WO2011112161A1

WO2011112161A1 - Extended release thiocolchicoside tablets

Info

Publication number: WO2011112161A1
Application number: PCT/TR2010/000174
Authority: WO
Inventors: Abdullah Bulgur
Original assignee: Ali Raif Ilac Sanayi Ve Ticaret A.S.
Priority date: 2010-03-12
Filing date: 2010-09-01
Publication date: 2011-09-15
Also published as: EP2566463B1; TR201001903A2; EP2566463A1

Abstract

Present invention is related to extended release pharmaceutical composition containing 8 to 16 mg thiocolchicoside with once a day dosage regime. The composition contains a polymer which controls the release of thiocolchicoside. 35 to 65% of thiocolchicoside in the formulation is released at the first hour in 0.1 N hydrochloric acid medium. The composition is equivalent to the conventional tablets taken twice daily.

Description

EXTENDED RELEASE THIOCOLCHICOSIDE TABLETS

DESCRIPTION

Technical Field:

Present invention is related to extended release pharmaceutical composition containing 8 to 16 mg thiocolchicoside with once a day dosage regime. The composition contains a polymer which controls the release of thiocolchicoside. 35 to 65% of total thiocolchicoside is released in the first hour in 0.1 N hydrochloric acid medium. The composition developed is equivalent to the conventional tablets taken twice daily.

Previous Technique:

Thiocolchicoside is the synthesized derivative of colchicoside, a natural glycoside, by adding sulphur (Formula I). Its chemical name is /V-[3-( -D-glucopyranosyloxy)-1,2-dimethoxy-10- (methylthio)-9-oxo-5,6,7,9-tetrahydrobenzo[a]heptalen-7-yl]acetamide and its molecular weight is 563.618.

Thiocolchicoside, which has the pharmacological muscle relaxing effect, reduces the contractions from central nervous system or completely relieves them similar to the situation of spastic hypertonus. Thiocolchicoside prevents residual spasm by reducing the passive resistance.

Muscle relaxing effect of thiocolchicoside is also observed in visceral muscles.

Thiocolchicoside exerts its effect through central nervous system and it does not cause motor plaque paralysis.

Thiocolchicoside is a specific gamma-aminobutiric acid (GABA) receptor antagonist. It has also glycinergic agonist effect. As a result, thiocolchicoside does not block voluntary muscle movements and does not constitute any risk of respiration paralysis.

In the commercially available, conventional, immediate release forms, the active metabolite of thiocolchicoside, 3-Desmethylthiocolchicine reaches the highest plasma concentration approximately in one hour. Its muscle relaxing effect starts in 1-2 hours and the effect increases cumulatively with the increasing doses. Elimination half of life of the drug in plasma is 4-5 hours. Most of the dose taken is renally excreted and the remaining part is excreted through extrarenal ways. W01999/039717 explains the nasal application of thiocolchicoside.

WO 1998/036751 is about the application of thiocolchicoside on oral mucosa.

WO 1996/041635 is about the concomitant administration of thiocolchicoside with diclofenac salts. Advantages of the invention:

As the elimination half life of the active metabolite Desmethylthiocolchicine, reaching maximum plasma concentration in one hour, is 4-5 hours, very low plasma concentrations are observed at the time of the next dose. As a result, deep releases occur in plasma concentrations with conventional tablets of 4-8 mg, taken every 12 hours. These releases get deeper with repeated doses. Present invention makes the plasma concentration more stable by reducing the deepness of these releases thanks to extended release. It is also more convenient for the patient with single daily dose.

Description of the invention:

Present invention is related to the formulation of extended release tablets containing 8 - 16 mg thiocolchicoside, which are bioequivalent to the commercially available, conventional 4 and 8 mg tablets administered twice daily.

The developed extended release tablet makes 35 to 65% immediate release in order to provide the sufficiently effective blood level and reach the Cmax level of the conventional tablets. Then, it makes extended release the remaining thiocolchicoside in 5 hours or more in order to keep the plasma concentration efficient for longer durations.

The tablet developed consists of the separate parts, one of which provides immediate release and the other provides extended release. 55-56% of thiocolchicoside content of the tablet is in the extended release part and the remaining 35/45% of it is in immediate release part. These two separate parts may be compressed as two layered tablets. In another form of the invention, extended release part constitutes the core of the tablet. Immediate release part is coated on the core tablet.

Extended release part is the matrix type formulation. Cellulose derivative polymers are used in matrix type of formulation. Preferred cellulose derivative used as polymer is hydroxypropyl methylcellulose and more preferably, hydroxypropyl methylcellulose 4000 cps commercially known as Methocel K4M CR. In coated tablet formulation, appropriate coating polymers may be used in the immediate release part. Preferred polymer is hydroxypropyl methy!cellu!ose, more preferably hydroxypropyl methylcellulose 3 cps, commercially known as Methocel E3-LV is used.

Examples related to the invention are given below and the invention is not limited to these examples given.

Example 1 :

Formulations of the extended release and immediate release parts are given in Table 1.1 and 1.2.

Table 1.1 Immediate release part

Preparation: 1 ,2,3 are sieved and mixed. 4 and 5 are dissolved by heating in water. Powder mix is granulated with this solution. Granules are dried at 60°C. It is sieved from 30 mesh. 6 and 7 are sieved and added.

These are mixed for 5 minutes.

Table 1.2 Extended release part

Preparation: 1 and 2 are sieved and mixed. It is dissolved in 3 water/alcohol (1 :1) mix. Powder mix is granulated with this solution. Granules are dried in 55°C. 4 and 5 are added and sieved from 30 mesh. 6 is sieved from 30 mesh and added and mixed for 5 minutes. Two layers are compressed in double feeding tablet machine in minimum 10 kp hardness. Tablets were tested for one hour in 500 ml 0.1 N HCI medium at 100 rpm in basket type dissolution device and then for 10 hours in 500 ml pH 6.8 phosphate buffer. Table 1 ,3 Dissolution profile

* rn=minutes, hr=hour

Example 2:

Tablets with parts of immediate and extended release are obtained as in Example I and tested by the methods given in Example I.

Table 2.1 Immediate release part

Table 2,3 Dissolution profile

* m=minutes, hr=hour Example 3:

Table 3,1 Immediate release part

Table 3,3 Dissolution profile

* m=minutes, hr=hours Example 4:

Tablet core which provides extended release was coated with the immediate release part which contains the active ingredient.

Table 4.1 Tablet core and the formulation of coating

Preparation: 1 and 2 are sieved and mixed. It is dissolved in 3 water/alcohol (1 :1) mix. Powder mix is granulated with this solution. Granules are dried in 55°C. 4 and 5 are added and sieved from 30 mesh. 6 is sieved from 30 mesh and added and mixed for 5 minutes. 200 mg tablets are compressed in round, convex moulds.

7, 8, 9, 10 are dissolved in water and the coating solution is prepared. Tablets are coated until they weigh 211.5 mg at inlet air temperature of 50°C.

Tablets were tested for one hour in 500 ml 0.1 N HCI medium at 100 rpm and then for 12 hours in 500 ml pH 6.8 phosphate buffer. The dissolution profile obtained is shown in Table 4.2.

Table 4 2 Dissolution test

* m=minutes, hr=hours

Example 5:

Tablets are obtained as in Example 4 and tested by the methods given in Example 4. Table 5.1 Tablet core and the formulation of coating

Tablo 5.2 Dissolution test

* m=minutes, hr=hours

Bioequivalence study

In this study, extended release thiocolchicoside tablet (Formula 4) was compared to commercially available, conventional immediate release, 2 Coltramyl 4mg tablets.

The study was performed as an open label pilot bioequivalence study on 12 volunteers. One group was administered 1 dose of Thiocolchicoside 16 mg SR (Formula 4) and the other group was given 2 Coltramyl 4mg tablets in 0 and 12th hours. 7 days of wash out period was used in the study.

Blood samples were taken 1 hour before Thiocolchicoside 16mg SR administration and 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 4.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours after the administration in order to establish the thiocolchicoside serum concentration.

As the reference product 2 Coltramyl 4mg tablets were given twice daily, in order to determine the peak plasma levels after the second dose, plasma was re-tested in additional time points. As a result, 17 time points were determined. These are 1 hour before the administration and 0.25, 0.50, 0.75, 1.00, 1.25, 1.50, 2.00, 4.00, 12.00, 12.25, 12.50, 12.75, 13.00, 14.00, 16.00 and 24.00 hours after the administration.

5 ml of blood was taken from the volunteers each time. Mean AUC₀._t, AUC_0-«, C_max and C_min values were calculated from the serum measurements of all volunteers. Results are given in Table 6.1-6.3. Table 6,1 Results of the bioequivalence study

Table 6.2: Findings of bioequivalence test - Thiocolchicoside 16 mg SR

Table 6,3: Findings of the bioequivalence test - 2XColtramyl 4 mg X 2 dose (0 and 12 hours)

Description of the figures

Figure 1 : Plasma concentration of Thiocolchicoside 16 mg SR(Formula 4) in log scale Figure 2: Plasma concentration of 2XColtramyl 4mg X2 dose (0,12hr) in log scale

Claims

CLAS S:

1. An extended release tablet composition comprising thiocolchicoside characterized in that the tablet composition comprises an immediate release part and an extended release part containing hydroxypropyl methylcellulose as gel forming polymer.

2. An extended release tablet according to claim 1 wherein the ratio of hydroxypropyl methylcellulose in the extended release part is 25-30% of extended release part in weight.

3. An extended release tablet according to the claim 1-2 wherein the viscosity of hidroksipropilmetilseluloz is 4000 cps.

4. An extended release tablet according to the claim 1 wherein each tablet contains 8 or 16 mg of thiocolchicoside.

5. An extended release tablet according to the claim 1 wherein extended release part comprises 55-65% and immediate release part comprises 35-45% of the total amount of thiocolchicoside in the tablet.

6. An extended release tablet according to claim 1 wherein tablet core comprises extended release part and coating on the core comprises immediate release part.

7. An extended release tablet according to claim 6;

a) a core comprises 4.5 to 9.5mg thiocolchicoside, lactose monohydrate, polyvinylpyrrolidone, hydroxypropyl methylcellulose, colloidal silicone dioxide and magnesium stereate,

a) a coating on the core comprises 3.5 to 6.5mg thiocolchicoside, hydroxypropyl methylcellulose, polyvinylpyrrolidone and polyethylene glycol.

8. An extended release tablet according to claim 1 wherein the tablet is two layered tablet.

9. An extended release tablet according to claim 8;

a) extended release part comprises 8 to 9.5 mg of thiocolchicoside, lactose monohydrate, polyvinylpyrrolidone, hydroxypropyl methylcellulose, colloidal silicone dioxide and magnesium stereate,

b) immediate release part comprises 6.5 to 8mg thiocolchicoside, lactose monohydrate, pregelatinized starch, sucrose, gelatin, talc and magnesium stereate.

10. An extended release tablet according to the previous claims wherein 35-65% of the total amount of active substance is released at first hour in 500 ml of 0.1 N hydrochloric acid at 100 rpm in a rotating basket type dissolution test equipment.