EP2525786A2

EP2525786A2 - Pramipexole extended release tablets

Info

Publication number: EP2525786A2
Application number: EP11700346A
Authority: EP
Inventors: Asad Abukhalil
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2010-01-18
Filing date: 2011-01-17
Publication date: 2012-11-28
Also published as: WO2011086182A2; WO2011086182A3

Abstract

An extended-release pramipexole tablet can be formed with a neutral water swelling polymer, a water swelling anionic polymer, and optionally a water-soluble diluent.

Description

PRAMIPEXOLE EXTENDED RELEASE TABLETS

BACKROUND OF THE INVENTION

The present invention relates to an extended-release tablet for delivering pramipexole; and to making and using such a tablet.

Pramipexole, or S(-)-2-amino-6-propylamino-4,5,6,7-tetrahydrobenzothiazole, can be represented by the formula (1) and is a pharmaceutically active agent that has been proposed for treating schizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension (see for example U.S. Patent 4,843,086 and EP 186087).

The current commercial pramipexole tablets contain pramipexole dihydrochloride and are marketed for treating Parkinson's disease under several brand names including MIRAPEX^®, MIRAPEXIN^®, and SIFROL^® by Boehringer. The original commercial tablets were immediate release tablets. But more recently several proposals for making a sustained- or extended-release tablet have been given.

WO 2004/010997 relates to a sustained-release pramipexole tablet based on a matrix comprising a hydrophilic polymer (e.g., HPMC) and a starch having a tensile strength of at least about 0.15 kN/cm². The starch of this grade is characterized as a "super binder" and is able to provide good mechanical hardness to the tablet. Although the hydrophilic polymer provides sustained-release, the tablet is preferably coated with a release-controlling coating. The specified starch permits the tablet to be made in a high speed tabletting operation and to be subsequently coated, a step that involves increased mechanical stresses. The need to have a controlled-release coating is illustrated in Examples 5 and 6 of the disclosure. Example 5 is an uncoated tablet while Example 6 is the same tablet but coated with a controlled-release coating. Though both tablets demonstrated sustained release, the uncoated HPMC and starch tablets of Example 5 released more of the pramipexole during the first two hours in vitro and had a higher C_max and significantly faster T_max than the coated Example 6 tablets. This faster early release, which was believed to be caused by the inability of the matrix to sufficiently hold the highly water-soluble pramipexole dihydrochloride, was suggested as a cause for the observed higher incidence of non- serious adverse events.

WO 2006/015944 relates to extended-release pramipexole tablets having a matrix that comprises at least pregelatinized starch as a water swelling polymer. Additional swelling polymers for use with the pregelatinized starch include other neutral polymers such as HPMC. In some embodiments the matrix further comprises a water swelling anionic polymer such as acrylic acid polymerisate, methacrylic acid copolymers, carmellose sodium, etc. The tablets are reported to be suitable for once-a-day dosing.

US 2009/0041844 Al is directed to an extended-release pramipexole tablet formulation having a matrix comprising at least one water swelling polymer other than pregelatinized starch. Preferably the tablet matrix comprises at least two water swelling polymers other than pregelatinized starch; typically a neutral polymer such as HPMC and an anionic polymer such as an optionally crosslinked acrylic acid polymer or carboxymethylcellulose. While excluding pregelatinized starch, other forms of starch are not necessarily excluded. Hence many of the examples use a combination of HPMC and corn starch. But in another embodiment all forms of starch are excluded and this embodiment is exemplified in Examples 8-10. These examples contain HPMC, carboxymethylcellulose sodium, lactose, and MCC, with Examples 9 and 10 further containing Carbopol.

Recently an extended-release pramipexole tablet has been approved for sale in Europe under the brand name SIFROL^® ER. The tablet contains HPMC, Carbopol, and corn starch in the matrix. According to published literature, starch in general, and especially a pregelatinized starch, has a synergistic effect with HPMC to delay release of an embedded drug. See, for example, Levina M. et al (2001), Poster presentation by Colorcon at AAPS 2001.

It would be advantageous to have alternative formulations for providing once daily dosing of pramipexole, which is confirmed by the fact that several formulations already have been suggested. Additionally it would be desirable to have a simple formulation that is convenient to form into tablets on a commercial scale. SUMMARY OF THE INVENTION

The present invention is based on the discovery that a matrix substantially composed of HPMC can sufficiently delay the release of pramipexole dihydrochloride without the use of starch.

Accordingly, a first aspect of the invention relates to a pharmaceutical tablet comprising 0.1-1% pramipexole dihydrochloride; 55-95%) of one or more neutral water swelling polymer(s), typically one or two grades of HPMC; 2-10% of one or more anionic polymer(s), typically a Carbomer; and optionally up to 30% of a water-soluble diluent, typically mannitol or sorbitol. The tablets typically further contain a glidant and/or lubricant.

BRIEF DESCRIPTION OF THE DRAWINGS

Figs 1-5 show the dissolution curve of the pramipexol-extended release (PAL-ER) tablets from Examples 1-5, respectively in comparison to SIFROL^® ER.

Fig. 6 shows the dissolution curves for Examples 6 and 7 in comparison to SIFROL^® ER.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is based on the discovery of an extended-release tablet that can have a similar release profile to the commercially available pramipexole extended-release tablet but without the need to incorporate starch. The tablet contains pramipexole dihydrochloride dispersed in a matrix comprising neutral water swelling polymer(s), anionic water swelling polymer(s), and optionally a water soluble diluent.

The pramipexole dihydrochloride embraces all polymorphs and states of hydration thereof. Typically the monohydrate form is used. The amount of pramipexole dihydrochloride monohydrate is generally 0.125 to 5 mg, typically 0.125, 0.375, 0.75, 1.0, 1.5, 3.0 or 4.5 mg. As a percentage of the total tablet weight the pramipexole dihydrochloride is in the range of 0.06 to 1.0%, typically 0.1 to 1.0%.

The matrix is composed mostly of neutral water swelling polymer(s), which account for 55 to 95%), more typically 70 to 95%>, and in some embodiments 80 to 95%>, of the weight of the tablet. The neutral water swelling polymers are generally known in the art and include alkyl celluloses; hydroxyalkyl celluloses; polysaccharides such as galactomannanes, agar-agar, carrageen, arabic gum, and sterculia gum; polyalkylene oxides such as polyethylene oxide;

polyvinylalcohols; and polyvinylpyrrolidones. Generally hydroxypropyl methylcellulose (HPMC) is used as the only neutral polymer, albeit in one or more grades or viscosities, or is at least present as one of the neutral polymers. A single grade of HPMC may be used, typically having a viscosity of greater than 100 cps and often greater than 1,000 cps such as 10,000 to 20,000 cps. Blends of high and low viscosity HPMC may advantageously be used as well wherein the lower viscosity HPMC (usually 5-20 cps) typically is used in lower amounts than the higher viscosity HPMC.

The tablet contains 2 to 10%, typically 2 to 6%, of an anionic water swelling polymer(s). Anionic water swelling polymers are known in the art and include polyacrylic acids including their copolymers and crosslinked polymers thereof, i.e. carbomers such as Carbopol^® 71G or 971 (B.F. Goodrich), Noveon, or polycarbophil; carboxymethylcellulose sodium (carmellose sodium); chitin derivatives such as chitosan; and xanthan gum. Typically the anionic polymer is limited to the polyacrylic acids and is often Carbopol^® 71G or 971. The anionic water swelling polymer, especially carbomers, are pH-dependent and the amount thereof can vary significantly without affecting the release in the pH<4 range. From pH 4.5 upward, these polymers provide a delay effect.

The matrix may further comprise a water-soluble diluent in an amount up to 30%, generally 1 to 25%, typically 3 to 20%, and often 5 to 15%, of the tablet weight. The water- soluble diluent includes polyols and sugars such as mannitol, sorbitol, lactose, etc., but is not limited thereto. Typically mannitol is used as the sole water-soluble diluent. Mannitol and to a lesser extent sorbitol, are preferred from a tablet stability perspective. In contrast, lactose is preferably excluded from the tablet because of concerns over reduced or poor tablet stability. Furthermore, the water-soluble diluent such as mannitol sufficiently modulates the release of pramipexole from the tablet composition so that the presence of starch is not necessary.

The tablet may further contain other excipients such as lubricants, glidants, colorants, pigments, taste masking agents, etc. Often the tablet will contain magnesium stearate as a lubricant and silicon dioxide as a glidant, each in amounts of 2% or less, typically 1% or less. The tablets of the invention do not require starch in order to achieve the desired release and tablet hardness properties. Thus in most embodiments, pregelatinized starch is excluded from the tablets and, more preferably, all starch is excluded from the tablets. Nonetheless, it is possible to use small amounts of starch, e.g. up to 10%, such as 1-5%, in some embodiments of the tablets of the invention. In addition, carboxymethylcellulose including

carboxymethylcellulose sodium is not required in the tablets of the invention and is preferably excluded.

The tablets of the invention typically have a total weight of 150 to 600 mg such as 250, 325, 350, 425, or 500 mg. Generally a higher tablet strength translates to a higher tablet weight; e.g., a 4.5 mg strength of pramipexole dihydrochloride monohydrate may have a tablet weight of about 500 mg, while a smaller strength of 0.75 may have a tablet weight of around 350mg, though such weights are not required. The tablet shape is not limited and is usually round.

The tablets of the invention exhibit good extended-release of pramipexole. Generally, the tablets of the invention exhibit an average in vitro dissolution of pramipexole in 0.1N HC1 such that 25%) or less of dose amount of pramipexole is released in 30 minutes; 50%> or less of the dose amount is released in 150 minutes; and 90%> or less of the dose amount is released in 9 hours. In some embodiments, the average dissolution curve of the tablet in 0.1N HC1 meets the following time/ release relationships:

3 hours - 39-51%) of dose released;

6 hours - 59-71%) of dose released;

9 hours - 71-85%) of dose released; and

12 hours - 82-92%o of dose released.

In a preferred embodiment the dissolution curve for tablets of the invention closely match the dissolution curve of the SIFROL^® ER product. That is using the commercial tablet as the reference standard, the tablets of the invention preferably exhibit a statistical similarity factor of at least 50, when measured under the same in vitro dissolution conditions. Likewise, the tablets are also preferably bioequivalent to SIFROL^® ER.

The tablets of the present invention can be made by any known tabletting technique.

Suitable techniques include direct compression, dry granulation, and wet granulation. Direct compression procedures generally comprise mixing the solid ingredients in one or more stages and compressing the uniform mixture into tablets. In general, dry granulation procedures comprise mixing the solid ingredients (except lubricants), compacting the mixture in a compactor (e.g. a roller compactor), milling the compacted mass, screening the milled granules, mixing with a lubricant and compressing the mixture into tablets. Wet granulation generally comprises mixing the pramipexole salt with a binder in the presence of a granulating liquid. The liquid, which is typically water, is removed from the formed granules by drying. The granules are then sieved and/or milled and combined with the remaining excipients in one or more steps and then compressed into tablets.

The tablets may optionally be coated. Typically such a coating, if applied, is for color, taste masking, and/or stability reasons using conventional materials and techniques. A release controlling coating is normally not needed and preferably is avoided. Likewise enteric coatings are typically avoided. For clarity, the weight percentages referred to herein are based on the uncoated tablet; i.e., the weight of a coating, if any, is not included.

The tablets of the invention are useful in treating diseases and conditions known to be treated with pramipexole. Typically these conditions include schizophrenia, Parkinson's disease or Parkinsonism, and/or hypertension, but is not limited thereto. By use of the tablets of the present invention, however, once-a-day dosing should be possible.

The invention will be further described with reference to the following non-limiting examples.

EXAMPLES

Example 1

Tablets having the following composition were made via direct compression as follows. Pramipexole dihydrochloride is triturated with hypromellose 2208 and screened/sieved to break up any drug lumps before adding it to the rest of the excipients, except for magnesium stearate. Further screening/sieving may ensue to break any lumps if present and ensure better mixing. The magnesium stearate is added at the final stage of blending for lubrication. The blend is then compressed into 10mm round tablets. The tablets may have a range of crushing strength ranging between 8 ON and 180N. Table 1

The tablets were subjected to dissolution testing in 0.1N HC1 media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 1.

Example 2

Tablets having the following composition were made via direct compression as follows. Pramipexole dihydrochloride is triturated with hypromellose 2208 and screened/sieved before adding it to the rest of the excipients except for magnesium stearate. Further screening/sieving may ensue to break any lumps if present and ensure better mixing. The magnesium stearate is added at the final stage of blending for lubrication. The blend is then compressed into 10mm round tablets. The tablets may have a range of crushing strength ranging between 80N and 180N. Table 2

The tablets were subjected to dissolution testing in 0.1N HC1 media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 2.

Example 3

Tablets having the following composition were made via direct compressions as follows. Pramipexole dihydrochloride is triturated with hypromellose 2208 and screened/sieved before adding it to the rest of the excipients except for magnesium stearate. Further screening/sieving may ensue to break any lumps if present and ensure better mixing. The magnesium stearate is added at the final stage of blending for lubrication. The blend is then compressed into 10mm round tablets. The tablets may have a range of crushing strength ranging between 80N and 180N. Table 3

The tablets were subjected to dissolution testing in 0.1N HC1 media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 3.

Example 4

Tablets of 0.325mg strength were made using direct compression. The tablets were subjected to dissolution testing in 0. IN HC1 or pH 6.8 (phosphate buffer) media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 4. Table 4

Example 5

Tablets of 4.5mg strength were made using direct compression. The tablets were subjected to dissolution testing in 0. IN HCl media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 5.

Table 5

Example 6:

Tablets of 0.75mg strength were made using direct compression. The tablets were subjected to dissolution testing in 0.1N HCl media using USP 1 apparatus at 100 rpm. The results were compared with SIFROL^® ER and shown in Fig 6.

Table 6

Example 7

Table 7

The invention having been described, it will be readily apparent to those skilled in the art that further changes and modifications in actual implementation of the concepts and

embodiments described herein can easily be made or may be learned by practice of the invention, without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1. A pharmaceutical tablet, comprising: 0.1-1% pramipexole dihydrochloride; 55-95%) of one or more neutral water swelling polymer(s); 2-10% of one or more anionic polymer(s); optionally up to 30% of a water-soluble diluent.

2. The tablet according to claim 1 , wherein said neutral water swelling polymer comprises HPMC.

3. The tablet according to claim 1-2, wherein said neutral water swelling polymer consists of one or more HPMC polymers.

4. The tablet according to claims 1-3, wherein said neutral water swelling polymer represents 70 to 95%, preferably 80 to 95% of said tablet.

5. The tablet according to claims 1-4, wherein said anionic polymer comprises a polyacrylic acid, preferably a carbomer.

6. The tablet according to claim 5, wherein said anionic polymer consists of a carbomer.

7. The tablet according to claim 6, wherein said tablet comprises from 2 to 6 % of said

carbomer.

8. The tablet according to claim 1-7, wherein said water-soluble diluent is present in an

amount of 3 to 20%>, such as 5 to 15%, of the tablet.

9. The tablet according to claim 1-8, wherein said water-soluble diluent is mannitol, sorbitol, or both.

10. The tablet according to claim 1-9, wherein said tablet does not contain pregelatinized starch, preferably does not contain any starch.

11. The tablet according to claim 1-10, wherein said tablet does not contain a controlled- release coating.

12. The tablet according to claim 1-1 1, wherein said tablet does not contain

carboxymethylcellulose.

13. The tablet according to claim 1-12, wherein said tablet exhibits an average in vitro dissolution of pramipexole in 0. IN HC1 such that 25% or less of dose amount of pramipexole is released in 30 minutes; 50% or less of the dose amount is released in 150 minutes; and 90%> or less of the dose amount is released in 9 hours.

14. The tablet according to claim 1-13, wherein said tablet exhibits an average dissolution in 0.1N HC1 such that:

3 hours - 39-51 ) of dose released;

6 hours - 59-71%o of dose released;

9 hours - 71-85%o of dose released; and

12 hours - 82-92%o of dose released.