FIELD OF INVENTION

The present invention relates to extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipients. The invention also relates to processes for preparing the extended release compositions of tramadol.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Tramadol, chemically known as (±)-Trans-2-[(dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol is an orally active opioid analgesic. It is commercially available in various dosage forms like tablets, capsules, injections, suppositories and drops. It is generally available in the form of its hydrochloride salt.

A number of inventions relating to extended release compositions and their process of preparations are known in the art. Such compositions provide controlled release of pharmacologically active substances contained in the compositions after oral administration to humans and animals leading to delayed absorption of medicament until it have reached certain portions of the alimentary tract. These dosage forms maintain a desired concentration of said medicament in the blood stream for a longer duration than would occur if conventional dosage forms are administered. Some of the prior art are cited below.

US6254887 discloses a controlled release formulation comprising a substrate comprising tramadol or pharmaceutically acceptable salts wherein the substrate is coated with a controlled release coat.

US7074430 discloses a controlled release formulation comprising a substrate comprising tramadol or pharmaceutically acceptable salts in a matrix, wherein the matrix is coated with a controlled release coat of a water insoluble polymer.

US5958452, US6261599, US6335033, US6706281 and US6743442 relates to sustained release dosage forms comprising oral opioid analgesic and hydrophobic materials, which is produced via melt extrusion technique.

US5811126 discloses a controlled release pharmaceutical composition of tramadol comprising a controlled release matrix consisting of sodium alginate and water swellable polymers.

US20050266072 discloses substrate comprising an opioid antagonist and a diffusion barrier coating comprising an anionic polymer.

EP624366 and EP1468679 relate to controlled released dosage forms comprising tramadol or pharmaceutically acceptable salt in a controlled release matrix, wherein the matrix contains 1 to 80% w/w of one or more hydrophilic or hydrophobic polymers, preferably cellulose ethers.

EP0642788 discloses a delayed release composition comprising a salt of tramadol as an active ingredient and at least one cellulose ether and/or cellulose ester, which has a viscosity between 3000 and 150,000 mPas in a 2% by weight aqueous solution at 20°C, as a pharmaceutically acceptable matrix former.

WO 03/080031 presents a tramadol formulation, in which the matrix-forming polymer is xanthan gum.

The above prior art disclose the use of cellulose ethers for preparing controlled release compositions of tramadol. But, till date the use of cellulose derivatives having viscosity greater than 150000 mPas when measured as a 2% by weight aqueous solution at 20° C, have not been reported for use as a matrix former, in the preparation of extended release compositions of tramadol.

The inventors of the present invention have been able to develop an extended release compositions of tramadol by using cellulose derivatives having viscosity greater than 150000 mPas when measured as a 2% by weight aqueous solution at 20° C as a matrix former; which demonstrate similar in vitro dissolution profile and in vivo bioequivalence to that of commercially available Zydol® SR.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipient.

More particularly, the invention relates to extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

Further, the invention also relates to processes for preparing extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

In one aspect, the invention provides extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity of about 200000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

In another aspect, the invention provides a process for preparing extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity of about 200000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

In yet another aspect, the invention provides extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity of 200000 mPas when measured as a 2% by weight aqueous solution at 20 °C, wherein the in vitro dissolution profile and in vivo bioequivalence of said compositions are similar to that of commercially available Zydol® SR.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE INVENTION

The invention relates to extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts thereof and one or more pharmaceutically acceptable excipients.

More particularly, the invention relates to extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

The term "pharmaceutical compositions" as used herein refers to dosage form for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably the dosage form is a tablet.

The term "matrix former" as used herein refers to any pharmaceutically acceptable water-soluble or water-dispersible excipient that will serve as a rate controller for the release of active ingredient from said dosage form.

The term "excipient" refers to any ingredient that may be added to the formulation besides the active ingredient.

The invention involves release of active ingredients by surface erosion of the hydrated matrix. For practically insoluble drugs which may dissolve slowly and have slow diffusion through the gel layer of a hydrophilic matrix, low viscosity grades of polymers can be used as matrix former. For drugs with very high water solubility, the drug dissolves within the gel layer (even with small amounts of free water) and diffuses out into the media. Therefore, it is important to ensure integrity of the gel layer after the drug has been dissolved and release. In this case, it is critical to have a strong gel layer through which diffusion can occur and hence, high viscosity grades of polymers are preferred as matrix former. The inventors use polymers having viscosity greater than 150000 mPas in a 2% by weight aqueous solution at 20 °C as suitable matrix former which controls the release of active ingredient from the dosage form.

Suitable pharmaceutically acceptable matrix formers according to the invention are selected from the group consisting of polymers selected from hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, and carboxymethylcellulose. Preferably hydroxypropylmethylcellulose is used as pharmaceutically acceptable matrix former. The amount of matrix former used in the composition ranges from about 20-80% w/w, preferably from 20-60% w/w of the composition and still more preferably from about 25-40% w/w of the composition.

The composition according to the invention may include other pharmaceutically acceptable excipients selected among, but are not limited to diluents, lubricants, film former, plasticizers, viscosity enhancers, preservatives, antioxidants and the like.

Diluents according to the invention may include, but are not limited to lactose, microcrystalline cellulose, silicified microcrystalline cellulose, dicalcium phosphate, sugar alcohols such as mannitol and the likes, dextrates, dextrin,calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide, starch, pregelatinized starch, and the like.

Suitable glidants and lubricants according to the invention may include, but are not limited to silica, colloidal silica, magnesium trisilicate, talc, stearates, behenates, fumarates, hydrogenated castor oil, and the like.

The dosage form according to the invention is prepared by direct compression process that comprises (1) sifting of active ingredient, matrix former and diluent together through suitable sieve (2) mixing the sifted material in suitable blender (3) sifting the glidants and lubricant through suitable sieve (4) mixing the sifted materials of step 3 with step 2 material (5) compressing the blend of step 4 using suitable tooling in to tablets (6) coating the prepared tablets by a suitable film coat.

The film coat used in the present invention may comprise polymers such as cellulose derivatives such as one which is commercially available as Instacoat™ or Opadry™.

In one of the embodiment there is also provided extended release pharmaceutical compositions comprising tramadol or its pharmaceutically acceptable salts, at least one matrix former and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C, wherein the in vitro dissolution profile of said compositions are similar to that of commercially available Zydol® SR.

In another embodiment there is also provided bioequivalence studies to evaluate the iv-vivo drug release of the compositions. The study was carried out between Zydol® SR and compositions of the invention in both fed and fasted state. Plasma samples were assayed for tramadol using a validated high performance liquid chromatographic procedure. The study was monitored in terms of Cmax,AUCo-t and AUC achieved with the test product and reference product [Zydol® SR].

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Table- 1

Unit Composition:
Sr. Ingredients Example Example Example Example
No. (in mg) 1 2 3 4
1. Tramadol HC1 100.00 100.00 100.00 100.00
2. Hypromellose 50.00 60.00 70.00 80.00
3. Microcrystalline 47.00 37.00 27.00 13.00 cellulose
4. Colloidal silicon 1.00 1.00 1.00 1.00 dioxide
5. Magnesium 2.00 2.00 2.00 2.00 stearate
Total 200.00
6 1 Instacoat™ 5.00 I 5.00 I 5.00 I 5.00
Total Tablet Weight | 205.00 | 205.00 | 205.00 1 205.00

Brief manufacturing procedure:

1. Sift Tramadol HC1, Hypromellose and microcrystalline cellulose through suitable sieve.

2. Mix step 1 materials in suitable blender for sufficient time.

3. Sift Colloidal silicon dioxide and magnesium stearate through suitable sieve.

4. Mix step 3 materials with step 4 material in a blender for suitable time.

5. Compress step 4 blend using suitable tooling.

6. Coat the tablets using aqueous dispersion of Instacoat White.

Dissolution studies:

The above compositions were tested for dissolution (drug release) in 900 ml of 0.1N HC1 at 75 rpm using USP Dissolution Apparatus - I and the results obtained are shown below.

Table- 2

Batch details Time in Hrs
1 1 2 I 4 I 6 1 8 I 10
Reference Product 30 46 70 84 94 101
(Zydol® SR)
Example 1 41 58 81 94 103 105
Example 2 37 55 78 91 97 100
Example 3 36 53 74 91 98 101
Example 4 | 37 | 63 | 77 ] 94 | 98 | 101

Bio-studies:

The compositions of the invention are evaluated for bioequivalent study under both fed and fasting conditions in healthy human volunteers and the results obtained are shown below.

Table- 3

In-vivo study results under fed condition (for example-2)

Parameters % T/R Confidence
Interval
Cmax 111.91 106.12-118.01
AUC 100.31 94.05-106.98
AUC 101.16 95.33-107.12

Table- 4

In-vivo study results under fasting condition (for example-2)

Parameters % T/R Confidence
Interval
C 109.23 103.17-115.65
AUC 103.03 94.10-112.81
AUC 102.97 94.19-112.57

WE CLAIM:

1. An extended release pharmaceutical composition comprising tramadol or its pharmaceutically acceptable salts thereof, at least one matrix former, and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

2. The extended release pharmaceutical composition according to claim 1, wherein said polymer is a cellulose derivative.

3. The extended release pharmaceutical composition according to claim 1, wherein said polymer is hydroxy propylmethyl cellulose.

4. The extended release pharmaceutical composition according to claim 1, wherein said polymer has a viscosity of about 200000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

5. The extended release pharmaceutical composition according to claim 1, wherein said matrix former is present in an amount about 20-80% by weight of the composition.

6. The extended release pharmaceutical composition according to claim 1, wherein said other pharmaceutically acceptable excipients is selected from a group comprising a filler, disintegrant, binder, surfactant, glidant, lubricant, film former and mixtures thereof.

7. The extended release pharmaceutical composition according to claim 1, wherein said composition is in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads or minitablets.

8. A direct compression process for the reparation of an extended release tablet comprising tramadol or its pharmaceutically acceptable salts thereof, at least one matrix former, and optionally other pharmaceutically acceptable excipient, wherein said matrix former is a polymer having a viscosity more than 150000 mPas when measured as a 2% by weight aqueous solution at 20 °C.

9. An extended release pharmaceutical composition comprising of 50 % w/w of tramadol hydrochloride, 30 % w/w of hydroxy propylmethyl cellulose, 18 %w/w of microcrystalline cellulose, 1% w/w of colloidal silicon dioxide and 1% w/w of magnesium stearate.