WO2012002644A2

WO2012002644A2 - Sustained-release pharmaceutical composition containing pramipexole or pharmaceutically acceptable salt thereof with improved stability

Info

Publication number: WO2012002644A2
Application number: PCT/KR2011/003515
Authority: WO
Inventors: Sang-Joon Lee; Kwan-Young Chang; Jae-Soon Ahn; Jae-Min Cho; Sung-Hoon Kam
Original assignee: Hyundai Pharm Co., Ltd.; Bio Pharmartis Co., Ltd.
Priority date: 2010-07-02
Filing date: 2011-05-12
Publication date: 2012-01-05
Also published as: EP2588106A2; KR101307334B1; WO2012002644A3; EP2588106A4; KR20120003278A; JP2013530212A

Abstract

Disclosed is a sustained-release pharmaceutical composition containing pramipexole or a pharmaceutically acceptable salt thereof and, more particularly, a pharmaceutical composition that uses a stabilizer for inhibiting production of related substances caused by additives and greatly enhances stability. The pharmaceutical composition shows an effectively controlled dissolution profile, realizing its usefulness in the manufacture of pramipexole-containing sustained-release preparations in various dosage forms easy for drug release control; includes a stabilizer to minimize impurity production of the drug-containing products during drug storage, remarkably improving chemical stability; and thereby eliminates a need for separate studies on the physical chemical structure analysis and/or on the toxicological effects of the corresponding impurities.

Description

[Description]

[Title of the invention]

SUSTAINED-RELEASE PHARMACEUTICAL COMPOSITION

CONTAINING PRAMIPEXOLE OR PHARMACEUTICALLY ACCEPTABLE SALT THEREOF WITH IMPROVED STABILITY

[Field of the invention]

The present invention relates to a sustained-release pharmaceutical composition containing pramipexole or a pharmaceutically acceptable salt thereof and, more particularly, to a pharmaceutical composition that uses a stabilizer for inhibiting production of related substances caused by additives and greatly enhances stability.

[Background of the invention]

Pramipexole is a known agonist for D2 dopamine receptors and used as a treatment for schizophrenia and Parkinson's disease. Pramipexole is structurally different from ergot-derived drugs such as bromocriptine or pergolide and pharmacologically distinctive in that it exhibits selectivity for D2 dopamine receptors and acts as a full agonist.

Pramipexole represented by the following formula 1 is (S)-2-amino-4,5,6,7- tetrahydro-6-(propylamino)-benzothiazol (molecular formula: Ci₀Hi₇N₃S; and molecular weight: 21 1.33).

[Formula 1]

Pramipexole or its salts are very stable at the room temperature but unstable in light and moisture. Particularly, pramipexole or its salts are very sensitive to moisture to accelerate production of related substances. Europe EMEA documents specify that regular pramipexole tablets (brand name: Mirapexin tablets) and sustained-release pramipexole tablets (brand name: Mirapexin prolonged-release tablets) are very susceptible to moisture. Those pramipexole tablets are thus specially wrapped to minimize the potential problems occurring on the distribution channels of the drug products.

To secure defined therapeutic effects of a drug, it is generally required to inhibit a loss of the content of each active ingredient during the storage period as well as shortly after production and to minimize an increase of the decomposition products of the active ingredients, namely impurities or related substances, during the storage period. Therefore, preventing intrusion of impurities in drugs is of a significant importance in the quality control of drugs. As for the regulations on the purity test in each country, the Korean Pharmacopoeia separately mentions related substances in the article regarding the purity test; the U.S. Pharmacopoeia defines the related substances as "ordinary impurities" and, unless not otherwise specified, prescribes the maximum allowable level of the impurities as the sum of the related substances not more than 2.0 %, or specifies the related compounds and the amount of each related substance in terms of chromatographic purity in each drug article; the European Pharmacopoeia and the British Pharmacopoeia define "related substances"; and the Japanese Pharmacopoeia defines "related substances" and the maximum allowable level of the related substances in the regulations on the purity test.

The control of impurities in drugs is such a matter of particular importance that every country in the world has made an international agreement for the impurity control.

The selection of appropriate excipients is therefore very important in order to enhance the stability of pramipexole-containing formulations. However, studies have not been yet made on the stabilizers applicable to the sustained-release formulations.

[Summary of the invention]

Accordingly, the present invention has been made in an effort to solve the above- mentioned problems occurring in the prior arts, and it is an object of the present invention to provide a pharmaceutical composition that inhibits production of related substances and greatly enhances stability.

[Solution to problem] To achieve the above object, the present invention provides a sustained -release pharmaceutical composition that includes: an active ingredient including an effective amount of pramipexole or its pharmaceutically acceptable salt; a sustained-release agent; and a pharmaceutically acceptable excipient including a stabilizer.

Hereinafter, a description will be given in further detail in regard to a pharmaceutical composition and its preparation method according to an embodiment of the present invention.

In accordance with an embodiment of the present invention, there is provided a sustained-release pharmaceutical composition that includes: an active ingredient including an effective amount of pramipexole or its pharmaceutically acceptable salt; a sustained-release agent; and a pharmaceutically acceptable excipient including a stabilizer.

The phrase "pramipexole or its pharmaceutically acceptable salt" as used herein is intended to include pramipexole, and its racemic body, enantiomer, polymorph, hydrate, or solvate.

Preferably, the pramipexole or its pharmaceutically acceptable salt is (S)-2- amino-4,5,6,7-tetrahydro-6-(propylamino)-benzothiazol that is the S-enantiomer of pramipexole.

Preferably, the pharmaceutically acceptable salt of pramipexole is a salt having middle or high water solubility, including, for example: salts prepared from hydrochloric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, sulfuric acid, methanesulfonic acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, p-hydroxybenzoic acid, toluenesulfonic acid, formic acid, acetic acid, propionic acid, benzoic acid, anthranilic acid, tartaric acid, maleic acid, malic acid, citric acid, isocitric acid, succinic acid, ascorbic acid, lactic acid, glycolic acid, gluconic acid, glucuronic acid, pyruvic acid, oxaloacetic acid, fumaric acid, aspartic acid, glutamic acid, stearic acid, salicylic acid, phenylacetic acid, mandelic acid, pamoic acid, pantothenic acid, sulfanilic acid, cyclohexylaminosulfonic acid, alganic acid, β- hydroxybutyric acid, galactaric acid, or galacturonic acid. More preferably, the pharmaceutically acceptable salt of pramipexole is dihydrochloride salt, most preferably dihydrochloride monohydrate.

The term "effective amount" as used herein means an appropriate content for treatment or prevention of diseases and may be adjusted depending on a variety of factors, including disease type, disease severity, the type and content of active ingredients or other ingredients contained in the composition, dosage form, patient's age, weight, health condition, gender and eating behavior, drug administration time, administration route, secretion rate of composition, duration of treatment, or concomitant medication. For example, an adult may take the pharmaceutical composition of the present invention in a maximum effective amount of 1 to 10 mg/day from once to several times a day through oral or non-oral administration route. It is evident for those skilled in the art that the content of each active ingredient is not so excessive to cause an overdose of the active ingredient and consequently side effects.

Preferably, the pramipexole or its pharmaceutically acceptable salt is contained in an amount of 0.0005 to 0.025 wt.% with respect to the whole pharmaceutical composition.

The sustained-release agent includes, but is not limited to: cellulose, such as hydroxypropylmethyl cellulose (HPMC, or hypromellose), hydroxypropyl cellulose (HPC), hydroxyethyl cellulose (HEC), or carboxymethyl cellulose (CMC); xanthan gum; sodium alginate; polyethylene oxide; hydrophilic polymer, such as cross-linked homopolymer or copolymer of acrylic acid; or mixtures of these compounds.

Preferably, the sustained-release agent includes HPMC (hypromellose), namely HPMC 2910 (E3, E5, E6, E15, E50, E4M, E10M), HPMC 2906 (F50, F4M), or HPMC 2208 (K3, K100, K4M, K15M, K100M), or mixtures of these compounds.

Preferably, the HPMC is contained in an amount of 20 to 50 wt.% with respect to the whole pharmaceutical composition. The HPMC content below the preferred range undesirably accelerates the drug release rate to cause side effects pertaining to dose dumping. The HPMC content above the range makes the drug release rate too much slow to reach an optimum Serum drug level, resulting in a failure to provide a sufficient therapeutic effect. The pharmaceutical composition according to an embodiment of the present invention contains a pharmaceutically acceptable excipient including a stabilizer.

Preferably, the stabilizer is hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 %, or a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.

The hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 % is also called "low-substituted hydroxypropyl cellulose (L-HPC)" and represented by the following formula 2.

[Formula 2]

where R is -H, or -CH₂CH(CH₃)OH (see Alvarez-Lorenzo et al., 2000).

L-HPC is a low-substituted hydroxypropyl ether of cellulose that contains a very small portion of hydroxypropoxy groups in the β-ο-glucopyranosyl ring of the cellulose. L-HPC (the average number of hydroxypropoxy substituents per glucose unit, namely "molar substitution" = 0.2 ~ 0.4) is not soluble but swollen in water, while a high- substituted hydroxypropyl ether (molar substitution = 3 ~ 5) is soluble in both water and alcohol. L-HPC is classified as given in Table 1 according to the substitution level and the particle size.

[Table 1]

Grade Hydroxypropoxy Average Bulk Density Tapped

Content (%) Particle Size (g/cm³) Density

(μπι) (g cm³)

LH-1 1 10.0 - 12.9 45 - 65 0.32 0.56

LH-21 10.0 - 12.9 35 - 55 0.36 0.62 LH-31 10.0 - 12.9 20 - 30 0.28 0.59

LH-22 7.0 - 9.9 35 - 55 0.36 0.62

LH-32 7.0 - 9.9 20 - 30 0.28 0.59

LH-20 13.0 - 15.0 35 - 55 0.36 0.62

LH-30 13.0 - 15.0 20 - 30 0.28 0.59

LH-1 1 has a middle substitution degree and the greatest particle size and is used as an anti-capping agent and disintegrant in the direct compression method. LH-21 is used as a binder and disintegrant in making tablets through the wet granulation method. LH-31 has a suitable particle size small enough to pass through nets and is used for extrusion molding to form granules. LH-22 and LH-32 are used in the case where there is no need for high binding strength, while LH-20 and LH-30 are used for high binding strength. In this manner, the change of the substitution degree and the particle size of L- HPC results from a subtle change of the physical properties and causes a change of the binding and disintegrating properties. Thus, an appropriate L-HPC is chosen according to the type of applications. Preferably, the L-HPC has a hydroxypropoxy content of 7.0 to 9.9 %.

The L-HPC is normally used as an excipient (disintegrant or binder) having a good disintegrating property but problematic when contained in a sustained-release agent and exposed in vivo, causing pores to form around the sustained-release agent and to make the drug release control difficult. For this reason, the L-HPC has never been used for the sustained-release preparations.

Surprisingly, the experimental results of the present inventors have found out that a composition using an appropriate combination of a sustained-release agent (e.g., HPMC) and a stabilizer (e.g., L-HPC) can be prepared to compensate for the problem and to realize excellent stability against moisture.

The L-HPC is preferably contained in an amount of 10 to 80 wt.%, more preferably 20 to 60 wt.% with respect to the whole pharmaceutical composition. Preferably, the sustained-release agent and the L-HPC are contained at a weight ratio of the sustained-release agent to the L-HPC in the range of 1 :0.2 - 4.

The weight ratio below the preferred range undesirably reduces the expansion of the sustained-release agent to lower the drug release rate, while the weight ratio above the range causes minute pores to form on the surface of the sustained-release agent or increases the expansion of the sustained-release agent upon in vivo exposure, imparting an unexpected release profile.

The stabilizer may also be a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.

Anionic acryl-based polymer such as carbomer, or carbopol® such as carbomer 941 (carbopol®71G, carbopol®971P) and carbomer 934P (carbopol®974P, carbopol®934P) causes a variance of the release rate of the sustained-release agent according to the diet-based stomach circumstances through pH-dependent drug release, and cannot consistently maintain the rigid matrix form at pH 4.5 or above, causing "dose dumping", rapidly releasing an excess of drug in a short period of time. Accordingly, a methacryl-based cationic polymer soluble in solution at pH 5.5 or below is preferred as the stabilizer.

Preferably, the methacryl-based cationic polymer includes, but is not limited to, a poly(butyl methacrylate, (2-dimethylaminoethyl)methacrylate, methyl methacrylate) 1 :2:1 copolymer (brand name: Eudragit E, Rohm GmbH) represented by the following formula 3.

[Formula 3]

where R¹ and R³ are CH₃; R² is CH₂CH₂N(CH₃)₂; and R⁴ is CH₃ or C₄H₉.

Eudragit E is a pH-dependent cationic polymer based on dimethylaminoethyl methacrylate and other neutral methacrylic acid esters. Eudragit E is soluble at pH 5.5 or below and hence used as a gastric soluble coating agent that is a solubilizing agent for drugs having a low solubility inside the stomach. The inventors of the present invention have found out that the use of Eudragit E not only realizes efficient release control of sustained-release pramipexole preparations but also remarkably improves the stability.

Preferably, the methacryl-based cationic polymer is contained in an amount of 1 to 8 wt.%, more preferably 1 to 5 wt.% with respect to the whole pharmaceutical composition. The content of the methacryl-based cationic polymer below the preferred range hardly secures the sustained-release property in an in vivo solution at pH 5.0 or above, completing the drug release too early and deteriorating the inhibitory effect on the formation of related substances. The content of the methacryl-based cationic polymer above the range excessively retards the drug dissolution rate.

Accordingly, the content of the methacryl-based cationic polymer can be controlled in accordance with the range not only to change the dissolution profile according to a desired purpose but also to much more enhance the stability of the pharmaceutical composition of the present invention.

Preferably, the stabilizer may include both the L-HPC and the methacryl-based cationic polymer to much more enhance the stability of the pharmaceutical composition of the present invention.

Preferably, the stabilizer contains the L-HPC and the methacryl-based cationic polymer at a weight ratio of the L-HPC to the methacryl-based cationic polymer in the range of 1.25: 1 to 40: 1.

Besides, the pharmaceutical composition of the present invention optionally contains other typical excipients, including diluents, such as microcrystalline cellulose, lactose, glucose, mannitol, alginate, alkaline earth metal salts, clay, polyethylene glycol or dicalcium phosphate; lubricants, such as magnesium stearate or silicon dioxide; or binders, such as microcrystalline cellulose or starch. These pharmaceutically acceptable excipients are specifically limited and may be appropriately selected according to the known techniques in the art. The pharmaceutical composition of the present invention shows an effectively controlled dissolution profile, realizing its usefulness in the manufacture of pramipexole-containing sustained-release preparations in various dosage forms easy for drug release control; includes a stabilizer to minimize impurity production of the drug- containing products during drug storage, remarkably improving chemical stability; and thereby eliminates a need for separate studies on the physical chemical structure analysis and/or on the toxicological effects of the corresponding impurities.

[Brief description of drawings]

FIG. 1 shows the results of the stability assessment according to the use of L- HPC in Experimental Example 1 of the present invention.

FIG. 2 shows the results of the stability assessment according to the use of Eudragit E in Experimental Example 2 of the present invention.

FIG. 3 shows the results of the dissolution control assessment in Experimental Example 3 of the present invention.

[Detailed description of the invention]

In the following are set forth specific examples according to the present invention, which are given only for illustrative purposes and are not intended to limit the scope of the present invention.

Example 1 and Comparative Examples 1, 2 and 3: Preparation of Sustained- Release Pharmaceutical Composition Containing L-HPC

Pramipexole-containing sustained-release pharmaceutical compositions were prepared in the form of tablets according to the composition and content in Table 2. More specifically, pramipexole was mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.

[Table 2]

Carbopol®71G 14 14 14 14

L-HPC (LH-22) 174.6 - - -

Corn Starch - 174.6 - -

Pregelatinized Starch 174.6

(Starch 1500)

Microcrystalline 174.6

Cellulose (AVICEL

PHI 02)

Colloidal Silicon 1.4 1.4 1.4 1.4

Dioxide

Magnesium Stearate 1.75 1.75 1.75 1.75

* Comparative Example 1 used the composition of pramipexole sustained-release tablets (brand name: Mirapexin Prolonged-release tablets) commercially available in Europe as disclosed in laid-open publication No. KR10-2007-7005700.

Examples 2 and 3: Preparation of Sustained-Release Pharmaceutical Composition Further Containing Eudragit E

Pramipexole-containing sustained-release pharmaceutical compositions were prepared in the form of tablets according to the composition and content in Table 3. More specifically, pramipexole was diluted geometrically by blending with HPMC and mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.

[Table 3]

mg/tablet Example 2 Example 3

Pramipexole 0.75 0.75

HPMC K15M 157.5 157.5

L-HPC (LH-22) 174.6 174.6

Eudragit E (Eudragit EPO) 14 -

Tromethamine - 14 Colloidal Silicon Dioxide 1.4 1.4

Magnesium Stearate 1.75 1.75

Example 4: Preparation of Sustained-Release Pharmaceutical Composition Containing Pramipexole

There was prepared a pramipexole-containing sustained-release pharmaceutical composition in the form of tablets according to the composition and content in Table 4. More specifically, pramipexole was diluted geometrically by blending with HPMC and mixed with all the respective components other than magnesium stearate. To the mixture was finally added magnesium stearate, and the resulting mixture was compressed into tablets on a rotary type tablet making machine.

[Table 4]

Experimental Example 1 : Stability Assessment of Pramipexole-Containing Sustained-Release Pharmaceutical Composition According to Use of L-HPC

The tablets prepared in Example 1 and Comparative Examples 1 , 2 and 3 were subjected to a stress testing during open storage (completely exposed without separate packaging) at 40 ^°C and 75 % RH and to an analysis on the impurity content by high performance liquid chromatography every week. The results are presented in FIG. 1.

As shown in FIG. 1, compared to the pharmaceutical compositions of Comparative Examples 1, 2 and 3, the novel pharmaceutical composition of Example 1 had the least rise in the impurity content. The results show that in the sustained-release pharmaceutical composition containing pramipexole or its salt, the use of a stabilizer such as L-HPC inhibits production of related substances, greatly improving the storage stability of the pramipexole-containing sustained-release pharmaceutical composition.

Experimental Example 2: Stability Assessment of Pramipexole-Containing Sustained-Release Pharmaceutical Composition According to Use of Eudragit E

The tablets prepared in Examples 2 and 3 were subjected to a stress testing in the same manner as described in Experimental Example 1. The results are presented in FIG. 2.

As shown in FIG. 2, compared to the pharmaceutical composition of Example 3, the novel pharmaceutical composition of Example 2 had a considerably lower yield of the related substances, extremely lower than the impurity content of the pharmaceutical composition of Example 1 shown in FIG. 1. The result shows that the stability can be more improved according to the ionic characteristic of the methacryl-based polymer and much more improved by using Eudragit E in combination with the L-HPC.

Experimental Example 3: Dissolution Control Assessment According to Use of Eudragit E

The dissolution profile of the pramipexole-containing sustained-release pharmaceutical composition prepared in Example 4 was assessed according to the dissolution test in the Korean Pharmacopoeia. The results are presented in FIG. 3. More specifically, the test solution (900 mL of 0.05 M phosphate buffer solution (pH 6.8)) was stirred at 50 rpm and 37 ^°C in accordance with the paddle method in the dissolution test of the Korean Pharmacopoeia. As can be seen from FIG. 3, the drug release rate of the pramipexole-containing sustained-release tablets shows a good sustained-release profile because of the Eudragit E content.

Claims

What is claimed is:

1. A sustained-release pharmaceutical composition comprising:

an active ingredient including an effective amount of pramipexole or a pharmaceutically acceptable salt thereof;

a sustained-release agent; and

a pharmaceutically acceptable excipient including a stabilizer.

2. The sustained-release pharmaceutical composition of claim 1 , wherein the pramipexole or the pharmaceutically acceptable salt thereof is contained in an amount of 0.0005 to 0.025 wt.% with respect to the whole pharmaceutical composition.

3. The sustained-release pharmaceutical composition of claim 1 , wherein the sustained-release agent is at least one selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, carboxymethyl cellulose, xanthan gum, sodium alginate, polyethylene oxide, and mixtures thereof.

4. The sustained-release pharmaceutical composition of claim 3, wherein the hydroxypropylmethyl cellulose is contained in an amount of 20 to 50 wt.% with respect to the whole pharmaceutical composition.

5. The sustained-release pharmaceutical composition of claim 1, wherein the stabilizer is hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 %, or a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.

6. The sustained-release pharmaceutical composition of claim 5, wherein the methacryl-based cationic polymer is a poly(butyl methacrylate, (2-dimethyl aminoethyl)methacrylate, methyl methacrylate) 1 :2:1 copolymer.

7. The sustained-release pharmaceutical composition of claim 5, wherein the hydroxypropyl cellulose is contained in an amount of 10 to 80 wt.% with respect to the whole pharmaceutical composition.

8. The sustained-release pharmaceutical composition of claim 5 or 6, wherein the methacryl-based cationic polymer is contained in an amount of 1 to 8 wt.% with respect to the whole pharmaceutical composition.

9. The sustained-release pharmaceutical composition of claim 1 , wherein the stabilizer is hydroxypropyl cellulose having a hydroxypropoxy content of 7.0 to 15.0 %, and a methacryl-based cationic polymer soluble in solution at pH 5.5 or below.