WO2009063484A2

WO2009063484A2 - Stable pharmaceutical composition of lamotrigine

Info

Publication number: WO2009063484A2
Application number: PCT/IN2008/000463
Authority: WO
Inventors: Ranjan Pradhan Manas; Urankar Manohar; Sathya Narayana Vemula; Singh Samprada
Original assignee: Alkem Laboratories Ltd
Priority date: 2007-08-03
Filing date: 2008-07-18
Publication date: 2009-05-22
Also published as: WO2009063484A3

Abstract

The present invention relates to a process for a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising pregelatinised starch, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

Description

TITLE:

STABLE PHARMACEUTICAL COMPOSITION OF LAMOTRIGINE AND PROCESS FOR ITS PREPARATION

FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof.

BACKGROUND OF THE INVENTION

Larnotrigine, an antiepileptic drug of the phenyJtriazine class, is chemically unrelated to existing antiepileptic drugs. Its chemical name is 3,5-diamino-6-(2,3-dichlorophenyl)-αs- triazine, its molecular formula is C9H7N5CI2, and its molecular weight is 256.09. Lamotrigine is indicated as adjunctive therapy for the treatment of partial seizures in adults with epilepsy. The precise mechanism(s) by which lamotrigine exerts its anticonvulsant action are unknown. However, one proposed mechanism of action of lamotrigine , the relevance of which remains to be established in humans, involves an effect on sodium channels. In vitro pharmacological studies suggest that lamotrigine inhibits voltage-sensitive sodium channels, thereby stabilizing neuronal membranes and consequently modulating presynaptic transmitter release of excitatory amino acids (e.g., glutamate and aspartate).

PCT Application No. 2004/082587A2 relates to a stable pharmaceutical composition of lamotrigine and pharmaceutically acceptable acid addition salts thereof. The pharmaceutical composition includes: (a) from about 0.1% to about 50 % by weight of lamotrigine or acid addition salt thereof; (b) from about 15.5% to about 70% by weight of microcrystalline cellulose; (c) from about 0.1% to about 14.5% by weight of sodium starch glycolate; and (d) from about 0.1% to about 4.5% by weight of polyvinylpyrrolidone. This formulation includes povidone as a binder, which hardens the tablet after certain period of storage. This may be due to the water gaining ability of povidone at 50% RH up to an extent of 10% weight. United States Patent No. 5698226 relates to a water-dispersible tablet comprises an active compound such as acyclovir or lamotrigine and a dispersing agent. The dispersing agent is swellable clay such as a smectite, e.g. Veegum F or bentonite, and is generally present within the granules of the tablet to provide a tablet, which is capable of dispersing in water within 3 minutes to provide a dispersion, which will pass through a 710 μm sieve. The tablet can be optionally film-coated in which case the dispersion time is less than 5 minutes.

While the lamotrigine formulations disclosed in the above patents are suitable for a commercial product, but they suffer from some drawbacks in terms of stability. A great deal of research has been done in mis area to incorporate lamotrigine with other pharmaceutically accepted excipients but it has always resulted in stability problems. To overcome the problems associated with the prior arts, an intensive and thorough research resulted in providing the most advantageous solid formulation in terms of bom stability and processing characteristics. This includes lamotrigine or a pharmaceutically acceptable salt thereof along with pregelatinised starch to overcome the shortcomings of povidone or any binder which retards disintegration & decrease solubility of drug as well.

OBJECT OF THE INVENTION

It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art in making a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof.

It is further an object of the invention to provide stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof.

It is further an object of the invention to provide stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof. It is further an object of the invention to provide stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof, wherein the tablet dosage form exhibits hardness and dissolution rate comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®.

It is further an object of the invention to provide stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof, wherein the tablet dosage form is bioequivalent to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^® tablets

At least one of the preceding objects is met, in whole or in part, by the stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thefeof of the present invention and process for the preparation thereof

SUMMARY OF THE INVENTION

The present invention provides stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof. The pharmaceutical composition of the present invention uses pregelatinised starch. Pregelatinised starch exhibits a dual functionality in formulation. As a disintegrant, it produces tablet of similar hardness to that of povidone, but, with significantly faster disintegration properties compared to the povidone formulation. It also exhibits self- lubricating properties. Thus, with the use of pregelatinised starch in the formulation of the present invention, the composition of the invention exhibits hardness, dissolution rate, disintegration time and bio-availability comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®. Unlike povidone, storing for a longer period of time, tablet containing pregel starch showed no alteration in hardness, dissolution time & dissolution profile.

The invention may be summarized as given below: A. A stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising pregelatiπised starch, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

B. A stable pharmaceutical composition as in A above, wherein, the pregelatinized starch is used in amounts ranging from about 0.1% w/w to about 15% w/w.

C. A stable pharmaceutical composition as in A above, further comprising one or more disintegrant.

D. A stable pharmaceutical composition as in C above, wherein the disintegrants are selected from the group comprising sodium starch glycol ate, croscaπnellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like and mixtures thereof.

E. A stable pharmaceutical composition as in A above, further comprising one or more diluents.

F. A stable pharmaceutical composition as in E above, wherein the diluents are selected from the group comprising monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof, like starch, mannitol, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, lactitol and fructose and the like; dextrates, dextrins, dextrose excipients, fructose, kaolin, and other polyols, starch pregelatinized, sugar compressible sugar confectioners, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate and the like or mixtures thereof. G. A stable pharmaceutical composition as in A above, further comprising one or more wetting agents.

H. A stable pharmaceutical composition as in G above, wherein the wetting agents are selected from the group comprising sodium dodecyl sulphate, sodium lauryl sulphate, polyoxyethylene sorbitan fatty acid esters (T weens), polyoxyethylene stearates, sorbitan fatty acid esters (Spans) and the like and mixtures thereof.

I. A stable pharmaceutical composition as in A above, wherein the dosage form is a tablet dosage form.

J. A stable pharmaceutical composition as in A above, wherein the tablet dosage form exhibits hardness and dissolution rate comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®. K. A stable pharmaceutical composition as in I above, wherein the tablet dosage form is bioequivalent to the commercially available lamotrigene tablet in Ae United States of America i.e. Lamictal^®.

L. A process for preparing a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising reacting the lamotrigine or a pharmaceutically acceptable salt thereof with pregelatinised starch and other exipients and converting the mixture into a pharmaceutical composition, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

DESCRIPTION OF THE INVENTION

Before the present formulations and methods are described, it is to be understood that this invention is not limited to particular compounds, formulas or steps described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

Where a range of values is provided, it is understood that each intervening value, to Ae tenth of Ae unit of Ae lower limit unless Ae context clearly dictates o Aerwise, between the upper and lower limit of that range and any other stated or intervening value in Aat stated range is encompassed wiAin Ae invention. The upper and lower limits of Aese smaller ranges may independently be included in Ae smaller ranges is also encompassed wiAin Ae invention, subject to any specifically excluded limit in Ae stated range. Where Ae stated range includes one or boA of Ae limits, ranges excluding eiAer boA of Aose included limits are also included in Ae invention.

Unless defined oAerwise, all technical and scientific terms used herein have Ae same meaning as commonly understood by one of ordinary skill in Ae art to which Ais invention belongs. AlAough any meAods and materials similar or equivalent to Aose described herein can also be used in Ae practice or testing of Ae present invention, Ae preferred meAods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.

It must be noted that as used herein and in the appended claims, the singular forms "a", "and", and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds and reference to "the step" includes reference to one or more step and equivalents thereof known to those skilled in the art, and so forth.

The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.

The present invention provides a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof.

The present invention provides stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof and process for the preparation thereof

The present invention provides stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof, wherein the tablet dosage form exhibits hardness and dissolution rate comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®.

The present invention provides stable tablet dosage form of lamotrigine or a pharmaceutically acceptable salt thereof, wherein the tablet dosage form is bioequivalent to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^® tablets Accordingly the present invention provides a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising pregelatinised starch, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

The present invention also provides a process for preparing a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising mixing the lamotrigine or a pharmaceutically acceptable salt thereof with pregelatinised starch and other exipients and converting the mixture into a pharmaceutical composition, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

The term "stable" as used herein refers to chemical stability of lamotrigine in solid dosage forms wherein there is no change in assay values, impurities percentages and dissolution data when kept at 40⁰C / 75% RH for 3 months.

As used herein, lamotrigine refers to its free base or acid addition salt, such as, methanesulphonate and isothionate salts. For example, the stable pharmaceutical composition of the invention may include from about 0.1% w/w to about 60% w/w of lamotrigine or a lamotrigine salt by weight of the composition.

The stable pharmaceutical composition of the present invention uses pregelatinised starch as a disintegrant and lubricant. Pregelatinised starch exhibits a dual functionality in formulation. As a disintegrant, it produces tablet of similar hardness to that of povidone, but, with significantly faster disintegration properties compared to the povidone formulation. It also exhibits self-lubricating properties. Thus, with the use of pregelatinised starch in Ae composition of Ae present invention, Ae composition of the invention exhibits hardness, dissolution rate, disintegration time and bio-availability comparable to the commercially available lamotπgene tablet in the United States of America i.e. Lamictal^®. Unlike povidone, storing for a longer period of time, tablet containing pregelatinised starch showed no alteration in hardness and dissolution profile. The pregelatinized starch is a starch mat has been chemically and/or mechanically processed to rupture all or part of the starch granules and so render the starch flowable and directly compressible. Partially pregelatinized grades are also commercially available. Typically, pregelatinized starch contains 5% of free amylose, 15% of free amylopectin, and 80% unmodified starch. Pregelatinized starch is available as commercially as Lycatab C; Lycatab PGS; Merigel; National 78-1551; Pharma-Gel; Prejel; Sepistab ST 200; Spress B820; Starch 1500 G; Tablitz; Unipure LD; Unipure WG220. The pregelatinised starch may be used in amounts ranging from about 0.1% w/w to about 15% w/w in the stable pharmaceutical composition of the present invention.

The stable pharmaceutical composition of the present invention may include one or more pharmaceutical excipients selected from diluents, desiccants, disintegrants, coloring agents, flavoring agents, surfactants or wetting agents, lubricants/glidants, plasticizers and preservatives.

Examples of disintegrants that may be used in the stable pharmaceutical composition of the present invention include sodium starch glycol ate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like and mixtures thereof. The disintegrants may be used in amounts ranging from about 0.1% w/w to about 15% w/w in the stable pharmaceutical composition of the present invention.

Exemplary pharmaceutical diluents mat may be used in the stable pharmaceutical composition of the present invention include monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof, for example, starch, mannitol, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, lactitol, fructose, and mixtures thereof. dextrates, dextrins, dextrose excipients, fructose, kaolin, and other polyols, starch pregelatinized, sugar compressible sugar confectioners, and the like, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, calcium carbonate and the like or mixtures thereof. The diluents may be used in amounts ranging from about 0.1% w/w to about 80% w/w in the stable pharmaceutical composition of the present invention. Examples of lubricants and glidants include colloidal silicon dioxide, magnesium stearate, and colloidal anhydrous silica, stearic acid, magnesium stearate, and calcium stearate, talc, hydrogenated castor oil, sucrose esters of fetty acid, microcrystalline wax, yellow beeswax, white beeswax, fomarates and Ae like. The lubricants may be used in amounts ranging from about 0.1% w/w to about 5% w/w in the stable pharmaceutical composition of the present invention.

The stable pharmaceutical composition of the present invention may include one or more wetting agents selected from sodium dodecyl sulphate, sodium lauryl sulphate, polyoxyethylene sotbitan fatty acid esters (T weens), polyoxyethylene stearates, sorbitan fatty acid esters (Spans) and the like and mixtures thereof. The wetting agents may be used in amounts ranging from about 0.1% w/w to about 5% w/w in the stable pharmaceutical composition of the present invention.

Examples of coloring agents include any FDA approved colors for oral use.

The pharmaceutical compositions of the present invention may be prepared by the conventional processes such as wet granulation, dry granulation or direct compression. In wet granulation, lamotrigene or its pharmaceutically acceptable salt is mixed with pregelatinised starch and various excipients and granulated, followed by screening and drying of the damp mass. The dried mass may be screened, lubricated and compressed. Dry granulation can be done by two processes: (1) slugging, which involves mixing the lamotrigene or its pharmaceutically acceptable salt with pregelatinised starch and the excipients, slugging, dry screening, lubrication and compression, or (2) roller compaction process. Direct compression involves compressing tablets directly from the physical mixture of lamotrigene or its pharmaceutically acceptable salt, pregelatinised starch and the excipients. Alternatively the pharmaceutical compositions of the present invention may be obtained by preparing placebo granules comprising the pregelatinised starch and pharmaceutically acceptable excipients, and mixing these with lamotrigene or its pharmaceutically acceptable salt to obtain a blend, which may be encapsulated or compressed into tablets. This method provides compositions of lamotrigene or its pharmaceutically acceptable salt that are stable.

The following examples are intended to illustrate the scope of the present invention in all its aspects but not to limit it thereto.

EXAMPLE 1

The stable pharmaceutical composition of the present invention was prepared as given in Table 1 below.

TABLE 1

Lamotrigine was mixed with microcrystalline cellulose, sodium starch glycolate, yellow ferric oxide, lactose and pregelatinised starch. This mixture was 1hen granulated with purified water. The wet mass was men screened to obtain wet granules & then the granules were dried, screened (or directly the wet mass is dried, screened) and mixed with extra granular excipients such as filler, disintegrant, lubricant etc. The resultant blend was then compressed into tablets using appropriate tooling. The tablet & granule parameters of Ae composition prepared above are given in Table 2 below:

TABLE 2

The composition prepared above was subjected to dissolution studies under the following dissolution conditions:

1. Type of Apparatus : The Paddle 2. Rotation speed : 50 rpm

3. Dissolution Medium composition : 0.1N HCl

4. Dissolution medium volume : 900ml

5. Time Points : 5,10,15 & 30 minutes The results are presented below as % of the total lamotrigine in the tablet, in Table 3 below:

TABLE 3

EXAMPLE 2

The stable pharmaceutical composition of the present invention was prepared as given in Table 4 below. TABLE 4

The lamotrigine, lactose monohydrate, microcrystalline cellulose 102 and Starch 1500L were sifted through # 40 mesh ASTM and sodium starch glycolate & yellow oxide of iron were sifted through 200# mesh ASTM and mixed together for 10 minute at slow speed. This blend was granulated at slow speed by a solution of sodium lauryl sulphate made in required quantity of purified water. The wet mass was dried at 60⁰C till the LOD reached less than 4.5%w/w. The dried granules were rasped through 30# mesh ASTM. Sodium starch glycolate, Avicel 102 were sifted through 60 # mesh ASTM and Magnesium stearate was sifted through 60# mesh ASTM separately. The rasped granules and sifted sodium starch glycolate, Avicel 102 were mixed in blender for 20 minutes. The sifted magnesium stearate was added for 5 minutes in the same blender. The above blend was compressed using appropriate punch.

Medium 0.1 NHCl

Quantity 900 ml

Apparatus Apparatus π (Paddle)

RPM 50

Profile Time 5, 10,15,20 and 30 minutes

Direct time 30 minutes

Temperature 37±0.5°C

The results are presented below as % of the total lamotrigine in the tablet, in Table 5 below:

TABLE 5

It can be seen that composition of the present invention had dissolution rate comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal .

The composition prepared above was subjected to hardness and disintegration time testing. The results are given in table 6 below.

Table 6

It can be seen that the composition of the present invention had hardness and disintegration time which are comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®

The composition prepared above was subjected to assay for determining th'e lamotrigene content in the composition of the present invention, using High Performance Liquid Chromatograph as known in the art.

The assay results are given in Table 7 below.

TABLE 7

The composition prepared above was subjected to accelerated studies for 3 months at 40°C/75%RH and 30°C/75%RH and the results are shown in Table 8

TABLE 8

It can be seen that the composition of the present invention is stable in terms of its dissolution, assay and impurities at 40°C/75%RH and 30°C/75%RH for a period of at least 3 months.

The composition prepared above was subjected to bioequivalence studies. An open label, two way crossover comparative bioavailability of the composition of the present invention i.e. composition of example 2 (2X 25mg) with Lamictal^® (Lamotrigene tablets 2 X 25mg) of GHaxoSmithkline, United States of America under fasting conditions was carried out.

Study design: A balanced, open label, randomized, two^treatment, twoφeriod, two sequence, single dose, crossover comparative bioavailability study under lasting conditions.

Study duration: Approximately 22 days including a washout period of at least 14 days between the two periods.

Investigational products: The test product was the lamotrigene composition of the present invention (Lamotrigene tablet 25 mg) prepared in example 2, whereas the Reference product was Lamictal (Lamotrigene tablet 25 mg).

Number of subjects: 13 healthy adult, human subjects

Drug administration: After an overnight fast of at least 10 hours, subjects were dosed in sitting posture with 240ml of water at ambient temperature. In each study period a single dose of Lamotrigine tablet (2 X25 mg) was administered to Ae subjects. Subjects receiving the test product in one study period received Ae reference product (Lamictal 25 mg) in the other period.

Blood Sample Collection: A total of 22 samples (including predose) were taken per period, one prior to dosing at 0.0 and at 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5, 6, 8, 12, 48, 72, 96, 120, 144 and 168 hours post dose.

Plasma samples of all the subjects completing Ae study were analyzed and Ae same were used in pharmacokinetic and statistical study.

The results of the above bioequi valence studies at fasting condition are given in Table 9.

TABLE 9

So it can be seen Aat the composition of Ae present invention is bioequivalent to Ae commercially available lamotrigene tablet in Ae United States of America i.e. Lamictal .

AlAough Ae invention has been described in terms of particular embodiments and applications, one of ordinary skill in Ae art, in light of this teaching, can generate additional embodiments and modifications wiAout departing from Ae spirit of or exceeding Ae scope of Ae claimed invention. It should be emphasized Aat Ae above- described embodiments of the present invention, particularly any "preferred" embodiments, are merely possible examples of the invention of implementations, merely set forth for a clear understanding of Ae principles of Ae invention. Accordingly, it is to be understood Aat Ae drawings and descriptions herein are proffered by way of example to facilitate comprehension of Ae invention and should not be construed to limit Ae scope Aereof.

Claims

Claims:

1. A stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising pregelatinised starch, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.

2. A stable pharmaceutical composition as claimed in claim 1, wherein, the pregelatinized starch is used in amounts ranging from about 0.1% w/w to about 15% w/w.

3. A stable pharmaceutical composition as claimed in claim 1, further comprising one or more disintegrant.

4. A stable pharmaceutical composition as claimed in claim 3, wherein the disintegrants are selected from the group comprising sodium starch glycolate, croscarmellose sodium, crospovidone, low substituted hydroxypropyl cellulose, and the like and mixtures thereof.

5. A stable pharmaceutical composition as claimed in claim 1, further comprising one or more diluents.

6. A stable pharmaceutical composition as claimed in claim 5, wherein the diluents are selected from the group comprising monosaccharides, disaccharides, polyhydric alcohols and mixtures thereof, like starch, mannitol, lactose, dextrose, sucrose, microcrystalline cellulose, sorbitol, xylitol, lactitol and fructose and the like; dextrates, dextrins, dextrose excipients, fructose, kaolin, and other polyols, starch pregelatinized, sugar compressible sugar confectioners, dicalcium phosphate, rribasic calcium phosphate, calcium sulphate, calcium carbonate and the like or mixtures thereof

7. A stable pharmaceutical composition as claimed in claim 1 , further comprising one or more wetting agents.

8. A stable pharmaceutical composition as claimed in claim 7, wherein the wetting agents are selected from the group comprising sodium dodecyl sulphate, sodium lauryl sulphate, polyoxyethylene soroitan fatty acid esters (T weens), polyoxyethylene stearates, sorbitan fatty acid esters (Spans) and the like and mixtures thereof

9. A stable pharmaceutical composition as claimed in claim 1, wherein the dosage form is a tablet dosage form.

10. A stable pharmaceutical composition as claimed in claim 1, wherein the tablet dosage form exhibits hardness and dissolution rate comparable to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®.

IL A stable pharmaceutical composition as claimed in claim 9, wherein the tablet dosage form is bioequivalent to the commercially available lamotrigene tablet in the United States of America i.e. Lamictal^®.

12. A process for preparing a stable pharmaceutical composition of lamotrigine or a pharmaceutically acceptable salt thereof, comprising reacting the lamotrigine or a pharmaceutically acceptable salt thereof with pregelatinised starch and other exipients and converting Ae mixture into a pharmaceutical composition, wherein the said composition is essentially free of a pharmaceutically acceptable clay or polyvinylpyrrolidone.