FIELD OF INVENTION

The invention relates to the pharmaceutical field. Specifically, it relates to extended release pharmaceutical compositions comprising pramipexole and one or more pharmaceutically acceptable excipient(s).

BACKGROUND OF THE INVENTION AND RELATED PRIOR ARTS

Pramipexole is a non-ergoline dopamine agonist indicated for treating early-stage Parkinson's disease (PD) and restless legs syndrome (RLS).

Pramipexole dihydrochloride, is chemically- (S)-2-amino-4,5,6,7-tetrahydro-6 (propylamino) benzothiazole dihydrochloride monohydrate. Its empirical formula is CioHnNaS^HCl'HbO, and its molecular weight is 302.26. It is a white to off-white powder substance. Melting occurs in the range of 296°C to 301 °C, with decomposition. Pramipexole dihydrochloride is more than 20% soluble in water, about 8% in methanol, about 0.5% in ethanol, and practically insoluble in dichloromethane.

In the U.S., pramipexole was re-introduced by Boehringer Ingelheim under the brand name Mirapex ER® and in Europe under the brand name of Sifrol® ER as an oral extended release tablet containing either 0.375mg, 0.75mg, 1.5mg, 3mg, 4.5mg, 2.25mg and 3.75mg of pramipexole dihydrochloride and following inactive ingredients: hypromellose, corn starch, carbomer homopolymer, colloidal silicon dioxide, and magnesium stearate.

EP Patent No. 1781260 discloses an extended release tablet formulation comprising pramipexole and least one anionic water swelling polymer preferably carbomer and neutral water swelling polymer preferably hydroxypropyl methylcellulose having most preferably a viscosity range of about 6,500 mPa.s to about 15,000 mPa.s to facilitate different release rate types pH dependent or pH independent. Also contains water insoluble fillers, such as starch and starch derivatives other than pregelatinised starch, preferably corn starch.

EP Patent No. 1531814 discloses an extended-release oral tablet formulation comprising a water-soluble salt of pramipexole, dispersed in a matrix comprising a hydrophilic polymer preferably hydroxypropyl methylcellulose (HPMC) having viscosity ranging from about 100 to about 10,000 mPa.s and a starch having a tensile strength of at least about 0.15 kN cm"2 at a solid fraction of 0.8 is desired for extended-release tablet. The patent also discloses that the commercially available starches having tensile strength less than about 0.15 kN cm" at a solid fraction of 0.8 are not suitable for commercial scale manufacturing of a sustained release matrix tablet formulation of a water-soluble drug or prodrug, because an uncoated tablet, or a tablet core prior to coating, comprising starch and a hydrophilic polymer acting as a matrix for a water-soluble drug or prodrug requires to have a certain minimum hardness in order to be able to resist breakage and/or attrition due to mechanical stresses imposed during high-speed tabletting operation (including all steps up to and including filling of the tablets into containers).

EP Patent No. 0933079 discloses directly compressible starches, among which it also discloses that the Starch 1500® (Colorcon®) has a tensile strength of about 0.2 to 1.6 (N/mm ) at a compression force of 5 to 30 (kN). This prior art does not teach preparation of pramipexole extended release tablet formulation using Starch 1500® (Colorcon®).

In the above mentioned prior arts, different attempts have been made to formulate extended release once a daily tablet formulation comprising pramipexole. As discussed in the prior art, the tensile strength of starch is an important parameter in commercial scale manufacturing of extended release tablet formulation of pramipexole, as it affects the hardness of the tablet.

Contrary to the teachings of EP1531814 patent, that the starch having tensile strength less than about 0.15 kN cm'2 at a solid fraction of 0.8 cannot be used for preparing extended release oral tablet formulation comprising pramipexole, the present inventors surprisingly found that extended release oral
tablet formulation comprising pramipexole, pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) can be prepared successfully, such composition having comparable physical quality attributes and comparable in-vitro dissolution profile to that of marketed Mirapex ER® or Sifrol®ER tablets.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to an extended release pharmaceutical composition comprising pramipexole and one or more pharmaceutically acceptable excipient(s). More specifically, it relates to an extended release pharmaceutical composition comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M) and pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s).

An objective of the invention is to prepare an extended release pharmaceutical composition comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s).

Another objective of the invention is to prepare an extended release pharmaceutical composition comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) by using direct compression process.

Another objective of the invention is to prepare an extended release pharmaceutical composition comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) by using dry granulation or compaction process.

Yet another objective of the invention is to prepare an extended release pharmaceutical composition comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) having comparable physical quality attributes and in-vitro dissolution profile and in-vivo pharmacokinetic parameters with that of the marketed Mirapex ER® or Sifrol® ER tablets.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

As discussed in the background, proper selection of filler(s) and extended release polymer(s) is important to achieve extended release of pramipexole from tablet formulation. Also the tensile strength of filler and viscosity of extended release polymer affects the release of the pramipexole from the tablet formulation.
The present inventors surprisingly found that extended release oral tablet formulation comprising pramipexole when formulated using hydroxypropyl methylcellulose (Methocel® K15M) and pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) exhibits comparable physical quality attributes and in-vitro dissolution profile to that of marketed Mirapex ER® or Sifrol® ER tablets.
More specifically, the embodiments of the invention relates to:

An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s).

An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s), wherein said tablet is prepared by direct compression process.

An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s), wherein said tablet is prepared by dry granulation process.

In context of the invention, terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for pramipexole or its pharmaceutically acceptable salts or esters or derivatives thereof.

As used herein, the term, "pramipexole" is intended to include the active agent itself, as well as its pharmaceutically acceptable salts or derivatives thereof. More preferably, it relates to pramipexole dihydrochloride. According to the invention, pramipexole may be present in an amorphous or crystalline form, more specifically it relates to pramipexole dihydrochloride monohydrate.

As used herein, the term "extended release" when used in connection with "tablet" relates to a tablet formulation which slowly releases the active ingredient in gastrointestinal tract over an extended period of time, preferably over 8 to 24 hours, more preferably over 12 to 24 hours.

As used herein, the term "solid fraction" relates to ratio of absolute to apparent density of a compact of the starch.

As used herein, the term "compact" is a compressed tablet, prepared for example on a tablet press, consisting only of starch for which it is desired to measure tensile strength.

As used herein, the term "tensile strength" related to ability of material to resist a force that tends to pull it apart. It is expressed as the minimum tensile stress (force per unit area) needed. For present purposes it is considered that crushing strength of the compact is equivalent to tensile strength. Thus tensile strength (ax, in kN cm") can be calculated from the equation (CTT = 2F/TTDH) wherein, F is the force required to cause crushing (in kN), D is diameter of the compact (in cm) and H is thickness of the compact (in cm).
According to an embodiment of the invention, extended release oral tablet formulation comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch and one or more pharmaceutically acceptable excipient(s) can be prepared by employing direct compression or by dry granulation process. Preferably direct compression process is employed.

As used herein, the term, "direct compression" relates to the process by which tablets are compressed directly from the powder blend of active ingredient and suitable pharmaceutically acceptable excipient(s).
As used herein, the term, "dry granulation" relates to the process of dry granulating the powder blend of active ingredients and suitable pharmaceutically acceptable excipient(s) without the use of granulating solvent/liquid.

As used herein, the term, "hydrophilic polymer" relates to polymers that contain polar or charged functional groups, rendering them being soluble in water or tending to swell in water.

As used herein, the term, "filler" when used in connection with "tablet" relates to pharmaceutically acceptable excipient(s) which are used to increase the bulk content of the dosage form to facilitate tablet compression.

According to an embodiment of the invention, Starch 1500®, a partially pregelatinised maize starch marketed by Colorcon® is most preferably used as filler for preparing extended release oral tablet formulation comprising pramipexole.

According to preferred embodiment of the invention, Starch 1500® having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 is used as a filler for preparing extended release oral tablet formulation comprising pramipexole.

According to an embodiment of the invention, preferably a cellulose ether is used as a hydrophilic polymer for preparing extended release oral tablet formulation comprising pramipexole, especially those commercially available under the brand name Methocel® Premium from Dow Chemical Co.

According to preferred embodiment of the invention Methocel® K15M Premium (hypromellose 2208) (19-24% methoxy content; 7-12% hydroxypropyl content; 11,250-21,000 cps of a 2% solution in water) is used as a hydrophilic polymer for preparing extended release oral tablet formulation comprising pramipexole.

According to preferred embodiment of the invention, pramipexole extended release tablet comprises from about 25% to 55% by weight of pregelatinised maize starch (Starch 1500®), from about 45% to 70% by weight of hydroxypropyl methylcellulose (Methocel® K15M premium CR), from about 0.1% to 3% by weight of colloidal silicon dioxide, and from about 0.1% to 3% by weight of magnesium stearate.

Tensile Strength Test for Starch 1500®:
Starch 1500® compacts were prepared by using manual tablet press fitted with flat-faced tooling (10mm for around 500mg compact) and operated at compression force of about 6 to about 21 kN, a dwell time of 90 seconds. Solid fraction of compacts was calculated and further the compacts were subjected for tensile strength test. The resultant data shows that tensile strength of Starch 1500 at a solid fraction of 0.8 is less than 0.15kN cm"2.

According to an another embodiment of the invention, preferred process for preparing extended release oral tablet formulation comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm"2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) comprises the steps of:

1. sifting separately pramipexole, pregelatinised maize starch and hydroxypropyl methylcellulose, through a suitable size sieve;

2. mixing and blending of sifted pramipexole with pregelatinised starch and hydroxypropyl methylcellulose in a blender for suitable period of time to get a uniform blend;

3. sifting colloidal silicon dioxide and magnesium stearate through suitable size sieve;

4. lubricating the blend obtained in step (2) using sifted colloidal silicon dioxide and magnesium stearate of step (3) to get final blend; and

5. compressing the final blend of step (4) using suitable tooling to get compressed tablets.
According to an another embodiment of the invention, preferred process for preparing extended release oral tablet formulation comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M), pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm'2 at a solid fraction of 0.8 and one or more pharmaceutically acceptable excipient(s) comprises the steps of:

1. sifting separately pramipexole, pregelatinised starch and hydroxypropyl methylcellulose through a suitable size sieve;

2. mixing and blending sifted pramipexole with pregelatinised maize starch and hydroxypropyl methylcellulose in a blender for suitable period of time to get uniform blend;

3. sifting colloidal silicon dioxide and magnesium stearate through suitable size sieve;

4. lubricating the blend obtained in step (2) using half the quantity of sifted colloidal silicon dioxide and magnesium stearate of step (3);

5. compacting the material of step (4) using roller compactor to get flakes;

6. sifting or passing the flakes of step (5) through Quadro-co-mill fitted with suitable size screen to get granules;

7. lubricating the granules obtained in step (6) using remaining quantity of sifted colloidal silicon dioxide and magnesium stearate of step (3); and

8. compressing the blend of step (7) using rotary tablet compression machine fitted with appropriate dies and punches.

According to the invention, extended release oral tablet formulation comprising pramipexole, hydroxypropyl methylcellulose (Methocel® K15M) and pregelatinised maize starch (Starch 1500® Colorcon®) having tensile strength less than about 0.15 kN cm'2 at a solid fraction of 0.8, further contain one or more pharmaceutically acceptable excipient(s) selected from a group comprising of glidant(s) and/or lubricants etc.

Suitable glidant(s) and/or lubricant(s) according to the invention include, but are not limited to, colloidal silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, calcium stearate or combinations thereof.

EXAMPLES:

Following examples are illustrative and does not limit the scope of this invention.

EXAMPLE - 1
Unit Composition:

Brief manufacturing process:

1. Sift separately pramipexole, pregelatinised starch and hydroxypropyl methylcellulose through a suitable size sieve.

2. Mix and blend sifted pramipexole with pregelatinised starch and hydroxypropyl methylcellulose in a blender for suitable period of time to get uniform blend.

3. Sift colloidal silicon dioxide and magnesium stearate through suitable size sieve.

4. Lubricate the blend obtained in step (2) using half the quantity of sifted colloidal silicon dioxide and magnesium stearate of step (3).

5. Compact the material of step (4) using roller compactor to get flakes.

6. Sift or pass the flakes of step (5) through Quadro-co-mill fitted with suitable size screen to get granules.

7. Lubricate the granules obtained in step (6) using remaining quantity of sifted colloidal silicon dioxide and magnesium stearate of step (3).

8. Compress the blend of step (7) using rotary tablet compression machine fitted with appropriate dies and punches.

EXAMPLE-2
Unit Composition:

Brief manufacturing process:

1. Sift separately pramipexole, pregelatinised starch, colloidal silicon dioxide and hypromellose through a suitable size sieve.

2. Mix and blend sifted pramipexole with pregelatinised starch, colloidal silicon dioxide and hypromellose in a blender for suitable period of time to get uniform blend.

3. Sift magnesium stearate through suitable size sieve.

4. Lubricated the blend of step (2) with sifted magnesium stearate of step (3) for suitable period of time.

5. Compressed the lubricated blend of step (4) using suitable tooling to get compressed tablets.

EXAMPLE-3
Unit Composition:

Brief manufacturing process

1. Sift separately pramipexole, pregelatinised starch, colloidal silicon dioxide and hypromellose through a suitable size sieve.

2. Mix and blend sifted pramipexole with pregelatinised starch, colloidal silicon dioxide and hypromellose in a blender for suitable period of time to get uniform blend.

3. Sift magnesium stearate through suitable size sieve.

4. Lubricated the blend of step (2) with sifted magnesium stearate of step (3) for suitable period of time.

5. Compressed the lubricated blend of step (4) using suitable tooling to get compressed tablets.
Physical Quality Attributes:

Tablets prepared according to Example 1 to 3 do not show sticking or picking or capping problems and has adequate hardness and resistance to friability to withstand mechanical stresses imposed during high-speed tabletting operation and packaging.

Stability Data:
Tablets prepared according to Example 2 where packed in Alu/Alu blister and HDPE bottles and were subjected to accelerated stability study at 40°C/75%RH and the resultant data is compiled in Table -1.

Table-1
Pramipexole tablets prepared according to Example 2 were found stable at the end of 24 weeks at 40°C/ 75% RH.

Comparative in-vitro dissolution data:
Tablets prepared according to Example 2, 3 and the marketed 0.26 mg Sifrol® ER were subjected to in-vitro dissolution test in USP type-I dissolution apparatus by using 500ml 6.8 phosphate buffer, at 100 rpm and the resultant data is compiled in Table 2.

Table-2
Above dissolution data shows that the tablets prepared according to Example 2 and 3 has comparative in-vitro dissolution profile as that of marketed Sifrol® ER tablets.

Bioequivalence Data:
(R)
Tablets prepared according to Example 3 (test product) and Sifrol ER 0.26 mg tablets (reference product) were evaluated for the in-vivo bioequivalence study in healthy human volunteers under fasting and fed condition and the resultant data is compiled in Table 3.

Table-3
Above bioequivalence data shows that the pramipexole extended release tablets prepared according to Example 3 has comparative in-vivo profile as that of marketed Sifrol® ER tablets.

WE CLAIM:

1. An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s).

2. An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s), wherein said tablet is prepared by direct compression process.

3. An extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500 ) and one or more pharmaceutically acceptable excipient(s), wherein said tablet is prepared by dry granulation process.

4. An extended release oral tablet comprising pramipexole having following unit composition:

5. The extended release oral tablet according to claims 1 to 4, wherein said hydroxypropyl methylcellulose has a viscosity in the range of 11,250 to 21,000 cps.

6. The extended release oral tablet according to claims 1 to 4, wherein said pregelatinised maize starch has tensile strength of less than about 0.15 kN cm"2 at a solid fraction of 0.8.

7. A process to prepare an extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s), wherein said process involves the following steps:

i. mixing and blending pramipexole with pregelatinised maize starch (Starch 1500®), colloidal silicon dioxide and hydroxypropyl methylcellulose;

ii. lubricating the blend of step (i) with magnesium stearate; and

iii. compressing the lubricated blend of step (ii) using suitable tooling to get compressed tablets.

8. A process to prepare an extended release oral tablet comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch (Starch 1500®) and one or more pharmaceutically acceptable excipient(s), wherein said process involves the following steps:

i. mixing and blending sifted pramipexole with pregelatinised maize starch (Starch 1500®) and hydroxypropyl methylcellulose;

ii. lubricating the blend obtained in step (i) using colloidal silicon dioxide and magnesium stearate;

iii. compacting the material of step (ii) using roller compactor to get flakes;

iv. sifting or passing the flakes of step (iii) through Quadro-co-mill fitted with suitable size screen to get granules;

v. lubricating the granules obtained in step (iv) using colloidal silicon dioxide and magnesium stearate; and

vi. compressing the lubricated blend of step (v) using suitable tooling to get compressed tablets.

9. The extended release oral tablet according to claims 1 to 3, wherein the pharmaceutically acceptable excipient(s) are selected from a group comprising of glidant(s), lubricant(s) or combinations thereof.

10. An extended release oral tablet formulation comprising pramipexole, hydroxypropyl methylcellulose, pregelatinised maize starch and one or more pharmaceutically acceptable excipient(s) as herein described and exemplified.