FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
&
THE PATENTS RULE, 2003 COMPLETE SPECIFICATION
(SECTION 10 and Rule 13)
TITLE OF THE INVETION
"Pharmaceutical Compositions comprising p-phenethylamine derivative"
Emcure Pharmaceuticals Limited.,
an Indian company, registered under the Indian Company's Act 1957
and having its registered office at
Emcure House, T-184, M.I.D.C., Bhosari, Pune-411026, India.

PHARMACEUTICAL COMPOSITIONS COMPRISING β-PHENETHYLAMINE DERIVATIVE
FIELD OF THE INVENTION
The present invention relates to a novel pharmaceutical composition comprising β-phenethylamine derivative. In particular it relates to compositions of (R)-Sibutramine free base and a process for preparation thereof.
BACKGROUND OF THE INVENTION
Sibutramine, which is also chemically known as l-(4-Chlorophenyl)-N,N-dimethyl-α-(2-methylpropyl)cyclobutanemethanamine, was initially reported for preventing or treating depression, Parkinson's disease in US 4,443,449. Subsequently, this tertiary amine was disclosed to be useful in treating obesity in US 5,436,272. Sibutramine is a centrally acting monamine-reuptake inhibitor that mainly acts to increase satiety. Sibutramine also inhibits serotonin, norepinephrine and to a lesser extent, dopamine re-uptake. Sibutramine was approved in the USA in 1997 and in the European Union in 1999.
Sibutramine is a racemic mixture containing equimolar amounts of the R(+) and S(-) enantiomers. R(+) and S(-) enantiomers of sibutramine differ in their physiological profile and R-sibutramine is presumed to be more efficacious sibutramine enantiomer. Further, (RS)-sibutramine has two active metabolites, desmethylsibutramine and didesmethylsibutramine that are also optically active.
Sibutramine is a semisolid substance, having low melting point and is hardly soluble in water. The solubility of sibutramine free base rapidly decreases with increase in pH of dissolution medium. Therefore, designing a phannaceutically acceptable composition of sibutramine has vexed researchers in this field. There are several attempts reported to solve this problem, which are as follows:
_ GB_2098 602 _of_Jeffrey_et._al_discloses_hydrochloride_salt _of_ sibutramine._However,_ hydrochloric acid salt was known to contain variable amounts of water and tends to be
2

hygroscopic. Normally, hygroscopic substances are not preferred for preparing a pharmaceutical composition.
To overcome limitation of hydrochloride salt, Jeffrey et. al. in US 4,929,629 discloses the hydrochloride monohydrate form. The said form is reported to be a non-hygroscopic product and suitable for. the preparation of capsules. Sibutramine hydrochloride monohydrate has a water solubility of 2.9 mg/ml at pH 5.2. Apparently racemic sibutramine hydrochloride monohydrate is used as active ingredient in marketed formulation Meridia "
However, Lim et. al. in WO 06/073290 reported that sibutramine hydrochloride monohydrate has relatively low solubility between pH 1.0 and pH 7.4. Further preparation of monohydrate form is complicated since it requires addition of a predetermined amount of water to a reaction mixture. To overcomes this problem, literature recommends use of a dicarboxylic acid salt, particularly sibutramine oxalate and sibutramine malonate. The anhydrous forms of these salts are reported to possess remarkably high solubility in water and also exhibit non-hygroscopicity and stability.
Subsequently, Lim et. al. in WO 06/073291 has also reported that sulphonic acid salts of sibutramine viz. besylate, camsylate, tosylate and edisylate also possess desired physicochemical properties.
Further, in WO 07/007971, Park et. al. has reported a pharmaceutical composition of sibutramine in a free base form comprising an acidifying agent selected from the group of citric acid, succinic acid, malic acid, maleic acid and a surfactant. The document discloses that by extraneous addition of acid and a surfactant, the problem of residual organic solvent found in process for the conversion of sibutramine to an acid addition salt form could be resolved without compensating for dissolution profile of sibutramine in aqueous medium.
WO 04/096202, Wain et. al. discloses a pharmaceutical composition comprising an anti-obesity agent and at least one acidulant together with a pharmaceutically acceptable carrier, diluent or excipient therefore. The acidulant is selected from acetic acid, citric
3

acid, fumaric acid, succinic acid, malic acid, phosphoric acid, sorbic acid, tartaric acid and the like.
WO 06/112649 of Jeon et. al. reports a pharmaceutical composition of sibutramine in the
form of a solid dispersion wherein sibutramine free base, acid and hydrophilic polymer
are uniformly dispersed. The hydrophilic polymer is at least one selected from the group
consisting of hydroxypropylcellulose, hydroxypropylmethyl cellulose,
polyvinylpyrrolidone, vinylpyrrolidone-vinylacetate copolymer, polyvinyl alcohol and polyvinylalcohol — polyethyleneglycol copolymer.
Chang et. al. in WO 07/040306 also discloses a solid dispersion formulation of sibutramine free base and surfactants. The preferred surfactants are those, which exists in the form of semisolid or solid at the room temperature, as they can easily be treated.
Further, Khan et. al. in WO 01/34140 also discloses a pharmaceutical composition which is useful in treating obesity. The disclosed formulation has sibutramine and a bulk forming agent. The patent discloses that the bulk forming agents swell in the stomach when taken with water, giving rise to a sense of satiety and thus reducing food intake. Therefore, it is beheved that a combination product containing sibutramine and an absorptive bulk forming agent would exhibit an enhanced therapeutic effect. The disclosed bulk forming agents are methyl cellulose, sterculia, wheat fibre/bran, isphagula husk, carboxymethyl cellulose, hydroxylethyl cellulose, hydroxypropylmethyl cellulose, guar gum, xanthun gum, carrageenan gum, tragacanth, carob, agar, locust bean gum, sodium alginate, alginic acid or matricor.
Thus, from the above it would be apparent that several attempts have been made to design a pharmaceutical composition of sibutramine. These could be categorized as follows:
a) Preparation of acid addition salts of sibutramine;
b) Addition of an acid to the composition of sibutramine free base; and
c) Preparation of solid dispersion
4

However, typically, preparation of salts having pharmaceutically useful physical properties always pose a challenge to manufacturer, as such salts should have good solubility, good stability, good non-hygroscopicity and compressibility in tablet form. Synthesis of salts involves an additional synthesis step, which enhances the manufacturing cost. Further, recourse to a different salt also has regulatory implications associated with it.
Use of an acid in pharmaceutical composition also has several disadvantages. First of all use of an acid poses a major threat to stability of formulation because of reactive nature of drug substance. Sibutramine has a reactive tertiary amine centre, which could react with high amounts of acids present in the formulation. Moreover, this reaction could further be enhanced by heat generated during various manufacturing steps of formulation such as mixing, compression etc. Secondly, relatively higher amounts of acids are required to maintain the pH in the acidic range to enhance the dissolution rate of free sibutramine at the site of absorption, which is not always feasible. Further there are no specific guidelines to choose a particular acid from various acids available. Thus, selection of a particular acid imparting desired dissolution profile to formulation could prove a difficult task for a formulator.
Solid solutions/dispersions are generally produced by a melt-extrusion method or by solvent evaporation method. An important prerequisite to manufacture solid solutions/dispersions by melt extrusion method is miscibility of the drugs and the carriers in the melt forms. Another limitation to the melt method is the thermo-instability of the drugs and carriers.
Further, the solid dispersions prepared by melt-extrusion method require utilization of water soluble excipients as carriers of solid solutions/dispersions. An ideal carrier should possess good solubility in water, low melting points, ability to solubilize active agents and capacity to improve wettability of therapeutic agent. Though, there exists a number of carrier, which could be utilized for preparation of solid dispersion, however, it is -generally-very—difficulty—if—not—impossibler to -select- an—ideal- carrier—which—has—all— abovementioned ideal properties. Further, other limitations associated with melt extrusion
5

method such as method of preparation, reproducibility of its physicochemical properties, formulation into suitable dosage forms, physical and chemical compatibility of the ingredients and active agents at the melting temperature, scale-up of manufacturing processes and physical and chemical stability of drugs and vehicles further aggravates manufacturer concerns for taking recourse to such a method which is not particularly commercially viable. With solvent evaporation method, a major limitation is problem associated with residual solvents remaining in the composition.
Thus, despite a large number of known formulations of sibutramine free base and/or its salt, for example as discussed above, still there exists a need for improved stable formulations of sibutramine free base.
OBJECTS OF THE INVENTION
A primary object of the present invention is to prepare a novel and stable pharmaceutical composition of sibutramine free base.
Another object of the present invention is to make a pharmaceutical composition of sibutramine free base that has desired dissolution profile.
A further object of the present invention is to provide a manufacturing method for novel and stable pharmaceutical compositions of sibutramine free base, which is simple, convenient and economical.
SUMMARY OF THE INVENTION
The present invention relates to a novel and stable pharmaceutical composition of sibutramine free base as an active ingredient.
The present inventors have surprisingly found that when a particular enantiomer of sibutramine is used, a pharmaceutical composition with desired dissolution property could be obtained even with the free base form of sibutramine.
6

Thus, in one aspect the present invention provides a stable pharmaceutical composition comprising therapeutically effective amounts of a sibutramine enantionmer free base.
In another aspect of the present invention, the tedious process of conversion of sibutramine free base to a corresponding acid addition salt for obtaining desired dissolution properties is obviated according to present invention.
In still further aspect, recourse to solid dispersion technique is avoided for preparation of pharmaceutical compositions having sibutramine free base.
Thus, present invention provides formulations comprising sibutramine enantiomers in free base form, which are novel and simple.
In still another aspect, there is provided a process for preparing such novel and stable pharmaceutical compositions comprising sibutramine enantionmer.
These objects of the present invention will become more fully apparent from the following detailed description.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a pharmaceutical composition comprising (R)-enantiomeric form of sibutramine free base.
The present inventors have surprisingly found that when (R)-sibutramine free base is used to prepare a pharmaceutical composition, then even with the formulations prepared by conventional processes such as granulation, desired release profile could be achieved.
As used herein the term "composition comprising (R)-enantiomer of sibutramine" means the therapeutic preparation may be enriched to provide predominantly (R)-enantiomer of sibutramine. An enantiomerically enriched mixture may comprise, for example, at least 60 mol percent of one enantiomer, or more preferably at least 75, 90, 95, or even 99 mol —percent. In certain embodiments. sibutramineis enriched in the (R) enantiomer.-In-certain-embodiments, (R)-sibutramine is substantially free of the (S)-enantiomer. Substantially
7

free, as the term is used herein, means that the (S)-enantiomer of sibutramine makes up less than 10%, or less-than 5%, preferably less than 1% as compared to the amount of the (R)-enantiomer of sibutramine.
The terms '(R)-enantiomer', '(R)-sibutramine' and '(R)-sibutramine enantiomer' are used interchangeably.
The (R)-sibutramine is typically present as a free base and is present in amount sufficient to achieve the desired therapeutic response. The dosage of sibutramine for achieving therapeutic response is already known in the art. The unit dosage is 10mg and 15 mg as monohydrate hydrochloride salt, which correspond to 8.37 mg and 12.56 mg, respectively, as sibutramine free base. Typically the instant formulation contains (R) — sibutramine free base in the range of 3 mg to 15 mg.
It is well known that each enantiomer by virtue of three dimensional structure can interact with binding sites of enzymes and receptors differently and one with strong binding provide pronounced pharmacological action. Hence the pharmacological differences caused by enantiomers can be pharmacokinetic or pharmacodynamic in nature. The present inventors have found that a formulation with desirable solubility profile could be prepared by using (R)-enantiomeric form of sibutramine rather than racemic sibutramine, which is available in commercially marketed product. A conventional formulation of racemic sibutramine is incapable of delivering the drug in biological fluids, the formulation of (R)-sibutramine in a conventional (non-solubility enhancing) formulation could achieve the desired dissolution profile and thereby delivery of the drug to the biological fluids.
A conventional formulation typically would contain pharmaceutically acceptable excipients to aid manufacture of the dosage form and release of the drug substance in the body. These excipients include, but are not limited to fillers, binders, disintegrant, lubricants, glidants, antiadherants, and surfactants.
8

A combination of excipients may also be used. Such excipients are known to those skilled in the art, and thus, only few representative examples for each class of excipient are mentioned herein below:
Diluents for the formulations are inert substances that may be used as a vehicle for the active agent, optionally in conjunction with other excipients, as long as the resulting formulation meets the dissolution profile desired and/or is stable. Suitable diluents include, lactose-based materials such as spray dried lactose; cellulosic materials such as microcrystalline cellulose; starches including partially pregelatinized starch, pregelatinized starch, partially hydrolyzed starch, maize starch, potato starch, rice starch, wheat starch, and tapioca starch; sugar such as sucrose, dextrose, fructose, and the like; sugar alcohols such as mannitol, sorbitol, xylitol, and the like; saccharides polysaccharides such as maltodextrin and the like; dibasic calcium phosphate, calcium sulphate, and the combinations thereof.
Combination of two or more diluents can be used in the dosage formulations. When used, the total amount of diluents can be up to about 99 weight percent of the total weight of the formulation; specifically about 30 to about 98 weight percent; more specifically about 60 to about 97 weight percent; and yet more specifically about 80 to about 95 weight percent. Preferably lactose is used as diluent.
Binders may be, for example, starch, sugars, gums, hydroxypropyl methyl cellulose, hydroxyl propyl cellulose or the like. Certain traditional tablet diluents may also function as a disintegrant (e.g. starch), while other materials provide superior results as a disintegrant, for example, croscarmellose sodium, crospovidone, low-substituted hydroxypropyl cellulose, sodium starch glycolate, alginates, and the like. The disintegrant can be present in the formulations in an amount of about 0.01 to about 20 weight percent of the total weight of the formulation.
A lubricant and/or glidant can also be used in the dosage formulations to aid in the processing of powder materials. Exemplary lubricants include calcium stearate, glycerol behenate, magnesium stearate, mineral oil, polyethylene glycol, sodium stearyl fumarate,
9

stearic acid, talc, vegetable oil, zinc stearate, and combinations thereof. Magnesium stearate is preferred as lubricant.
Other optional additives to the dosage formulations include, for example, sweetening agent, flavoring agents, stabilizing agents, colorants, antioxidants and combinations comprising one or more of the foregoing additives.
Typically, the pharmaceutical composition of the present invention could be in any conventional form of dispensing the medicine and is selected from the group consisting of a powder, tablet, capsule, pellets, caplet, troche, rapid-disintegration tablet, aqueous suspension produced from powder. Preferably, the pharmaceutical composition is in the form of a capsule. More preferably, the pharmaceutical composition is in the form of hard gelatin capsule.
The pharmaceutical composition according to the present invention may be prepared by using any known process in the art. Such process includes wet granulation, dry granulation, direct compression etc. In general, a process for preparing a capsule formulation of R-Sibutramine free base comprises of following steps:
a) Sifting the drug and excipients;
b) Mixing the drug with excipients other than lubricants;
c) Adding sufficient amount of water to mixture of step b) and mixing to get wet cohesive mass;
d) Milling wet cohesive mass obtained above to get granules;
e) Drying and sifting the granules;
f) Adding sifted lubricants to the above granules; and
g) Filling the above mass of step f) into capsule
The above disclosed process may further include any one of the features known to a person skilled in the art. The dosage formulation may comprise the active agent and excipients in the form of particles having a particle size distribution that allows for the ease of processing the material, for example into tablets, by direct compression techmques, without segregation of the excipients. The desired particle range of active
10

agent and excipients and other components may be obtained by processes known in the art, including granulating, screening, milling, and the like.
Further, in the preferred embodiment, a process of preparing a pharmaceutical dosage formulation comprises passing of (R)-sibutramine and excipients through appropriate mesh sizes, either independently or collectively. The mixing or blending is done according to process known in the art such as by using a suitable blender or mixer etc.
The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing specification. The invention which is intended to be protected herein, however, is not construed to be limited to the particular forms disclosed, since these are to be regarded as illustrative rather than restrictive. Variations and changes may be made by those skilled in the art, without departing from the spirit of the invention.
The invention is further explained with the help of following illustrative examples, however, in no way these examples should be construed as limiting the scope of the invention.
EXAMPLES
Example-1:
Preparation of (R)-sibutramine capsules:
Capsules were prepared with components and contents presented in Table -1. (R) -sibutramine is in free base form, lactose, microcrystalline cellulose, colloidal silicon dioxide, magnesium stearate, were used to prepare the granules.
Sibutramine and excipients are sifted through suitable mesh size. Sibutramine was mixed with lactose by using cone blender. The said mass was granulated using water. The obtained granules were sieved and dried. The dried granules were then mixed with colloidal silicon dioxide and magnesium stearate. The obtained mass was filled into capsules.
11

Table -1: Capsule Formulation of (R)-Sibutramine

Components Content (mg)

Example -1 Example — 2 Example — 3
(R) - sibutramine 4.19 4.19 4.19
Lactose monohydrate 67.25 - 134.51
Microcrystalline cellulose 67.25 134.51 -
Colloidal silicon dioxide 0.65 0.65 0.65
Magnesium stearate 0.65 0.65 0.65
Purified water q.s. q.s. q.s.
Total weight 140 mg 140 mg 140 mg
Example -2:
Excipient compatibility study:
Various experiments were evaluated for compatibility with (R)- sibutramine free base. The various excipients were mixed with (R)-sibutramine in 1:1 ratio and compatibihty was evaluated at room temperature and at 40 °C / 75%RH for 15 days. Assay was analyzed by HPLC method. The results of these experiments are summarized in Table -2.
Table -2: (R)-Sibutramine ~ Excipient Compatibility Study

Sample % Assay (15 days)

Room temperature 40 0C7-75%RH

(R)-sibutramine 101.15 100.54
(R)-sibutramine + lactose 101.14 100.80
(R)-sibutramine + microcrystalline cellulose 102.09 101.72
(R)-sibutramine + Dibasic calcium phosphate 96.66 95.11
(R)-sibutramine + colloidal silicon dioxide 97.90 97.82
(R)-sibutramine + magnesium stearate 100.60 99.54
(R)-sibutramine + talc 101.09 98.52
(R)-sibutramine + sodium stearate fumarate 100.08 100.45
(R)-sibutramine + sodium starch glycolate 104.44 104.94
After 15 days, all the API-excipient mixture does not show any degradation at accelerated stability conditions of 40 C temperature and 75% Relative humidity. This study demonstrates good compatibility of (R)-sibutramine with all the above excipients.


Example -3:
Dissolution test:
Capsule of (R)-sibutramine was prepared with components and contents as shown in Table-3. The same capsules were compared for dissolution profile with commercially available sibutramine capsule from Kuhnil Pharma Korea. The results of this study are summarized in Table — 4. The dissolution experiments were performed according to Paddle type Dissolution Test Method (USP Type II) and 0.05M acetate buffer as dissolution medium. All samples were analyzed by HPLC method.
Table -3: Capsule Formulation of (R)-Sibutramine

Components Content (mg)

Example - 4 Example - 5
(R) - sibutramine 4.19 6.28
Lactose monohydrate 174.35 201.48
Colloidal silicon dioxide 0.65 0.65
Magnesium stearate 0.65 0.65
Purified water q.s. q.s

Total weight 180 mg 210 mg
Table -4: Comparative dissolution profile of capsule Formulation of (R)-Sibutramine

Sampling time (min) Example - 4 Example - 5 Commercial Sibutramine capsule (Kuhnil Pharma)

(R)-Sibutraminc (%) (R)-Sibutramine
(%) Sibutramine (%)
10 79.3 75.05 64.72
20 87.27 87.08 87.06
30 88.85 89.77 90.58
45 90.22 90.00 92.14
60 90.58 90.70 92.62
As seen from Table — 4, the capsule of the present invention exhibited a comparative dissolution profile to that of commercially available capsule formulation.
13

CLAIMS:

1. A pharmaceutical composition comprising (R) - enantiomers of sibutramine free base along with pharmaceutically acceptable excipients.
2. The pharmaceutical composition according to claim 1, wherein the said composition is prepared by granulation.
3. The pharmaceutical composition according to claim 1, wherein lactose, colloidal silicon dioxide and magnesium stearate are present as excipients.
4. The pharmaceutical composition according to claim 3, wherein lactose is present in amount of at least 90% by weight of the composition.
5. The pharmaceutical composition according to claim 3, wherein the content of (R)-sibutramine in the free base form is less than 1% by weight of the composition.
6. The pharmaceutical composition according to claim 3, which is formulated into tablet or capsule.
7. The pharmaceutical composition according to claim 6, wherein the composition comprises of (R) - sibutramine free base in the range of 3 mg to 15 mg.
8. The pharmaceutical composition according to claim 3, prepared by granulation, wherein at least 90% of drug is release within first one hour after oral administration.
9. A process for preparing pharmaceutical composition according to claim 2 comprising steps of granulating (R)-sibutramine free base with pharmaceutically acceptable excipients, mixing the said granules with lubricants and filling them into capsules.
10. A pharmaceutical composition of (R) - sibutramine free base as described herein with the help of foregoing examples.


(Signed)
und.
K. Gurjar
Chief Scientific Officer Emeu re Pharmaceuticals Ltd.
Dated this Eleventh (11th) day of August, 2008