FORM2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10; rule 13)

1. Title of the invention.

STABILIZED PHARMACEUTICAL COMPOSITION OF PRAMIPEXOLE AND METHOD OF PREPARATION THEREOF

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 INVENTION:
The present invention relates to a stabilized pharmaceutical composition of pramipexole dihydrochloride comprising of at least a cyclodextrin or cyclodextrin derivative. The invention also relates to method of preparation of stabilized pramipexole dihydrochloride pharmaceutical composition. The invention further relates to method of preventing degradation of pramipexole dihydrochloride composition using cyclodextrins or cyclodextrin derivatives.
BACKGROUND OF INVENTION:
Fig. 1: Structure of Pramipexole dihydrochloride.
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Pramipexole is a dopamine D2 receptor agonist useful in treatment of Parkinson's disease. Pramipexole is disclosed in US patent 4886812. The chemical name of pramipexole dihydrochloride is (S)-2-amino-4,5,6,7-tetrahydro-6-(propylamino) benzothiazole dihydrochloride monohydrate (Figure 1). Its empirical formula is C10H17N3S • 2 HCI • H20 and molecular weight is 302.27. Pramipexole dihydrochloride is a white to off-white powder substance. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol and practically insoluble in dichloromethane. Pramipexole as its dihydrochloride salt is commercially available as MIRAPEX tablets of Pharmacia & Upjohn. These are immediate-release tablets in 0.125 mg, 0.25 mg, 0.5 mg, 1.0 mg and 1.5 mg strengths, designed for oral administration of a single tablet three times per day to provide a daily dose of 0.375 to 4.5 mg. Doses herein are expressed in amounts of pramipexole dihydrochloride monohydrate unless otherwise specified; 1.0 mg pramipexole dihydrochloride monohydrate is equivalent to about 0.7 mg pramipexole base.


There are limitations of prior art. These are,
The problem is addressed in NDA submitted to United States FDA for MIRAPEX tablets that in solid state, the pramipexole dihydrochloride itself has good stability but the tablet formulation is susceptible to photo degradation. Also it was found that the pramipexole dihydrochloride composition is not stable. Pramipexole dihydrochloride with excipients causes the degradation of the pramipexole dihydrochloride which results in the fall in potency of the composition on storage at different stability conditions. This also affects the shelf life of pramipexole dihydrochloride compositions (Unpublished studies). Prior art does not suggest the use of cyclodextrins or cyclodextrin derivatives for the stabilization of pramipexole dihydrochloride comopositions.
In present invention it was surprisingly found that the use of cyclodextrin or cyclodextrin derivative in pramipexole dihydrochloride composition improved stability of pramipexole dihydrochloride composition. It is desirable to provide a stabilized pharmaceutical composition of pramipexole dihydrochloride. It is also desirable to provide a method preparing a stabilized pharmaceutical composition of the pramipexole dihydrochloride that comprises of at least a cyclodextrin or cyclodextrin derivative.
SUMMARY OF THE INVENTION
The present invention relates to a stabilized pharmaceutical composition of pramipexole dihydrochloride comprising of at least a cyclodextrin or cyclodextrin derivative. One aspect of the invention is to provide a stabilized composition of pramipexole dihydrochloride comprising at least a cyclodextrin or cyclodextrin derivative that further contains one or more pharmaceutically acceptable conventional excipients. In said composition the cyclodextrin or cyclodextrin derivative may be present as co-excipient, or cyclodextrin or cyclodextrin derivative - pramipexole dihydrochloride, inclusion complex. The said composition can be formulated for oral, nasal, ocular, urethral, buccal, transmucosal, intramuscular, intravenous, vaginal, topical or rectal delivery. The said composition can be formulated for controlled release wherein the controlled release may be immediate release, pulsatile release, extended
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release, delayed release, targeted release, targeted delayed release, or mixtures thereof.
In a preferred embodiment of the invention pramipexole dihydrochloride is dissolved in purified water along with polyvinyl pyrrolidone (Povidone). The blend of mannitol, beta- cyclodextrin and maize starch is granulated with above solution. The granules were dried at ,50-60°C and sifted through suitable mesh. The granules are lubricated with glidants and anti-adherents such as, colloidal silicon dioxide and magnesium sterate. This lubricated blend is compressed using suitable tablet press.
Another embodiment of this invention is to provide stabilized formulation in form of inclusion complex of pramipexole dihydrochloride with beta-cyclodextrin. Herein the inclusion complex of pramipexole dihydrochloride with beta-cyclodextrin was prepared in stable mole ratio. The inclusion complex prepared was then admixed with suitable conventional excipients. The granulation was carried out using either 'dry granulation' process, or 'wet granulation' process; which may be as aqueous or non - aqueous. These granules further dried, sifted and lubricated. This lubricated blend was compressed using suitable tablet press.
The stability studies of above said tablet formulations was performed in accordance with industry standards by storage from two weeks to twenty four weeks at various accelerated stability conditions such as 40°C with 75% relative humidity; and also at 50°C. The pramipexole dihydrochloride tablets with beta-cyclodextrin as co-excipient and inclusion complex showed no degradation of pramipexole dihydrochloride at accelerated stability condition in comparison to formulation without beta-cyclodextrin.
The present invention can be illustrated by the following examples without being limited by them.
Example 1
Pramipexole dihydrochloride tablets were prepared having composition shown in Table 1. Pramipexole dihydrochloride was dissolved in purified water along
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with polyvinyl pyrrolidone (Povidone). The blend of mannitol, 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 are lubricated with glidants and anti-adherents such as, colloidal silicon dioxide and magnesium sterate. This lubricated blend is compressed using suitable tablet press.
Table 1 Composition of pramipexole tablets of example 1

Ingredients Percent (%) quantity per tab et D
Formulation Name 0 A B C
Pramipexole Dihyrochloride 0.15 0.15 0.15 0.15 0.15
Mannitol 59.85 58.85 54.85 - -
Beta-cyclodextrin 0 1 5 59.85 94.85
Maize starch 35 35 35 35 -
Polyvinyl pyrrolidone (Povidone) 2 2 2 2 2
Colloidal silicon dioxide 1.5 1.5 1.5 1.5 1.5
Magnesium sterate 1.5 1.5 1.5 1.5 1.5
Example 2
The inclusion complex of pramipexole dihydrochloride with beta-cyclodextrin was prepared using suitable method. Inclusion complex of pramipexole dihydrochloride with beta-cyclodextrin was prepared in stable mole ratio. Pramipexole dihydrochloride tablets were prepared having composition shown in Table 2. The inclusion complex prepared was then admixed with suitable conventional excipients. The granulation was carried out using either 'dry granulation' process, or 'wet granulation' process; which may be as aqueous or non - aqueous. These granules further dried, sifted and lubricated. This lubricated blend was compressed using suitable tablet press.
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Table 2 Composition of pramipexole tablets of example 2

Ingredients Percent (%) quanl ity per tablet
E F
Pramipexole dihyrochloride : Beta-cyclodextrin Inclusion Complex [molar ratio 1:1] 0.75 2.50
Mannitol 59.25 57.50
Maize starch 35 35
Polyvinyl pyrrolidone (Povidone) 2 2
Colloidal silicon dioxide 1.5 1.5
Magnesium sterate 1.5 1.5
Example 3
Accelerated stability study:
Table 3 Accelerated Stability Data of example 1 formulations

PprinH % Potency % Potency
(No. of Weeks) 40° C/ 75 RH 50UC
Formulation Name 0 A B C D O A B C D
% Concentration of Cyclodextrin in formulation 0 1 5 60 94.85 0 1 5 60 94.8S
0 101.0 101.1 101. 9 102.7 103.5 101.1 101.0 101.0 101.9 103. 1
2 99.1 100.8 101. 5 102.6 103.5 94.8 100.4 100.6 101.5 103. 1
4 98.2 99.7 100. 1 101.5 103.2 92.9 98.6 99.0 99.6 102. 1
8 96.1 99.0 100. 0 100.8 103.0 - - - - -
12 93.5 98.6 99.2 99.7 103.0 - - - - -
24 90.1 98.3 98.7 99.1 102.3 - - - - -
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Example 4
Accelerated stability study:
Table 3 Accelerated stability data of example 2 formulations

% Potency % Potency
Period (No. of Weeks) 40u C/ 75 RH 50UC
Formulation Name 0 E F O E F
Pramipexole dihyrochloride : Beta-cyclodextrin Inclusion Complex [mole ratio 1: 1] % concentration in formulation. 0 0.75 2.50 0 0.75 2.50
0 101. 0 103.2 8 103.30 101.1 104.31 104.27
2 99.1 103.2 0 103.29 94.8 104.30 104.26 104.26
4 98.2 103.1 6 103.27 92.9 104.28
8 96.1 102.9 6 103.27 - - -
12 93.5 102.0 0 103.26 - - -
Dated this 1st day of December 2005