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Method of reducing somnolence in patients treated with tizanidine

a technology of tizanidine and somnolence, applied in the field of somnolence, can solve the problems of increasing the likelihood of somnolence, and achieve the effect of reducing somnolen

Inactive Publication Date: 2012-02-02
KING GEORGE HLDG LUXEMBOURG IIA S A R L
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0012]Now it has surprisingly been found that administration of an immediate release multiparticulate pharmaceutical composition of tizanidine taken at or around the time food is consumed cause the least overall somnolence in patients receiving tizanidine therapy as compared with the tablet formulation administered with or without food. This result is wholly unexpected in comparison to earlier clinical studies of the tablet formulation which, when taken with food, significantly increases likelihood of somnolence.
[0013]One aspect of this invention is a method of reducing somnolence in a human receiving tizanidine therapy wherein the tizanidine is contained in an immediate release multiparticulate pharmaceutical composition, which method comprises administering a therapeutically effective amount of tizanidine to the patient with food.
[0014]Another aspect of the invention is providing a method of reducing the peak plasma level concentration attained in the blood stream of a patient receiving an immediate release multiparticulate pharmaceutical composition, which method comprises administering a therapeutically effective amount of tizanidine to the patient with food.
[0019]A further inventive aspect is providing an immediate release multiparticulate pharmaceutical composition including a therapeutic amount of tizanidine in multiparticulate form having similar bioavailability to the tablet form without an increased likelihood of somnolence when taken with food and / or less somnolence associated with its use if taken with food than a tablet formulation of same dosage strength.
[0050]The reformulation of tizanidine into a multiparticulate capsule resulted in a reduced food effect on Cmax and AUC compared to the commercial tablet formulation. The effect of food causing an increase in the Cmax and AUC of tizanidine was diminished by the new capsule formulation. The capsule formulation also resulted in a greater delay in absorption (median 2 hours) when administered with food composed to the tablet formulation (median 25 minutes). Administration of tizanidine tablets and capsules in fed and fasted conditions appeared to be safe and generally well tolerated by the healthy male and female subjects participating in the study.

Problems solved by technology

This result is wholly unexpected in comparison to earlier clinical studies of the tablet formulation which, when taken with food, significantly increases likelihood of somnolence.

Method used

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  • Method of reducing somnolence in patients treated with tizanidine

Examples

Experimental program
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Effect test

example 2

(a) Immediate Release Multiparticulates

[0060]A Tizanidine HCl Application Solution is prepared as described in the Description of Individual Process Steps above according to the formulation in Table 3. The Tizanidine HCl Application Solution is then coated onto nonpareil sseds to a level of approximately 7.0% solids weight gain using for example a Glatt GPCG 5 (Glatt, Protech Ltd., Leicester, UK) fluid bed coating apparatus to form Immediate Release Multiparticulates as described in the Description of Individual Process Steps above.

TABLE 3Tizanidine HCl Application SolutionAmountIngredient(% w / w)Tizanidine HCl3.59Hydroxypropyl Methylcellulose 6 cps2.50Silicon Dioxide1.65Purified Water92.26

[0061]Immediate Release Capsules

[0062]The Immediate Release Multiparticulates prepared according to Example 2(a) above are encapsulated into hard gelatin capsules to the required dosage strength as described in the Description of Individual Process Steps above.

TABLE 4Immediate Release Capsules2 mg ...

example 3

(a) Immediate Release Multiparticulates

[0064]A Tizanidine HCl Application Solution is prepared as described in the Description of Individual Process Steps above according to the formulation in Table 5. The Tizanidine HCl Application Solution is then coated onto non-pareil seeds to a level of approximately 9.5% solids weight gain using for example a Glatt GPCG 3 (Glatt, Protech Ltd., Leicester, UK) fluid bed coating apparatus to form Immediate Release Multiparticulates as described in the Description of Individual Process Steps above.

TABLE 5Tizanidine HCl Application SolutionAmountIngredient(% w / w)Tizanidine HCl3.59Polyvinylpyrrolidone4.96Silicon Dioxide1.65Purified Water89.79

(b) Immediate Release Capsules

[0065]The Immediate Release Multiparticulates prepared according to Example 3(a) above are encapsulated into hard gelatin capsules to the required dosage strength as described in the Description of Individual Process Steps above.

TABLE 6Immediate Release Capsules2 mg Capsule4 mg Caps...

example 4

(a) Immediate Release Multiparticulates

[0067]A Tizanidine HCl Application Solution is prepared as described in the Description of Individual Process Steps above according to the formulation in Table 7. The Tizanidine HCl Application Solution is then coated onto non-pareil seeds to a level of approximately 8.6% solids weight gain using for example a Glatt GPCG 30 (Glatt, Protech Ltd., Leicester, UK) fluid bed coating apparatus to form Immediate Release Multiparticulates as described in the Description of Individual Process Steps above.

TABLE 7Tizanidine HCl Application SolutionAmountIngredient(% w / w)Tizanidine HCl2.54Hydroxypropyl Methylcellulose 3 cps3.95Talc1.50Purified Water91.56

(b) Immediate Release Capsules

[0068]The Immediate Release Multiparticulates prepared according to Example 4(a) above are encapsulated into hard gelatin capsules to the required dosage strength as described in the Description of Individual Process Steps above.

TABLE 8Immediate Release Capsules4 mg Capsule6 mg...

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Abstract

An article and method for reducing somnolence in a patient receiving tizanidine therapy. Tizanidine may be administered in the form of an immediate release multiparticulate composition at or around the time food is consumed. The composition may be packaged in a container for distribution.

Description

FIELD OF THE INVENTION[0001]This invention relates to a method and composition for reducing a side effect, namely somnolence, in patients receiving tizanidine drug therapy.BACKGROUND OF THE INVENTION[0002]Tizanidine is pharmacologically characterized as a central-acting alpha2(α2) adrenoceptor agonist which has myotonolytic activity useful in the treatment of spasticity in patients with cerebral or spinal injury, muscle spasm and pain. The imidazoline chemical structure of tizanidine is related to that of the anti-hypertensive drug clonidine and other alpha2 adrenergic agonists, however therapeutic indications are different between the two. Tizanidine has one-tenth to one-fiftieth ( 1 / 50) of the potency of clonidine in lowering blood pressure while clonidine is ineffective in treating spastic conditions. This spectrum of activities is true of the 2-amino-imidazoline alpha2 agonists in general where differences in the ring structures to which the amino group attaches cause marked dif...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/48A61K31/433A61P25/00A61K9/14A61K9/16A61K31/41A61K31/415
CPCA61K9/1676A61K31/41A61K31/415A61K31/433A61K9/48A61K9/50A61K9/0002A61P25/00A61K9/4808
Inventor PELLEGRINI, CARA A.STARK, PAUL
Owner KING GEORGE HLDG LUXEMBOURG IIA S A R L
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