 Isopropyl alcohol Dichloro methane q.s
5 Purified water q.s.
Ethyl cellulose was dispersed in isopropyl alcohol-dichloro methane mixture under constant stirring. Lactose monohydrate was dispersed in isopropyl alcohol-dichloro methane mixture and size reduced using homogenizer. The homogenized mass was then added to the ethylcellulose dispersion. Polyethylene glycol was dissolved in purified water and then added to the coating dispersion formed above. The core tablets of Bupropion hydrochloride were then coated using Accela Cota type coating
machine
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Composition of second coat:

S.No. Ingredient Percent Composition
1 Methacrylic acid copolymer (Eudragit L 100 55) 74.1
2 Triethyl citrate 18.5
3 Talc 7.4
4 Isopropyl alcohol q.s
Eudragit LI00 55 was dispersed in isopropyl alcohol under stirring. Talc was added to the dispersion. Triethyl citrate was added to the dispersion formed above. The ethyl cellulose coated tablets were then coated with Eudragit LI00 55 coating dispersion.
Tablets of examples 1 and 2 were subjected to accelerated stability studies
Example 3
Ingredient Weight(mg)
Bupropion hydrochloride 150
Talc 6
Maltodextrin (Lycatab DSH) 7
Talc 1
Sodium stearyl fumarate (Pruv) 2
Total 166
The drug and talc were admixed. Maltodextrin was dissolved in the granulating solvent and the blend was granulated with the maltodextrin solution. The granules were lubricated with talc, colloidal silicon dioxide and sodium stearyl fumarate. The lubricated granules were compressed using 8mm round, standard concave punches.
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These uncoated tablets were investigated for their impurity profile.
Example 4
Ingredient Weight(mg)
Bupropion hydrochloride 150
Maltodextrin (Lycatab DSH) 10
Colloidal silicon dioxide (Aerosil R972) 1
Polycarbophil 4
Colloidal silicon dioxide (Aerosil R972) 1
Talc 1
Sodium stearyl fumarate (Pruv) 2
Total 166
The drug, maltodextrin and colloidal silicon dioxide were admixed. Polycarbophil was dispersed in granulating solvent and the blend was then granulated with the polycarbophil dispersion. The granules were lubricated with talc, colloidal silicon dioxide and sodium stearyl fumarate. The lubricated granules were compressed using 8mm round, standard concave punches.
The tablets of example 4 were coated with a novel coating composition disclosed in
our copending application number which is referred herewith, in its
entirety
Composition of first coat

S.No. Ingredient Percent Composition
1 Ethyl cellulose 40
2 Polyethylene glycol (Polyglykol 6000P) 40
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3 Lactose monohydrate 20
4 Denatured alcohol q.s
5 Purified water q.s.
Ethyl cellulose was dispersed in denatured alcohol under constant stirring. Lactose monohydrate was dispersed in denatured alcohol and size reduced using homogenizer. The homogenized mass was then added to the ethyl cellulose dispersion. Polyethylene glycol was dissolved in purified water and then added to the coating dispersion formed above. The core tablets of Bupropion hydrochloride were then coated using Accela Cota type coating machine.
Composition of second coat:

S.No. Ingredient Percent Composition
1 Methacrylic acid copolymer (Eudragit L 100 55) 57
2 Polyethylene glycol (Polyglykol 6000P) 14
3 Talc 29
4 Purified Water q.s
5 Isopropyl alcohol q.s
Eudragit L100 55 was dispersed in isopropyl alcohol under stirring. Talc was added to the dispersion. Polyethylene glycol was dissolved in purified water and then added to the dispersion formed above. The ethyl cellulose coated tablets were then coated with Eudragit L100 55 coating dispersion.
The final tablets were analyzed using suitable analytical methods to find out the impurity profiles of all the formulations (Examples 1-4). The data obtained showed
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surprising results. Formulations using maltodextrin or polycarbophil alone (Examples 2-3) or formulations with a mixture of both (Example 4) showed significantly lower values of total impurities both initially and when subjected to accelerated conditions of stability than the formulations devoid of any of them
Following are the tabulated values of the total impurity contents of the above given examples
Table 1

Stabilizer added Total impurities (Initial) Acceleratedstability studies(2 months)
Example 1 - 0.78 19.522
Example 2 Polycarbophil 0.34 1.009
Table 2

Stabilizer added Total impurities (Initial)
Example 3 Maltodextrin 0.229
Table 3

Stabilizer added Total impurities (Initial)
Example 4 Polycarbophil+Maltodextrin 0.436
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It is thus evident from the above tables that compositions having stabilizers of the present invention have lower impurity levels and hence higher stability over a period of time (2months as illustrated in table1).
Claim
1. A stable pharmaceutical composition of bupropion.
Dated this on 14th September, 2006

Sonali Bhokarikar
Of S. Majumdar&Co. Applicant's agent