WO2012140604A1

WO2012140604A1 - Stable formulations of pramipexole hydrochloride

Info

Publication number: WO2012140604A1
Application number: PCT/IB2012/051819
Authority: WO
Inventors: Shilpa D. VIBHUTE; Sunil Agarwal; Yogesh JOSHI
Original assignee: Sandoz Ag
Priority date: 2011-04-15
Filing date: 2012-04-13
Publication date: 2012-10-18

Abstract

The present invention relates to a stable pharmaceutical composition comprising Pramipexole or pharmaceutically acceptable salt thereof and a stabilizer which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine impurity. It further relates to the methods for preparing the same. In particular, the present invention encompasses pharmaceutical compositions in the form of compressed tablets or sustained release tablets comprising the pharmaceutical composition of the present invention.

Description

STABLE FORMULATIONS OF PRAMIPEXOLE HYDROCHLORIDE

Field of invention The invention encompasses a stable pharmaceutical composition comprising Pramipexole or pharmaceutically acceptable salt thereof and methods for preparing the same. Preferably the salt is the hydrochloride salt. In particular, the invention encompasses pharmaceutical compositions in the form of compressed tablets or sustained release tablets.

Background of the Invention

Pramipexole dihydrochloride monohydrate, 2-amino-6-N-propylamino-4, 5, 6, 7- tetrahydrobenzo-thiazole-dihydrochloride monohydrate, of formula (I), is a dopamine - D₃/D₂ agonist. Pramipexole dihydrochloride is known primarily for the treatment of schizophrenia, and particularly for the treatment of Parkinson's disease, and is marketed as the dihydrochloride monohydrate under several brand names, such as Mirapex. It has the following structure:

,2HCLH₂0

Formula (I)

The salt form commonly used is Pramipexole dihydrochloride monohydrate (molecular formula C1₀H₂1C1₂N₃OS; relative molecular mass 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs in the range of 296°C to 301°C, with decomposition. Pramipexole is a chiral compound with one chiral centre. Pure (S)-enantiomer is obtained from the synthetic process by chiral recrystallization of one of the intermediates during synthesis.

Pramipexole dihydrochloride monohydrate is a highly soluble compound. Water solubility is more than 20 mg/ml and solubility in buffer media is generally above 10 mg/ml between pH 2 and pH 7.4. Pramipexole dihydrochloride monohydrate is not hygroscopic, and of highly crystalline nature. Under milling the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, yet in solution it is light sensitive. Pramipexole dihydrochloride and other tetrahydrobenzothiazoles were first discovered by Schneider et al. and described in European Patent 0 186 087 (the '087 patent) and U.S. Patent No. 4,886,812 (the '812 patent).

Pramipexole dihydrochloride degrades into its corresponding imine during manufacture and /or storage. The imine is a degradation product, which reduces the effective dosage of Pramipexole dihydrochloride when it is administered to a patient.

Thus there is a need to develop a pharmaceutical composition of Pramipexole dihydrochloride having improved stability.

The present invention overcomes the aforesaid problem by providing pharmaceutical composition of Pramipexole dihydrochloride which is stable to aforesaid degradation.

The present inventors have surprisingly developed a stable pharmaceutical composition of Pramipexole dihydrochloride which comprises a stabilizer which is capable of inhibiting nucleophilic addition elimination reaction which leads to the formation of Pramipexole dihydrochloride imine impurity i.e degradation product.

The present inventors have found that employing stabilizer which is capable of inhibiting nucleophilic addition/ elimination reaction which may be effected in the microenvironment of the tablet thereby causing the formation of imine impurity, a stable pharmaceutical composition of Pramipexole dihydrochloride having improved stability can be prepared which overcome the drawback/problem of degradation of Pramipexole or pharmaceutically acceptable salt thereof during manufacture and /or storage.

Summary of the invention

According to an aspect of the present there is provided a pharmaceutical composition comprising Pramipexole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine, wherein the Pramipexole contains its corresponding imine and the amount of the corresponding imine has not increased by more than 1% by weight from the initial amount of Pramipexole after storage at about 40°C and about 75% relative humidity for 6 months.

According to another aspect of the present invention there is provided a compound of formula (II) or a salt thereof.

Formula (II) Detailed description of the invention

Pramipexole dihydrochloride compositions are subject to degradation during manufacture and storage. It is known that the Pramipexole dihydrochloride degrades into its corresponding imine. The corresponding imine is a degradation product, which reduces the effective dosage of Pramipexole dihydrochloride when it is administered to a patient. The present invention overcomes this problem by providing compositions of Pramipexole dihydrochloride that are stable to this degradation.

As used herein, unless otherwise defined, the term "corresponding imine" refers to Pramipexole or a pharmaceutically acceptable salt thereof, wherein the imine impurity is as shown below.

Formula (II) As used herein, unless otherwise defined, the term "pharmaceutically acceptable salt" refers to Pramipexole dihydrochloride. As used herein with respect to pharmaceutical compositions, unless otherwise defined, the term "stable" means that the amount of the corresponding imine within the Pramipexole dihydrochloride in the packaged pharmaceutical composition has not increased by more than 1% by weight from the initial amount of Pramipexole dihydrochloride after storage at about 40°C and about 75% relative humidity for 6 months. Preferably, the corresponding imine content has not increased by more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride after storage at about 40°C at about 75% relative humidity for 6 month.

As used herein, unless otherwise defined, the term "accelerated storage conditions" refers to storage of Pramipexole dihydrochloride at about 40°C at about 75% relative humidity for 6 months.

Comparative testing with Pramipexole dihydrochloride was performed to determine the conditions which cause the degradation of Pramipexole dihydrochloride into the corresponding imine. Compositions of Pramipexole dihydrochloride and each of the excipients of the prior art tablets were prepared and subjected to stressed storage conditions. The amount of the corresponding imine present in each of the compositions was measured by high performance liquid chromatography ("HPLC") both before and after storage. It was found that the amount of the corresponding imine in the composition increased by over 10 times in the presence of excipients which generate formaldehyde over the storage period.

Not to be limited by theory, it is known that the poor stability of the prior art compositions of Pramipexole dihydrochloride can be attributed to the presence of celluloses or any other excipients which may contain formaldehyde or formaldehyde in traces, which can catalyze the conversion of Pramipexole dihydrochloride to its corresponding imine. Those skilled in the art would appreciate that most of the excipients which are used in the pharmaceutical composition would release some amount of formaldehyde or any other aldehyde in the micro-environment of the tablet which may lead to the formation of the imine impurity. In one embodiment of the present invention there is provided a pharmaceutical composition comprising Pramipexole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine, wherein the Pramipexole contains its corresponding imine and the amount of the corresponding imine has not increased by more than 1% by weight from the initial amount of Pramipexole after storage at about 40°C and about 75% relative humidity for 6 months. Preferably, the corresponding imine content has not increased by more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride after storage at about 40°C at about 75% relative humidity for 6 month.

In another embodiment of the present invention there is provided a pharmaceutical composition comprising Pramipexole or its pharmaceutically acceptable salt and pharmaceutically acceptable excipients selected from at least one of diluents, binder, polymers, disintegrant, stabilizer or lubricant.

In yet another embodiment of the invention, immediately after preparation of the pharmaceutical composition, the corresponding imine is present in an amount of not more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride in the pharmaceutical composition.

In further embodiment of the invention, the stable compositions of the invention encompass solid pharmaceutical dosage forms. Preferably, the solid pharmaceutical dosage forms are compressed tablets or sustained release tablets. The compressed tablets comprise Pramipexole dihydrochloride, mannitol, microcrystalline cellulose, starch, colloidal silicon dioxide, stabilizer and magnesium stearate. The stabilizer added to the formulation is such that it can inhibit the nucleophilic addition/ elimination reaction which may be effected in the microenvironment of the tablet thereby causing the formation of imine impurity.

The sustained release tablets comprise Pramipexole dihydrochloride, sustained release polymer, microcrystalline cellulose, colloidal silicon dioxide, stabilizer and magnesium stearate.

Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and care giver to handle. Diluents used in the composition include diluents commonly used in solid pharmaceutical compositions. Diluents include, but are not limited to, calcium carbonate, calcium phosphate (dibasic or tribasic), calcium sulfate, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, sorbitol, sucrose, starch, pregelatinized starch, talc.

Binders help to bind the active ingredient and other excipients together. Binders used in the composition include binders commonly used in solid pharmaceutical compositions. Binders include, but are not limited to, acacia, alginic acid, carbomer, hydrochloride carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, starch, methylcellulose, polyethylene oxide.

Disintegrants increase the dissolution rate of a solid pharmaceutical composition in the patient's body. Disintegrants used in the composition include disintegrants commonly used in solid pharmaceutical compositions. Disintegrants include, but are not limited to, alginic acid, croscarmellose hydrochloride, crospovidone, potassium polacrilin, sodium starch glycolate, starch.

Lubricants are added to a pharmaceutical composition for ease in processing, to prevent adhesion to the equipment used during processing. Lubricants used in the composition include lubricants commonly used in solid pharmaceutical compositions. Lubricants used in the composition include, but are not limited to, calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, hydrochloride stearyl fumarate, stearic acid, talc, vegetable oil, hydrochloride lauryl sulfate, zinc stearate.

Glidants improve the flowability of a non-compacted solid composition and improve the accuracy of dosing. Glidants used in the composition include glidants commonly used in solid pharmaceutical compositions. Glidants used in the composition include, but are not limited to, colloidal silicon dioxide, magnesium trisilicate, starch, talc, tribasic calcium phosphate.

Stabilizers used in this composition which would stabilize the formulation include but not limited to Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Sodium- metabisulphite, Meglumine, Sodium citrate, Povidone, Glycine, Arginine. The solid pharmaceutical dosage forms of the invention may be prepared by conventional processes known to those of ordinary skill in the art, including, but not limited to, wet granulation, dry granulation such as slugging or compaction, or direct compression of the formulation into tablets or filling into capsules.

Preferably, Pramipexole or a pharmaceutically acceptable salt thereof is blended with diluents and binders to form a blend. Disintegrant is then added to the blend and blended. Lubricant is then added to the blend and blended. The blend is compressed into a tablet.

Typically, the sustained release tablets are prepared by wet granulation. In wet granulation, Pramipexole or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in powder form are blended and then further mixed in the presence of a liquid, typically water or organic solvents like isopropyl alcohol, ethanol, which causes the powders to clump into granules. The granulate can be screened and/or milled, dried and then screened and/or milled to the desired particle size. The dried granulate is compressed into a sustained release tablet or other excipients optionally be added prior to tabletting. Preferably, Pramipexole or a pharmaceutically acceptable salt thereof, sustained release polymer, binder, disintegrant, diluent and stabilizer is blended and mixed with a lubricant to form a blend. The blend is then compressed into a sustained release tablet.

Having described the invention with reference to certain preferred embodiments, other embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail methods for the preparation and testing of the Pramipexole dihydrochloride pharmaceutical compositions. It will be apparent to those skilled in the art that many modifications both to materials and methods may be practiced without departing from the scope of the invention.

The following examples are meant to illustrate the present invention. The examples are presented to exemplify the invention and are not to be considered as limiting the scope of the invention.

Examples Example 1 :

Sample mixtures of Pramipexole dihydrochloride with each of the excipients were prepared. Each sample was stored at 40 °C/ 75%RH for 2 weeks. The percentage weight of imine impurity was measured using HPLC. HPLC was performed on a C-18 column 150 x4.6mm, packed with 5micron diameter packing ( inertsil ODS #v or equivalent) using a gradient system of buffer pH 2.8 and acetonitrile at a flow rate of 1.8 ml/min and UV detector set at 264 nm , column temperature was maintained at 45°C. Condition Composition Percentage of imine

impurity

40 °C/ 75%RH for

Pramipexole dihydrochloride Not detected

2 weeks

40 °C/ 75%RH for

Pramipexole dihydrochloride +HPMC 0.06

2 weeks

40 °C/ 75%RH for Pramipexole dihydrochloride + HPMC

Not detected.

2 weeks + Meglumine

Example 2:

The composition of Pramipexole dihydrochloride containing a stabilizer was subjected to stress conditions in an open pertidish for 7 days at 50°C/ 75%RH , and the percentage of imine impurity was measured using HPLC as described in example 1.

Example 3:

Ingredients Quantity per tablet

%w/w

Pramipexole dihydrochloride

.monohydrate 0.1-1.5

Hypromellose 40-80

Hydrogenated Castor oil 10-30

Colloidal Anhydrous Silica 0.25-2

Meglumine 0.05-1

Microcrystalline cellulose 10-15

Magnesium stearate 0.05-0.1%

Total Weight 100

Method of preparation:

Pramipexole Dihydrochloride Monohydrate hypromellose, hydrogenated castor oil, meglumine, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.

Example 4:

Ingredients Quantity per tablet

%w/w

Pramipexole dihydrochloride

.monohydrate 0.1-1.5

Hypromellose 40-80

Glyceryl monostearate 10-30

Colloidal Anhydrous Silica 0.25-2

Meglumine 0.05-1

Microcrystalline cellulose 10-15

Magnesium stearate 0.05-0.1%

Total Weight 100 Method of preparation:

Pramipexole Dihydrochloride Monohydrate hypromellose, glyceryl monostearte, meglumine, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.

Example 5:

Method of preparation:

Pramipexole Dihydrochloride Monohydrate, hypromellose, PVP, meglumine, microcrystalline cellulose, were blended and mixed and were granulated using Isopropyl alcohol. The granules were lubricated with magnesium stearate and colloidal silicon dioxide was added as a glidants and the tablets were compressed. Example 6:

Method of preparation:

Pramipexole Dihydrochloride Monohydrate hypromellose, meglumine, mannitol, corn starch, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.

Example 7:

Method of preparation:

Pramipexole Dihydrochloride Monohydrate, hypromellose, PVP, sodium metabisulphite, microcrystalline cellulose, were blended and mixed and were granulated using Isopropyl alcohol. The granules were lubricated with magnesium stearate and colloidal silicon dioxide was added as a glidants and the tablets were compressed.

Example 8:

Method of preparation:

Pramipexole Dihydrochloride Monohydrate hypromellose, glyceryl monostearte, sodium metabisulphite, microcrystalline cellulose and colloidal silicon dioxide, were blended and mixed. The final blend was lubricated with magnesium stearate and the tablets were compressed.

Claims

A stable pharmaceutical composition comprising Pramipexole or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine, wherein the Pramipexole contains its corresponding imine and the amount of the corresponding imine has not increased by more than 1 % by weight from the initial amount of Pramipexole after storage at about 40°C and about 75% relative humidity for 6 months.

The pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is Pramipexole dihydrochloride and the corresponding imine is the imine of formula (II).

Formula (II)

The pharmaceutical composition according to claim 1 , wherein the amount of the corresponding imine does not increase by more than 0.5% by weight of the initial amount of Pramipexole dihydrochloride after storage at about 40°C and about 75% relative humidity for 6 months.

The pharmaceutical composition according to claim 1, wherein the diluents is selected from the group consisting of calcium carbonate, calcium phosphate (dibasic or tribasic), calcium sulfate, dextrates, dextrin, dextrose excipients, fructose, kaolin, lactitol, anhydrous lactose, lactose monohydrate, maltose, mannitol, sorbitol, sucrose, starch, pregelatinized starch, talc. The pharmaceutical composition according to claim 1, wherein the binder is selected from the group consisting of acacia, alginic acid, carbomer, hydrochloride carboxymethylcellulose, dextrin, ethylcellulose, gelatin, glucose, guar gum, hydroxypropylcellulose, maltose, methylcellulose, povidone, starch, methylcellulose, polyethylene oxide.

The pharmaceutical composition according to claim 1 , wherein the disintegrant is selected from the group consisting of alginic acid, croscarmellose hydrochloride, crospovidone, potassium polacrilin, sodium starch glycolate, starch.

7. The pharmaceutical composition according to claim 1, wherein the lubricant is selected from the group consisting of calcium stearate, glyceryl behenate, magnesium stearate, mineral oil, polyethylene glycol, hydrochloride stearyl fumarate, stearic acid, talc, vegetable oil, hydrochloride lauryl sulfate, zinc stearate.

8. The pharmaceutical composition according to claim 1, wherein the Glidant is selected from group consisting of colloidal silicon dioxide, magnesium trisilicate, starch, talc, tribasic calcium phosphate.

9. The pharmaceutical composition according to claim 1, wherein the stabilizer is selected from the group consisting of Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Sodium-metabisulphite, Meglumine, Sodium citrate, Povidone, Glycine, Arginine.

10. The pharmaceutical composition according to claim 1, wherein the composition is in a solid dosage form.

11. The pharmaceutical composition according to claim 10, wherein the solid dosage forms are compressed tablets or sustained release tablets.

12. A compressed tablet comprising the pharmaceutical formulation according to claim 1.

13. The compressed tablet according to claim 12, comprising Pramipexole dihydrochloride, mannitol, microcrystalline cellulose, Povidone, starch, colloidal silicon dioxide, stabilizer and magnesium stearate. 14. The compressed tablet according to claim 13, wherein the stabilizer is selected from the group consisting of Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Sodium-metabisulphite, Meglumine, Sodium citrate, Povidone, Glycine, Arginine. 15. A sustained release tablet comprising the pharmaceutical formulation according to claim 1.

16. The sustained release tablets according to claim 15 comprising Pramipexole dihydrochloride, sustained release polymer, microcrystalline cellulose, colloidal silicon dioxide, stabilizer and magnesium stearate.

17. The sustained release tablet according to claim 16, wherein the stabilizer is selected from the group consisting of Butylated Hydroxytoluene (BHT), Butylated Hydroxyanisole (BHA), Sodium-metabisulphite, Meglumine, Sodium citrate, Povidone, Glycine, Arginine.

18. A process for preparing the pharmaceutical composition of claim 1 comprising combining Pramipexole or a pharmaceutically acceptable salt thereof with a pharmaceutically acceptable excipients selected from at least one of diluent, binder, disintegrant, lubricant, glidant and stabilizer, provided that the stabilizer is the one which can inhibit the reaction of nucleophilic addition/ elimination which leads to the formation of corresponding imine.

19. The process according to claim 18, wherein each of the pharmaceutically acceptable excipients is first tested in order to assess its suitability in a stable Pramipexole pharmaceutical composition.

20. The process according to claim 18, wherein the pharmaceutical composition is prepared by wet granulation or dry granulation or direct compression. The process according to claim 20 comprising the steps of:

i. Blending Pramipexole or a pharmaceutically acceptable salt thereof with diluents , binders and stabilizer;

ii. Adding disintegrant to the blend obtained in step (i) followed by blending; iii. Adding Lubricant to the blend obtained in step (ii) followed by blending; iv. The blend obtained in step (iv) is compressed into a tablet.

The process according to claim 20 comprising the steps of:

i. Blending Pramipexole or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipients in powder form and then further mixed in the presence of a liquid, typically water or organic solvents like isopropyl alcohol, ethanol which causes the powders to clump into granules;

ii. Granulate obtained in step (i) can be screened and/or milled, dried and then screened and/or milled to the desired particle size;

iii. The dried granulate is compressed into a sustained release tablet or other pharmaceutically acceptable excipients optionally be added prior to tabletting.

The process according to claim 20 comprising the steps of:

i. Blending Pramipexole or a pharmaceutically acceptable salt thereof, sustained release polymer, binder, disintegrant, diluent and stabilizer; ii. Adding lubricant to the blend obtained in step (i) followed by blending; iii. The blend obtained in step (iii) is compressed into a sustained release tablet.

A compound of formula (II) or a salt thereof.

Formula (II)