FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)
1. Title of the invention. - IMPROVED PHARMACEUTICAL
COMPOSITIONS CONTAINING MINITABLETS OF PRAMIPEXOLE

2. Applicant(s)
(a) NAME:
(b) NATIONALITY
(c) ADDRESS:

ALEMBIC LIMITED
An Indian Company.
Alembic Campus, Alembic Road, Vadodara - 390 003, Gujarat, India.

3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention

FIELD OF THE INVENTION
This invention relates to pharmaceutical compositions comprising minitablets comprising low-dose, water-soluble drugs, intimately mixed with one or more water-soluble, non-swellable excipients and to methods of making the same.
BACKGROUND OF THE INVENTION
Low-dose, water-soluble drugs generally pose problems in attaining acceptable content uniformity (accuracy and precision of unit dose content). Also, inability of the low dose containing diffusion systems to generate an optimum concentration gradient leads to variable and erratic drug release profile. Thus dosage form development of such drugs poses a challenge to the pharmaceutical formulator.
It has now been surprisingly found that problems of content uniformity and erratic release profile can be overcome by formulating low dose drugs in the form of mini-tablets comprising one or more water-soluble, non-swellable excipients intimately mixed with the low dose drug.
OBJECTS OF THE INVENTION
It is an object of the invention to provide a pharmaceutical composition comprising mini-tablets comprising low-dose, water-soluble drugs intimately mixed with one or more water-soluble, non-swellable excipients.
It is another object of the invention to provide a pharmaceutical composition comprising mini-tablets comprising a low-dose, water-soluble drug intimately mixed with one or more water-soluble, non-swellable excipients which gives acceptable content uniformity of the low-dose, water-soluble drug.
It is another object of the invention to provide a pharmaceutical composition comprising mini-tablets comprising a low-dose water-soluble drug intimately mixed with one or more water-soluble, non-swellable excipients, which gives a reproducible drug release profile in vitro and in vivo.
Yet another object of the invention is to provide a process for the preparation of a pharmaceutical composition comprising mini-tablets comprising a low-dose, water-soluble drug intimately mixed with one or more water-soluble, non-swellable excipients.
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SUMMARY OF THE INVENTION
According to one aspect of the present invention there is provided a pharmaceutical composition comprising mini-tablets comprising a therapeutically effective amount of a low-dose, water-soluble drug, intimately mixed with one or more water-soluble non-swellable excipients.
According to another aspect of the present invention, there is provided a pharmaceutical composition comprising mini-tablets comprising low-dose, water-soluble drug intimately mixed with one or more water-soluble, non-swellable excipients which gives acceptable content uniformity of the low dose water soluble drug.
According to a further aspect of the present invention, there is provided a pharmaceutical composition comprising mini-tablets comprising a low dose water-soluble drug intimately mixed with one or more water-soluble, non-swellable excipients, which provides a reproducible in vitro and in vivo release profile of the drug.
According to another aspect of the present invention there is provided a process for preparation of a pharmaceutical composition comprising mini-tablets comprising a low dose, water-soluble drug, intimately mixed with one or more water-soluble, non-swellable excipients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed to a pharmaceutical composition comprising mini-tablets comprising a low dose, water-soluble drug, intimately mixed with one or more water-soluble, non-swellable excipients.
The term "mini-tablet" as used herein refers to any tablet of diameter between 2 to 5 mm.
The term "low dose" as used herein refers to any drug whose weight in a unit dosage form is less than or equal to 50 mg. In preferred embodiments, the weight may be less than or equal to 10 mg.
The low dose active ingredient can be selected from the group comprising of adrenergic agent; adrenocortical steroid; adrenocortical suppressant; aldosterone
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antagonist; amino acid; anabolic; analeptic; analgesic; anesthetic; anorectic; antiacne agent; anti-adrenergic; anti-allergic; anti-amebic; anti-anemic; anti-anginal; anti-arthritic; anti-asthmatic; anti-atherosclerotic; antibacterial; anticholinergic; anticoagulant; anticonvulsant; antidepressant; antidiabetic; antidiarrheal; antidiuretic; anti-emetic; anti-epileptic; antifibrinolytic; antifungal; antihemorrhagic; antihistamine; antihyperlipidemia; antihypertensive; antihypotensive; anti-infective; antiinflammatory; antimicrobial; antimigraine; antimitotic; antimycotic, antinauseant, antineoplastic, antineutropenic, antiparasitic; antiparkinson; antiproliferative; antipsychotic; antirheumatic; antiseborrheic; antisecretory; antispasmodic; antithrombotic; anti-ulcerative; antiviral; appetite suppressant; blood glucose regulator; bone resorption inhibitor; bronchodilator; cardiovascular agent; cholinergic; depressant; diagnostic aid; diuretic; dopaminergic agent; estrogen receptor agonist; fibrinolytic; fluorescent agent; free oxygen radical scavenger; gastric acid supressant; gastrointestinal motility effector; glucocorticoid; hair growth stimulant; hemostatic; histamine H2 receptor antagonists; hormone; hypocholesterolemic; hypoglycemic; hypolipidemic; hypotensive; imaging agent; immunizing agent; immunomodulator; immunoregulator; immunostimulant; immunosuppressant; keratolytic; LHRH agonist; mood regulator; mucolytic; mydriatic; nasal decongestant; neuromuscular blocking agent; neuroprotective; NMDA antagonist; non-hormonal sterol derivative; plasminogen activator; platelet activating factor antagonist; platelet aggregation inhibitor; psychotropic; radioactive agent; scabicide; sclerosing agent; sedative; sedative-hypnotic; selective adenosine A, antagonist; serotonin antagonist; serotonin inhibitor; serotonin receptor antagonist; steroid; thyroid hormone; thyroid inhibitor; thyromimetic; tranquilizer; amyotrophic lateral sclerosis agent; cerebral ischemia agent; Paget's disease agent; unstable angina agent; vasoconstrictor; vasodilator; wound healing agent; xanthine oxidase inhibitor and the like.
In a preferred embodiment the low dose water-soluble drug is pramipexole or a pharmaceutically acceptable salt thereof.
The term "intimate mixing" as used herein means mixing at a particulate level, which can be achieved, by means such as wet granulation, co-micronization, spray drying or adsorption. In a preferred embodiment intimate mixing of a low dose water-soluble drug with one or more water-soluble, non - swellable excipients is achieved by mixing the water-soluble, non -swellable excipient(s) with a solution of the low dose water-soluble drug in a suitable solvent and subsequent drying so as to adsorb the drug onto the excipient. In a yet preferred embodiment, the water soluble, non-swellable excipient can also act as a binder for wet granulation and the intimate mixing step
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can be a part of a wet granulation process. The solvent may be aqueous, nonaqueous or a mixture thereof.
The term "water-soluble, non - swellable" excipient refers to any non-toxic pharmaceutically acceptable compound which has good aqueous solubility i.e. one part of excipient dissolves in 30 parts of water but which does not swell when it contacts water. The amount of the water-soluble, non - swellable excipient may be from about 10 to 95 wt % and preferably from about 40 to 80 wt % based on the total weight of the compressed core.
The water soluble excipients include but are not limited to water soluble organic acids, water soluble salts of organic acids, water soluble organic bases, water soluble salts of organic bases, inorganic salts, saccharides, water - soluble polymers, surfactants and the like. Saccharides include but are not limited to monosaccharides, disaccharides, oligosaccharides, polysaccharides or sugar alcohols and the like. Suitable water-soluble polymers include but are not limited to polyethylene glycol, polyvinyl pyrrolidone, polyvinyl alcohol and the like. Suitable surfactants include hydrophilic surfactants with a HLB value of atleast 10. The term hydrophilic surfactant also includes those anionic, cationic, or zwitterionic compounds for which the HLB scale is not generally applicable.
In a preferred embodiment, the water-soluble excipient is polyethylene glycol. In a yet preferred embodiment the water soluble excipient is polyethylene glycol having molecular weight 6000, i.e. PEG 6000.
The mini-tablets of low dose water - soluble drug 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, and the like.
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.
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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.
The mini tablets of the present invention can be prepared by any of the granulation methods known in the art, e.g., dry granulation, wet granulation, melt granulation or direct compression.
In a preferred embodiment, the intimate mixing of the drug and the water-soluble, non - swellable excipients can be a part of the wet granulation process. Thus, the pharmaceutical composition of the present invention comprising mini-tablets of low dose water- soluble drugs in the form of mini-tablets and one or more water-soluble, non - swellable excipients are formed by a process comprising the steps of (1) preparing/melting a drug solution in hydroalcoholic solvent (2) blending a water-soluble, non-swellable excipient and optionally a filler (3) granulating the blend with the drug solution (4) drying/cooling the mass (5) lubricating the contents of step 4 and compressing the lubricated mass to a target weight.
The pharmaceutical composition comprising mini-tablets of a low-dose, water-soluble drug, intimately mixed with one or more water-soluble, non-swellable excipients can exhibit either an immediate release profile or an extended release profile. In a preferred embodiment, the tablet is an extended release tablet.
In a preferred embodiment of the present invention an extended release pharmaceutical composition comprising mini-tablets comprising a low-dose, water-soluble drug, intimately mixed with one or more water-soluble, non-swellable excipients can further comprise a coating which may be a functional coating, an enteric coating or compression coating or combinations thereof.
The functional coating may comprise water soluble polymers/excipients, water insoluble polymers or combinations thereof well known to a person skilled in the art. The water insoluble polymer may be, for example, but not limited to, is cellulose ethers such as ethylcellulose, cellulose esters such as cellulose acetate, methacrylic derivatives (such as Eudragit@ RL, RS) and the like. The water soluble polymer / excipient may be, for example, but not limited to hydroxypropyl methylcellulose,
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polyethylene glycol, copovidone (Plasdone S-630*), hydrated colloidal silica, sucrose, mannitol or any other substance capable of playing the same role.
The enteric coating polymer may comprise one or more polymers for example, but not limited to, shellac, methacrylic acid copolymers (such as Eudragit S or L) cellulose acetate phthalate, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate trimellitate and polyvinyl acetate phthalate, acryl EZE (methacrylic acid copolymer type C). The thickness of the coating is selected to provide the desired release rate which is dependent on the thickness of the coating and the particular coating.
Coating can be accomplished by means of spraying a dispersion of the coating material on a tablet bed in suitable coating equipment by methods well known in the art, for example, in a perforated pan, or in a fluid bed processor.
These mini-tablets can then be used as such, filled into hard gelatin capsule or further compressed as cores in compression coated systems.
In a preferred embodiment of the present invention an extended release pharmaceutical composition comprising mini-tablets comprising a low-dose, water-soluble drug, intimately mixed with one or more water-soluble, non-swellable excipients of the present invention can further be compression coated. The compression coating comprises suitable excipients which are capable of sustained, controlled, modified or delayed release. Thus, for example, the compression coating comprises suitable hydrophilic cellulosic polymers such as but not limited to hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and their derivatives. The compression coating can also comprise binders, fillers, lubricants and the like.
The tablets of the present invention exhibit specific dissolution profiles i.e. consistent in vitro and in vivo release profiles.
in a preferred embodiment of the present invention, the pharmaceutical composition comprises pramipexole or a pharmaceutically acceptable salt thereof as an active ingredient. In a further preferred embodiment, the pharmaceutical composition of the present invention comprising pramipexole or a pharmaceutically acceptable salt thereof is intended for extended release of pramipexole. Thus, in a preferred
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embodiment, the pharmaceutical composition of the present invention comprising mini-tablets comprising pramipexole or pharmaceutical acceptable salts thereof and one or more water-soluble, non - swellable excipients are formed by a process comprising the steps of (1) dissolving pramipexole or a pharmaceutically acceptable salt thereof in a hydroalcoholic solvent (2) blending polyethylene glycol 6000 and microcrystalline cellulose (3) granulating the blend with the drug solution (4) drying/cooling the mass (5) lubricating the contents of step 4 and compressing the lubricated mass to a target weight (6) dissolving Ethylcellulose and Plasdone S-630 in ethanol (7) functionally coating the mini-tablets with the coating solution prepared in step 6 and curing the coated mini-tablets (8) filling the cured functional coated mini-tablets into hard gelatin capsule.
The following are few representative examples of the invention and in no way construed as limiting the invention.
Example 1
Pramipexole dihydrochloride was dissolved in ethanol-water mixture. The blend of polyethylene glycol 6000 and microcrystalline cellulose was sifted through 40 mesh s.s. sieve and granulated with above solution. The granules were dried and sifted through 30 mesh sieve. The mass was lubricated with sifted lubricants. Minitablets were compressed to an average weight. Ethylcellulose and Plasdone S-630 were dissolved in ethanol under stirring. The compressed tablets were coated using the solution prepared above to a weight gain of 10% w/w. Suitable number of functionally coated mini-tablets were filled in hard gelatin capsules.
Example 2
Pramipexole dihydrochloride was dissolved in ethanol-water mixture along with povidone K-30. The blend of beta- cyclodextrin and maize starch was granulated with above solution. The granules were dried at 50-60° C and sifted through suitable mesh. The granules were lubricated with glidants and anti-adherents such as, colloidal silicon dioxide and magnesium sterate. This lubricated blend was compressed using suitable tablet press into mini tablets to an average weight. Ethylcellulose, hydroxypropyl methyl cellulose (3 cps) and polyethylene glycol 4000 were dissolved in ethanol under stirring. The compressed tablets were coated using the solution prepared above to a weight gain of 7% w/w. Suitable number of functionally coated mini-tablets were filled in hard gelatin capsules.
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Dissolution Method
For all examples, the capsule containing tablets were tested for dissolution of
pramipexole dihydrochloride in 900 ml of phosphate buffer at a pH of 6.8 as
dissolution media at 37° C and in 40-mesh basket (USP Type 1) and rotated at 100
rpm.
In the following examples, the composition and its dissolution profiles are given in a
tabular form.
Table 1: Composition of Pramipexole dihydrochloride mini-tablets of Example 1 to 2

Ingredients

Quantity (Mg/tab)

Core Example 1 Example 2
Pramipexole Dihydrochloride. IH 0.375 0.125
Polyethylene glycol 6000NF 14 -
B-cyclodextrin - 7.65
Microcrystalline cellulose USP 13.625 9.10
Maize starch - 9.833
PVP K-30 - 0.566
Ethanol 95 % Q.S. Q.S.
Water Q.S. Q.S.
Colloidal silicon dioxide NF (Aerosil 200) 0.50 0.316
Purified Talc NF 0.50 -
Magnesium stearate NF 1.00 0.41
Weight of tablet 30 28
Coat
Ethyl cellulose 7 cps 3.00 1.274
HPMC E-3 3 cps - 0.49
Plasdone S 630 1.00 -
PEG - 0.196
Ethylalcohol 95% Q.S. Q.S.
Total 34 29.96
Table 2: In vitro dissolution data for Example 1 to 2

Time (hour)

% dissolved

%RSD

Example 1
8

Example 2
49

Example 1
17.3

Example 2
28.7

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2 19 78 10.5 20.1
4 38 82 5.1 15.1
6 58 86 12.6 10.7
8 69 90 10.2 8.3
12 80 93 6.5 6.7
16 84 95 4.7 5.2
24 87 95 6.0 3.0
It is thus evident from the above examples that composition of the present invention (Example 1) has lower RSD as compared to Example 2 and hence has a better release profile.
We claim:
1. A pharmaceutical composition comprising mini-tablets of a low dose water soluble drug, said composition comprising said drug intimately mixed with one or more water-soluble, non - swellable excipients.

Dated this 5th day of December 2006

Ashwini Sandu
Of S. Majumdar & Co. Applicant's Agent
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