Sunday, May 17, 2009

compositions of tolperisone for oral administration description

BACKGROUND OF THE INVENTION

Tolperisone is the international non-proprietary name for the muscle relaxant (RS)-2,4′dimethyl-3-piperidinopropiophenone. The enantiomeric separation of tolperisone present as racemate is described in JP-A-53-40779. In this case, enantiomerically pure tolperisone is formed by diastereomer formation from racemic tolperisone and enantiomerically pure acetylphenylglycine salts. The diastereomers were separated by selective precipitation so that after separation of the acetylphenylglycine groups both R(−) and S(+)tolperisone was obtained in enantiomerically pure form.

Zsila et al. (Chirality 12: 720-726, 2000) have also dealt with the stereochemistry of tolperisone and established that the absolute configuration of (−)tolperisone corresponds to an R-configuration. This has also been confirmed by a monocrystal analysis which has shown that (+)tolperisone corresponds to the S configuration.

The pharmacological effect of the two enantiomers was also discussed in JP-A-53-40779. The pharmacological investigations describe a muscle-relaxing effect of R-tolperisone and a vaso- or bronchodilatory effect of S-tolperisone.

Despite the proven pharmaceutical efficacy of enantiomerically pure tolperisone and its pharmaceutically compatible salts, the oral administration is problematical insofar as the desired effect diminishes rapidly and the patient must therefore take tolperisone-containing preparations several times a day whereby the gastrointestinal tract of the patient can sometimes be damaged.

Tolperisone is metabolised relatively rapidly in the body wherein the enzyme CYP2D6 substantially influences the type and duration of the metabolism. Four different genotypes have been determined for this enzyme, namely “poor metabolisers” (approximately 7% of the population), “ultrafast metabolisers” (approximately 3%), “extensive metabolisers” (approximately 45%) and “intermediate metabolisers” (approximately 45%). The last two groups mentioned are only genotypically distinguishable but not phenotypically distinguishable. Especially in the group of “poor metabolisers”, there is a risk of toxicity since tolperisone is only converted very slowly.

In order to nevertheless achieve the desired long-term effect, it was proposed in JP-A-3277239 to develop transdermal formulations. However, practice shows that transdermal transport of medicinal products is limited especially with regard to dosage since unit doses of max. 150 mg can only be administered transdermally whereby an effective therapy is not yet established.

WO-A-00/59508 describes tolperisone-containing formulations which can be administered orally but do not have the disadvantages of the known tolperisone preparations which can be administered orally. In this case, an attempt was made to utilise the delayed effect of tolperisone insofar as the release behaviour of tolperisone should also be influenced by a defined selection of the enantiomeric ratio of R(−) to S(+)tolperisone. The adjustment of a defined enantiomeric ratio by chemical reaction is occasionally expensive and besides need not result in the desired pharmaceutical effect. Thus, in their article “Determination of Tolperisone Enantiomers in Plasma and Their Disposition in Rats” (Chem. Pharm. Bull. 4001, 272-274, Vol. 40 (1992)), Teruyoshi Yokoyama et al. have shown that an in-vivo inversion can be detected when using enantiomerically pure tolperisone. This means that through this in-vivo inversion enantiomerically pure S(+)tolperisone is converted into R(−)tolperisone to an extent of up to 20% or enantiomerically pure R(−)tolperisone is converted into S(+)tolperisone in a fraction up to 20%. This in-vivo inversion can reduce the desired pharmaceutical effect and also casts into question the use of enantiomerically pure tolperisone.

The object of the invention is to influence this in-vivo inversion by a particular, orally administrable pharmaceutical formulation wherein at the same time the controllability of the active substance release should also be modulated with the objective of long-term therapy.
DESCRIPTION OF THE INVENTION

According to the present invention, a controlled release pharmaceutical composition for oral administration of tolperisone to a subject contains an amount of enantiomeric mixture of tolperisone, or pharmaceutically acceptable salts thereof, and a controlled release agent to provide for controlled release of the enantiomeric mixture of tolperisone upon such oral administration resulting in stereoselective disposition of tolperisone enantiomers in the blood plasma of the subject wherein the plasma area under the curve (AUC) concentration ratio of R-tolperisone to S-tolperisone is higher than that of a non-controlled release composition containing the same amount of enantiomeric mixture of tolperisone. Alternatively, the pharmaceutical composition may further contain (a) a core which includes (i) the enantiomeric mixture of tolperisone and (ii) the controlled release agent and (b) a controlled release coating associated with the core. By definition, an “enantiomeric mixture” of tolperisone contains both enantiomers R and S in more than trace amounts, i.e. with each at least 2% by weight. This is illustrated by a variety of mixtures, such as without limitation 10% S and 90% R tolperisone, a mixture of 98% R and 2% S, or a racemic mixture. Also by definition, a “racemic mixture” of tolperisone, or racemic tolperisone, has equal or almost equal amounts of the R and S enantiomers, meaning both enantiomers are present with each at least 45% by weight. This is illustrated by a mixture of 45% R and 55% S tolperisone. In the preferred embodiment, the enantiomeric mixture of tolperisone in the core is a racemic mixture, and the amount of racemic tolperisone in the core is within the range of 100-500 mg. As an alternative embodiment, the enantiomeric mixture of tolperisone may have at least 50% by weight the R-tolperisone and no less than 10% by weight the S-tolperisone.

The controlled release agent may be a mixture of anionic and cationic polymers, which may be exemplified by a mixture of Eudragit RS, Eudragit L and Eudragit S. The controlled release coating may be pH independent, i.e. meaning that the acidic or basic pH of the gastrointestinal tract do not appreciably effect dissolution of the active drug. Alternatively, the coating may be pH dependent, especially where it is resistant to acidic environment, favoring dissolution post-gastricly.

The subject receiving oral administration may be any mammal, preferentially a human.

By definition, “controlled release” involves dissolution profiles like those of examples 1-8, but excludes the dissolution profile of example 9 which exemplified “non-controlled release”. In general, “controlled release” results in no more than 80% (by weight) release at two hours (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C. “Non-controlled” release encompasses the range of more than 80% (by weight) release at one hour. According to preferred embodiments, such cut-off for controlled release of 100-249 mg of tolperisone may be no more than 45% or 55% (by weight) release at 2 hours. Also, such cut-off for controlled release of 250-500 mg of tolperisone may be no more than 20% or 30% by weight release at 2 hours.

Also according to the present invention, controlled release pharmaceutical composition for oral administration of tolperisone to a subject contains an amount of racemic tolperisone, or pharmaceutically acceptable salts thereof, and a controlled release agent to provide for controlled release of the racemic tolperisone upon such oral administration resulting in stereoselective disposition of tolperisone enantiomers in the blood plasma of the subject wherein the plasma area under the curve (AUC) concentration ratio of R-tolperisone to S-tolperisone is 3:1 or higher. In the preferred embodiment, the plasma area under the curve (AUC) concentration ratio is 4:1 or higher, and the amount of racemic tolperisone in the core is within the range of 100-500 mg. As an alternative, the pharmaceutical composition may further contain (a) a core which includes (i) the racemic tolperisone and (ii) the controlled release agent and (b) a controlled release coating associated with the core.

Further according to the present invention, a method of oral administration of tolperisone to a subject involves, oral administration by controlled release of a dose of an amount of racemic tolperisone in the range of 100-500 mg to provide a stereoselective disposition of tolperisone enantiomers in the blood plasma of the subject. In a preferred range of 250-500 mg of racemic tolperisone, wherein the plasma area under the curve (AUC) concentration of R-tolperisone is 100 ng*h/ml or higher and such concentration of S-tolperisone is 25 ng*h/ml or lower. In the preferred embodiment, the amount of racemic tolperisone is in the range of about 300 mg.

Throughout this specification and attached claims, “about” when modifying a single number such as “about 50” means the number ±10% such as 50±10%. When modifying a range such as “about 50-100”, it means the range consisting of the lower number −10% and the higher number +10% such as 45-110.

As further examples of preferred embodiments, the controlled release pharmaceutical composition may have racemic tolperisone in the amount of 100-200 mg, or pharmaceutically acceptable salts thereof, wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C.) where after 2 hours no more than 45% (by weight) of the racemic tolperisone is released. Alternatively, the composition may exhibit an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C.) where after 2 hours no more than 55% (by weight) of the racemic tolperisone is released.

As a further alternative, the controlled release pharmaceutical composition may have racemic tolperisone in the amount of 201-500 mg, or pharmaceutically acceptable salts thereof, wherein the composition exhibits an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C.) where after 2 hours no more than 20% (by weight) of the racemic mixture is released. The controlled release pharmaceutical composition may exhibit an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C.) where after 2 hours no more than 30% (by weight) of the racemic tolperisone is released. The controlled release pharmaceutical composition may exhibit an in vitro dissolution profile (measured using the USP Basket Method at 75 rpm in 1,000 ml 0.1 N HCL at 37° C.) where after 4 hours no more than 60% (by weight) of the racemic tolperisone has been released.

The present invention further involves a method of treating a chronic disease, benefiting from administration of a muscle relaxant, comprising the daily administration of any of the foregoing discussed controlled release pharmaceutical compositions. Examples of such chronic diseases include multiple sclerosis, fibromyalgia, Parkinson's disease, climacteric symptoms, spasticity resulting from a stroke, spasticity resulting from neurological diseases, cervical syndrome, lumbago, cervico-brachial syndrome, osteoporosis, arthritis, rheumatic diseases such as soft tissue rheumatism and chronic polyarthritis.

The present invention still further involves a controlled release pharmaceutical composition for oral administration to a subject of tolperisone having a core including about 125-175 mg of racemic tolperisone, or pharmaceutically acceptable salts thereof, and a controlled release agent comprising a homogeneous mixture of about 9-12 mg of Eudragit S, about 1.5-2.25 mg Eudragit RS and about 9-12 mg Eudragit L; and a controlled release coating comprising about 1-4 mg Eudragit L associated with the core to provide for controlled release of the racemic tolperisone upon such oral administration resulting in stereoselective disposition of tolperisone enantiomers in the blood plasma of the subject. Preferred embodiments include the controlled release table wherein the controlled release agent comprises a homogeneous mixture of about 10.5 mg Eudragit S, about 1.88 mg Eudragit RS and about 105 mg Eudragit L and the controlled release coating comprises about 2 mg Eudragit L.

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