FORM 2

THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule l3)
1. TITLE OF THE INVENTION:
"Modified release composition of Lamotrigine and process thereof
2. APPLICANT (S)
(a) NAME: IPCA LABORATORIES LIMITED
(b)NAT10NALITY: an Indian Company incorporated under the Indian Companies ACT, 1956
(c) ADDRESS: 48, Kandivli Industrial Estate, Charkop, Kandivli (East) Mumbai - 400 067, Maharashtra, India

3. PREAMBLE TO THE DESCRIPTION

The following specification particularly describes the invention and the manner in which it is to be performed.
483/MUM/2007
1 4 MAR 2007

Technical Field of the invention:
The present invention relates to modified release composition of Lamotrigine incorporated in a monolithic matrix to facilitate the drug release for an extended period of time which enhances the therapeutic effectiveness of the drug and improves pharmacokinetic profile. More particularly the invention relates to reducing the dosage frequency of Lamotrigine thus minimizing the side effects and preventing dose dumping.
Background and Prior Art:
Controlled release pharmaceutical compositions and dosage forms are designed to improve the delivery profile of agents, such as drugs, medicaments, active agents, diagnostic agents or any substance internally administered to an animal including humans. A controlled release composition is typically used to improve the effect of administered substance by optimizing the kinetics of delivery, thereby increasing the bioavailability, convenience, and patient compliance, as well as minimizing the side effects associated with inappropriate immediate release rates such as high initial release rate and, if undesired uneven blood or tissue levels.
Lamotrigine, an antiepileptic drug of phenyltriazne class is chemically unrelated to the existing antiepileptic drug, the chemical name is 3, 5-diamino-6(2, 3-diclorophenyl)-l, 2, 4 trizine, it's molecular formula is C9H7N5Q2 and is disclosed in EP-A-0021121.
It is valuable broad spectrum drug that is well tolerated and has a few adverse effects apart from skin rash (Besage FMC, CNS Drugs 2000). Pharmacokinetically, Lamotrigine show linear plasma concentration, with dose (Ramsay RE 1991) over the range of 50 to 400 mg as a single dose Cmax from 0.58 to 4063 ug/ml.
According to acute and chronic studies on Lamotrigine suggest that the adverse event is dizziness, ataxia, diplopia, somnolence, headache but this type of side effect is around only 10 % (Ramsay RE 1991). Overall 8.6 % of patients were removed from clinical trial because of adverse experience that includes, in addition to rash, vomiting and intolerable
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episode of the CNS - related events (Ramsey RE 1991). Neurological side effects are normally seen at a higher concentration (which is most likely to occur at peak plasma concentration). During the first 18 weeks of Lamotrigine treatment 16.7% of patients reported nausea and vomiting at mean concentration of 6.00 to 7.99 jag/ml and 100 % reporting headache and ataxia at > 10 µg/ml (Goa KL et al 1993).
Presently Lamotrigine is prescribed in conventional tablets, dispersible/chewable tablet from doses ranging from 25 to 600 mg/day, once a day or two divided doses. Immediate release dosage form provides a rapid dissolution and rapid increase in blood plasma level after each dosing, which causes adverse effects. The reason for giving divided dose for Lamotrigine is to prevent very high concentration in the plasma, which can occur with single daily dose.
To overcome aforementioned problems, dose reduction and slow dose escalation is required. The present invention therefore relates specifically to controlling Cmax of Lamotrigine by using controlled release formulation based on monolithic matrix technology which will maintain steady state concentration of the drug, reduce the neurological side effects and improve patient compliance with therapy.
The prior art discloses different types of multiple unit dosage forms, multiparticulate controlled release formulations and stable compositions of Lamotrigine.
U.S. 4927640 describes a multiple unit system containing small inert cores with an active substance and a release controlling polymeric membrane. The mechanical properties of such multiple units formulated in to tablets are reported in pharmaceutical research 10 (1993), p. 274. There are examples in prior art that disclose pellets formulated in controlled release tablet.
WO2004012741 discloses a sustained release formulation of lamotrigine or a pharmaceutically acceptable derivative thereof. Lamotrigine is released from the formulation 2 to 20 hours after administration to a patient.
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Patent application US2004043996/ WO03104192 discloses rapidly disintegrating multiparticulate controlled release formulations of lamotrigine and process of preparing the formulations. The formulation comprises discrete pelleted cores covered with one or more different rate controlling membrane. The present invention Lamotrigine composition possesses advantages over a peptization method which include; less manufacturing steps and hence is economic. The release period is modified over pellets.
WO2004082587 discloses 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. But at least 90% by weight of the lamotrigine or the acid addition salt thereof dissolves within 30 minutes.
Therefore in view of aforementioned prior art preparations it is obvious that there still exists a need for improved formulation of Lamotrigine which are safe, stable, simple to manufacture and cost effective. It is obvious that there exists a need for improved formulation of Lamotrigine which provides modified release Lamotrigine composition with a modified escalation of Lamotrigine concentration with reduced dosage frequency to once daily providing enhanced therapeutic efficacy and better patient compliance.
Object of the invention:
The main object of the present invention is to provide a modified release composition comprising Lamotrigine incorporated in a monolithic matrix, wherein the delayed dissolution of the drug release from the matrix maintains relatively constant drug concentration in the blood providing enhanced therapeutic effectiveness and minimal side effects.
Further object of the invention is to provide Lamotrigine composition with reduced dosage frequency to once daily which inhibits dose dumping and improves pharmacokinetic profile.
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Summary of the invention:
Disclosed herein is modified release composition of Lamotrigine comprising;
(a) a modified release of the drug using monolithic matrix technology,
(b) a modified escalation of drug concentration by decreasing the initial dose hence inhibiting dose dumping.
The invention discloses a monolithic matrix with dosage form that improves patient compliance and reduces the dosage frequency to once daily and also improve the pharmacokinetic profile on administration, hence reducing or eliminating neurological side effects and skin reactions.
The invention further discloses a dosage form of Lamotrigine that control the release of Lamotrigine in such a manner that an effective concentration in blood can be maintained over an extended period of time to improve therapeutic efficacy and minimize the side effects.
Detailed description of the invention:
The present invention describes modified release pharmaceutical composition comprising Lamotrigine or a pharmaceutically acceptable salt thereof dispersed in matrix material. The dispersion of Lamotrigine within the matrix material is effective to delay the release profile of the drug facilitating an improved pharmacokinetic profile on administration of the said composition. The composition of the invention describes a modified release composition with reduced dosage frequency of once daily which improves patient compliance and inhibits dose dumping.
The present invention describes modified release composition of Lamotrigine useful for the treatment of epilepsy (an anti-convulsant agent helps control some types of seizures, post-traumatic stress disorder (PTSD) and/or borderline personality disorder (BPD), Bipolar Disorders and unipolar depressions).
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Dose reduction and slow dose escalation described as per the present invention controls Cmax of Lamotrigine by using controlled release composition using monolithic matrix technology. Monolithic matrix technology describes a steady state concentration of the drug in the plasma and reduces the neurological side effects thereby improving patient compliance with therapy. In-vitro dissolution profile of the modified release composition of the invention describes dissolution rate of Lamotrigine at 2hrs, 6hrs and 8hrs which described herein.
The invention describes Lamotrigine or pharmaceutically acceptable salts thereof along with water-soluble /insoluble and /or water dispersible and or/ water disintegrate and optionally rate controlling excipients.
The ratio of Lamotrigine or pharmaceutically acceptable salt thereof with rate controlling polymer is in the ratio of 1:100, more particularly from 1:20 to 20:1 and most preferable from 10:1 to 1:10 or in alteration ratio 5:1 to 1:5 may be used.
According to the present invention, the preferred embodiment comprises, the rate controlling monolithic matrix comprising pharmaceutically acceptable hydrophilic polymer hydroxypropyl methyl cellulose and purified water along with the active ingredient. The major advantage of the monolithic matrix is that, there is a modified escalation of drug concentration in the blood achieved by decreasing the initial dose and inhibiting dose dumping.
The modified release pharmaceutical compositions preferably comprise water soluble/hydrophilic polymeric coating effective in delaying the release profile on administration of the said composition. The uniform mix of drug and hydrophilic polymer retards the drug release from the polymer matrix.
The monolithic matrix technology of the present invention possesses advantages over peptization method which include; less manufacturing steps and hence is economic (less expensive). The release period is modified over pellets.
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In another embodiment, the process of preparation of the said modified release pharmaceutical composition comprises the following steps;
i. Sift the Lamotrigine through mesh of size 20.
ii.Sift avicel pH 101, lactose monohydrate, hydroxypropyl methylceIluIose-15
through mesh size 40. iii. Mix all ingredients step (i) and (ii) in geometric proportion and dry mix in rapid
mix granulator (RMG). iv. Prepare polyvinylpyrrolidone K30 (PVPK30) solution with sufficient quantity
of isopropyl alcohol (IPA). v.Granulate the above blend (iii) in rapid mixing granulator (RMG) with slow and
high speed impeller using polyvinylpyrrolidone K30 (PVP-K30). vi. Screen the wet mass through mesh 8 and dry the resulting granules in fluid bed
drier (FBD) and sift granules through mesh 20. vii. Lubricate the blend with hydroxy propyl methyl cellulose K-15, sodium starch
glycolate, colloidal silicon dioxide and purified talc, viii.Finally lubricate the above blend with magnesium stearate and mill through
mesh 40 in octagonal blender and compress the blend on suitable compression
machine by using oval shaped punch.
Lamotrigine or pharmaceutically acceptable salt is used in the range of 2 to 200mg and preferably 50mg and lOOmg.
The water soluble/permeable polymer preferably is hydroxy propyl methyl cellulose used in range of about 5 tol5%.
Pharmaceutically acceptable binders are selected from the group containing maize starch, polyvinylpyrrolidone wherein the preferred binder is polyvinylpyrrolidone used in the range of about 3 to 15%. The preferable grade of polyvinylpyrrolidone is varying from 10-120 with preferable K value 30 or with grade 30.
The preferred diluents are microcrystalline cellulose, lactose monohydrate or their modified forms used in the range of 5 to 95% of tablet weight.
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The disintegrants are selected from the group containing starch or derivative of starch wherein the preferred disintegrant is sodium starch glycolate used in the range of about 1 to 6%.
The preferred lubricant is magnesium stearate used in the range of about 0.5 to 1%. And the preferred glidant is colloidal silicon dioxide used in the range of 0.2 to 0.4%.
The invention is more specifically explained by following examples. However, it should be understood that the scope of the present invention is not limited by the examples in any manner. It will be appreciated by any person skilled in this art that the present invention includes the following examples and further can be modified and altered within the technical concept of the present invention.
Example 1:

Sr. No. Ingredient Qty % w/w of total weight
1 Lamotrigine 19.61%
2 Hydroxy propyl methyl cellulose (K15M) 13.72%
3 Polyvinylpyrrolidone (K30) 1.96%
4 Isopropyl alcohol qs
5 Macrocrystalline cellulose, 27.84%
6 Lactose monohydrate 31.37%
7 Sodium starch glycolate 2.94%
8 Magnesium stearate 0.98%
9 Colloidal silicon dioxide 0.58%
10 Purified talc 0.58%
The process of preparation of uncoated tablets is as follows:
i. A dry mix made of all components including Lamotrigine, avicel pH 101, lactose monohydrate, hydroxy propyl methyl cellulose K 15 is mixed using a rapid mixer granulator -SMG-10 which is high share mixer granulator for ten minutes.
ii. Polyvinylpyrrolidone K30 is dissolved in aqueous alcohol to form granulation solution.
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iii. The granulation solution is added to approximate quantity of 430 ml per Kg dry
weight to the dry mixture to form granules. Wet mixing was carried out for
approximately five minutes to granulate the above-prepared mixture in rapid
mixing granulator (HSMG-10). High shear mix granulator for six minutes at slow
speed impeller and for one min at high speed impeller, iv. The wet granules are passed through mesh 8 and dried at 55°C in fluid bed drier
(FBD) till to loss on drying (LOD) not less than 1.5 % w/w at 105°C and the
granules are then sifted through mesh 20. v. The blend is lubricated with hydroxy propyl methyl cellulose K-4M, sodium
starch glycolate, colloidal silicon dioxide, purified talc which are sifted through
mesh 40 in Ganson's octagonal blender for five minutes, vi. Finally lubricate the above blend with magnesium stearate, which is sifted
through mesh size 40 in Gauger octagonal blender for two minutes, vii. The dried granules are compressed to form a tablets using (Jauger PMD -4-8)
rotary press fitted with caplet round shape punches of approximate 11.6mm
diameter and 5.01 mm height. The tablets are compressed to a weight of 520mg ±
5%. viii.These granules can be used to make other strengths of Lamotrigine tablets of
different strength.
Example 2:
The dissolution profile of the modified release composition is studied and shown as follows:
Dissolution profile of lOOmg and 50 nig Lamotrigine tablets:

Hrs. Limits For lOOmg For 50mg
2 30-60% 47.37%-49.68% 15.5%- 17.96%
6 NLT 70% 78.00%-84.25% 76.53%-85.58%
8 NLT 75% 86.30%-89.97% 91.25%-98.96%

Example 3:
The pharmaceutical composition of Lamotrigine of the present invention is physically and chemically stable over its shelf life period. The stability data is as follows:
(i) For lOOmg Lamotrigine tablets:

Test Specification Batch
no. Hrs. Initial After 03 months
Appearance white to off-white in color, round shaped, biconvex, with break line on one side and plain on other side 1 Complies Complies

II

Dissolution 25±2°C & 60±5%Rh
2 hrs 30-60% 6 hrs NLT 70% 8 hrs NLT 75% I 2 47.37% - 49.68% 52.31%-56.68%

6 78.00%-84.25% 86.86%-91.63%

8 86.30% - 89.97% 91.58%-97.19%

II 2 43.29%-51.22% 50.73% - 56.34%

6 77.57% - 88.76% 86.90% - 90.78%

8 83.13%-94.89% 90.19%-95.42%

40±2°C & 75±5%Rh
2 hrs 30-60% 6 hrs NLT 70% 8 hrs NLT 75% I 2 47.37%- 49.68% 50,l2%-67.08%

6 78.00%- 84.25% 82.96%-103.08%

8 86.30%- 89.97% 90.19%-111.43%

II 2 43.29%-51.22% 50.96%-56.41%

6 77.57%-88.76% 79.45%-93.74%

8 83.13%-94.81% 89.88%-103.21%
Assay 25±2°C & 60±S%Rh
90%-110% I 102.62% 100.14%

II
105.52% 101.96%

40±2°C & 75±5%Rh 90%-110% I 102.62% 99.59%

II
105.5% 100.89%
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(ii) For 50mg Lamotrigine tablets:

Test Specification Batch
no. Hrs. Initial After 03 months
Appearance white to off-white in color, round shaped, biconvex, with break line on one side and plain on other side I Complies Complies

II

Dissolution 25±2°C & 60±5%Rh 2 hrs 30-60% 6 hrs NLT 70% 8 hrs NLT 75% I 2 15.5%-17.96% 34.48% - 39.48%

6 76.53%-85.58% 81.74%-88.10%

8 91.25%-98.96% 89.91%-97.86%

II 2 17.95%-19.84% 29.51%-36.18%

6 84.26%-91.51% 81.59%-86.16%

8 99.26%-103.87% 92.15%-93.19%

40±2°C &
75±5%Rh 2 hrs 30-60% 6 hrs NLT 70%8 hrs NLT 75% I 2 15.5%-17.96% 32.33%-37.24%

6 76.53% - 85.58% 79.67%-84.01%

8 91.25%-98.96% 90.36%-94.38%

II 2 17.95%-19.84% 32.86%-38.07%

6 84.26%-91.51% 80.22%-83.66%

8 99.26%-103.87% 87.66%-93.09%
Assay 25±2°C & 60±5%Rh
90%-110% I 100,51% 101.62%

II
99.50% 101.06%

40±2°C &
75±5%Rh 90%-110% I 100.51% 100.74%

II
99.50% 101.91%
Conclusion: Dissolution rate at 2hrs, 6hrs and 8hrs were within limit initially and after 3 months at 25±2°C & 60±5%Rh for both batches.
Dissolution rate at 2hrs, 6hrs and 8hrs were within limit initially and after 3 months at 40±2°C & 75±5%Rh for both batches.
The present invention has been described by way of example only, and it is to be recognized that modifications thereto which fall within the scope and spirit of the appended claims, and which would be obvious to a skilled person based upon the disclosure herein, are also considered to be included within the invention.
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We claim;
1. A modified release composition of Lamotrigine or pharmaceutically acceptable salt thereof used for treating epileptic seizures comprising dispersing the said active in a release rate controlling polymer forming a monolithic matrix, formulated alongwith other pharmaceutically acceptable excipients; wherein the said composition comprises a modified escalation of Lamotrigine concentration in the blood, the said composition provides an in- vitro dissolution profile in which NLT 75 % of the Lamotrigine is dissolved in 2 to 8 hours,
2. Pharmaceutical composition as claimed in claim 1, wherein the ratio of Lamotrigine or pharmaceutically acceptable salt thereof with rate controlling polymer is in the range of 1:20 to 20:1 and preferably from 10:1 to 1:10 or in alteration ratio 5:1 to 1:5.
3. Pharmaceutical composition as claimed in claim 1, wherein the said Lamotrigine or pharmaceutically acceptable salt thereof is in the range of 2 to 200mg, preferably in the range of 50mg and lOOmg.
4. Pharmaceutical composition as claimed in claim 1, wherein water soluble rate controlling polymer such as hydroxy propyl methyl cellulose preferably in the range of about 5 tol5%
5. Pharmaceutical composition as claimed in claim 1, wherein the said binders are selected from the group containing maize starch, polyvinylpyrrolidone, wherein preferred binder is polyvinylpyrrolidone used in the range of 3 to 15%, in grade varying from 10 tol20 and preferably with K value 30 or with grade 30.
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6. Pharmaceutical composition as claimed in claim 1, wherein the said diluents are microcrystalline cellulose, lactose monohydrate or their modified forms used in the range of 5 to 95% of tablet weight.
7. Pharmaceutical composition as claimed in claim 1, wherein the said disintegrants are selected from the group containing starch or derivative of starch and preferably sodium starch glycolate used in the range of lto 6%.
8. Pharmaceutical composition as claimed in claim I, wherein the said lubricant is magnesium stearate used in range of 0.5 to 1%.
9. Pharmaceutical composition as claimed in claim 1, wherein the said glidant is colloidal silicon dioxide used in range of 0.2 to 0.4%.
10. A modified release composition as claimed in claim 1, wherein the said composition is prepared by a process comprising;
a. dispersing the drug in the polymer matrix by blending a therapeutic
dose of finely ground drug particles into mixer modified release
retardant polymer such as hydroxy propyl methyl cellulose K-4M
wherein pharmaceutically acceptable diluent is added to above
mixture with mixing,
b. granulating (non-aqueous) by preparing binder solution and adding
it to drug-polymer mixture till uniform distribution, to form a
monolithic matrix, drying the granules and sifting dried granules
through mesh 20,
c. geometrically mixing pharmaceutically acceptable excipients like
polymers, diluents, lubricants, disintegrants and sifting through
mesh 40,
d. blending step (c) with dried granules of step (b) and lubricating
Lamotrigine granules with magnesium stearate and
e. compressing the lubricated granules on a compression machine into
tablets.
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11. Modified release pharmaceutical composition as claimed in any of the preceding claims 1 to 10 and their process of preparation as described herein with reference to the foregoing examples.
Dated this 14th day of March 2007

Dr. P. Arunasree Agent for the Applicant
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