WO2011086568A1

WO2011086568A1 - Controlled release composition for lamotrigine

Info

Publication number: WO2011086568A1
Application number: PCT/IN2010/000210
Authority: WO
Inventors: Santosh Shrikrishna Joshi; Kavita Vikram Inamdar; Abhijit Vishwanath Gothoskar; Smita Prashant Dhuri; Parag Manohar More
Original assignee: ACCUTEST RESEARCH LABORATORIES (I) PVT Ltd
Current assignee: ACCUTEST RESEARCH LABORATORIES (I) PVT Ltd
Priority date: 2010-01-13
Filing date: 2010-03-31
Publication date: 2011-07-21
Anticipated expiration: 2012-07-13

Abstract

A controlled release composition for pharmaceutical agent giving controlled release of pharmaceutical agent in two phases, the first phase being in stomach and the second phase being in the lower regions of the gastrointestinal tract giving comparatively fast (still controlled) release than in stomach. It comprises a core containing pharmaceutical agent in controlled release form, and a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. It provides effective controlled release till defined period for pharmaceutical agents having higher solubility in stomach than in the lower gastrointestinal tract regions by making them available in vivo for longer period with concentrations falling within therapeutic window without linear increase in blood concentrations, as opposed to the conventional controlled release compositions which gives linear increase in blood concentrations due to the uniform release rate of pharmaceutical agents.

Description

TITLE OF THE INVENTION:

CONTROLLED RELEASE COMPOSITION FOR LAMOTRIGINE

FIELD OF INVENTION:

This invention relates to a controlled release composition for the pharmaceutical agent. Particularly, the invention relates to a composition giving controlled release of pharmaceutical agent in two phases, it is also concerned with the materials and methods of preparing such compositions.

BACKGROUND OF INVENTION:

Pharmaceutical agents are formulated in various dosage forms. For getting the desired effect of pharmaceutical agent with least adverse effects, its concentration maintenance within therapeutic window is very essential. Some pharmaceutical agents require their presence in the blood for long period to give desired

pharmacological effect. Immediate release compositions in such cases need to be administered frequently to maintain the required level of pharmaceutical agent in blood. Compared with immediate-release compositions, controlled-release compositions can decrease the frequency of administration by making available the pharmaceutical agent for longer period with concentration falling within therapeutic window. In addition, by producing more constant blood levels, such compositions can reduce the large changes in blood concentration levels observed between consecutive immediate release doses.

Some pharmaceutical agents have the higher solubility in stomach than in the lower regions of the gastrointestinal tract. In such cases the controlled release compositions even if they give uniform release rate for pharmaceutical agent may lead to substantially linear increase in the blood concentrations of the pharmaceutical agent in vivo. There are some compositions which try to address this problem. Currently available Lamicta!® XR sustained release tablet for sustained release composition gives the two phase release for lamotrigine, wherein the release in stomach is slower

l than the release in intestine. In this tablet, the core of pharmaceutical agent is surrounded by a pH dependent coat which is substantially impermeable to the entrance of environmental fluid in core and to the exit of the pharmaceutical agent from core to environmental fluid. This coating has one or more orifices extending from the outside of the coating substantially completely through said coating but not penetrating the inner core. These orifices have an area or combined area from about 10 to about 60 percent of the face area of composition. The release of pharmaceutical agent is controlled by these orifices. This tablet provides the controlled release in two phases because the pH dependent coat remains intact in stomach and does not permit the release of pharmaceutical agent through it or in other words, limiting the release only through orifice whereas when the tablet reaches intestinal region, the coat get dissolved and release rate of pharmaceutical agent is higher than the release rate in stomach.

Although, this approach seems satisfactory, it requires highly specialized techniques and specialized equipments for manufacturing. For example, while making orifice to the coat, one has to be very careful that it should not lead to the destruction of core as well as the destruction of coating. Further, the orifice circumference should be very precise as any deviation may affect the release rate of the pharmaceutical agent.

Another approach showed in US6514531 describes controlled-release dosage of Zolpidem giving two phase release from an immediate release phase and from prolonged release phase. It showed the single capsule containing the prolonged release units and immediate release units which require separate preparation of these two units and then their incorporation in common capsule. It also showed the multilayer tablet containing distinct pharmaceutical agent containing layers of which one is immediate release layer and the second is a prolonged release layer. For preparing this tablet, the preparation of two separate layers, each containing pharmaceutical agent is necessary. US6372255 disclosed multilayer tablet giving immediate release of pharmaceutical agent from first layer which is in contact with second layer made up of nonbiodegradable inert porous polymeric matrix which give prolonged release of pharmaceutical agent.

Thus, there is a further need to provide a composition which will give controlled release of pharmaceutical agent in two phases.

SUMMARY OF INVENTION:

In the first aspect, the invention describes a composition giving controlled release of pharmaceutical agent in two phases comprising a core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

The core containing a pharmaceutical agent in controlled release form comprises a core selected from a matrix core having release retarding polymers, a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually. Such individual pharmaceutical agent containing units comprises granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof.

The outer coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. Such material comprises alginates, gums, ionic synthetic or semi-synthetic polymers etc.

In another aspect, the invention describes method and materials for preparation of such composition. The composition is prepared by first preparing the core and then applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pK 5. In one embodiment, a core containing the pharmaceutical agent in controlled release form comprises matrix core having release retarding polymers therein. Such matrix core is prepared by a method selected from direct compression method, dry granulation method or wet granulation method. The release retarding polymer used in matrix core comprises the polymers bearing hydrophi!ic properties, hydrophobic properties, gelling properties, ionic nature, swelling property or combinations thereof.

In another embodiment, a core containing the pharmaceutical agent in controlled release form is a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually. Such pharmaceutical agent containing units comprise granules, beads, spherules, mini- tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof. The methods for preparation of such pharmaceutical agent containing units comprises granulation method for preparing granules, spray coating onto non-pareil seeds for preparing beads, spheronization method for preparing spherules, fluid bed coating or granulation for preparing polymer coated pharmaceutical agent particles, microencapsulation methods for preparing micro-capsules.

The coating is applied on core by a method selected from compression coating, spray coating, fluid bed coating. The coating comprises a material which forms gel upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. Such material is selected from alginates, gums, ionic synthetic or semi-synthetic polymers or combinations thereof. The coating further comprises the material selected from film formers, diluents, lubricants, compression aid, surfactants, preservatives, p!asticizers, opacifying agents, coloring agents or any combinations thereof.

Further, the composition optionally comprises a seal coat between the core and the coating.

In yet another aspect, the invention specifically relates to a composition giving controlled release of pharmaceutical agent in two phases comprising a matrix core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. This matrix core comprises pharmaceutical agent, release retarding polymer, diluent and lubricant. Preferably, the amounts of pharmaceutical agent, release retarding polymer, diluent and lubricant suitable for incorporation in matrix core are from about 5 to about 75%, from about 5 to about 95%, from about 0 to about 90% and from about 0.05 to about 2% of the composition respectively. The method for preparing matrix core comprises mixing above materials to form a blend followed by compressing this blended material to form core.

The coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. More preferably, such material comprises sodium alginate. The method for preparation of such composition comprises preparing a matrix core and applying on said core above mentioned coating. Preferably, such coating is applied with spray coating technique. More preferably, core is sprayed with coating comprising dispersion of sodium alginate in water.

BRIEF DESCRIPTION OF DRAWINGS

Figures 1 , 2 and 3 shows the dissolution profile for Lamotrigine controlled release compositions giving controlled release in two phases, prepared according to examples 1 , 2 and 3 respectively.

DETAILED DESCRIPTION OF INVENTION:

According to the main embodiment of the invention, a composition giving controlled release of a pharmaceutical agent in two phases comprises a core containing a pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

There are two release controlling parts in above mentioned composition, one being the core and another being the coating.

The controlled release of a pharmaceutical agent from the core is achieved by various means. The non limiting examples for achieving controlled release of pharmaceutical agent from the core include forming matrix core having release retarding polymers therein, forming core by compacting together the plurality of pharmaceutical agent containing units giving slow release of pharmaceutical agent individually etc.

Individual pharmaceutical agent containing units mentioned above include without limitation, granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules or combinations thereof.

As mentioned in the main embodiment, the core is surrounded with coating which forms gel structure upon contact with water or gastrointestinal fluid. This gelation further controls the release of the pharmaceutical agent to outer environment. More particularly, the composition after oral administration reaches the stomach and due to contact with gastric fluid; the outer coating forms the gel structure due to presence of gel forming material in said coating. The penetration of gastric fluid through the said coating starts the first controlled release of pharmaceutical agent from the core. The released pharmaceutical agent from the core is slowly diffused from the gelled coating and reaches the outer environmental fluid. Thus, the coating possesses leaky enteric property and it acts as further rate controlling unit after the core. The coating material used herein dissolves and/or looses its integrity above pH 5. Thus, the coating gets dissolved and/or looses its integrity when the composition reaches the intestine resulting in direct exposure of the core to the intestinal fluid. Thus, after dissolving of and/or disintegration of the outer coating, the further release of pharmaceutical agent from remaining composition is attributable only to the core. The release achieved only from the core is comparatively faster than the release from core and coating together. Ultimately, the composition gives the two phase release of the pharmaceutical agent, first phase being in the stomach with slower release rate and second phase being in intestine with release rate higher than that of first phase. Yet, in both the phases the release of pharmaceutical agent is in the controlled manner and specifically for those pharmaceutical agents which have higher solubility in stomach than in the lower regions of gastrointestinal tract, the two phases release enable to achieve the desired non linear increase in blood concentrations of pharmaceutical agent for the defined period. Whereas, these pharmaceutical agents if delivered through the conventional controlled release compositions then there is a linear increase in the blood concentrations of pharmaceutical agents due to their throughout uniform release from the conventional controlled release composition. The outer coating as mentioned above can be made from any material suitable for coating and which dissolves and/or looses its integrity at pH above 5. The non limiting examples of such material include alginates, gums, ionic synthetic or semisynthetic polymers etc.

According to second embodiment of invention, the composition is prepared by first preparing the core containing a pharmaceutical agent in controlled release form and then applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

The core containing a pharmaceutical agent in controlled release can be prepared by various means. The non limiting examples for preparing a core giving controlled release of pharmaceutical agent include forming matrix core having release retarding polymers therein, forming core by compacting together the plurality of

pharmaceutical agent containing units giving slow release of pharmaceutical agent individually etc. Thus, the materials used with pharmaceutical agent for preparation of such core also vary according to type of core. The examples of such materials include but not limited to release retarding polymers, bead materials, diluents, granulation aids, lubricants, binders, anti -adherents and compression aids or any combinations thereof. The particular choice of such material from the available variety at the time of core preparation should be based on suitability of such material with respect to pharmaceutical agent, type of core, compatibility and interaction of the said material with other materials of core and/or coating etc.

The release retarding polymers to be used in matrix core include without limitation, the polymers bearing hydrophilic properties, hydrophobic properties, gelling properties, ionic nature, swelling property or combinations thereof. Polymers bearing hydrophobic properties include lipids, fatty acids, waxes and their chemical modifications etc.

Without limiting the use of other methods, the matrix core can be produced by direct compression method, dry granulation method or wet granulation method. The various processes involved in these methods are sizing, blending, granulating, drying, compacting, lubricating etc.

The preparation methods for core containing plurality of individual units giving slow release of pharmaceutical agent as mentioned above vary according to the type of unit. For example granules can be prepared by wet granulation using planetary or high shear granulation or in a fluid bed granulator by top spray or rotor granulation. Beads are usually prepared by bottom spray coating in fluid bed coater onto nonpareil seeds. Spherules can be prepared by extrusion-spheronization or spheronization alone. Mini tablets refer to tablets having diameters of 2 -3 mm or smaller which can be compressed into a single tablet. These can be prepared by conventional methods for preparing tablets using specific tablet tooling. Pharmaceutical agent coated particles include pharmaceutical agent particles coated with polymer and are generally prepared by coating or granulating in a fluid bed coater or granulator respectively. Micro-capsules refer to discrete particles of the active agent

encapsulated by the polymer and prepared by various techniques known in the art for microencapsulation. The above mentioned methods are exemplary in nature and do not limit the scope of invention in any way. Slow release pharmaceutical agent containing units can be prepared in any other way and using any other material based on their suitability to the current invention and without limiting to the materials and methods described above. Also, plurality of different types of individual units giving slow release of pharmaceutical agent can be compacted together to form the core. For example plurality of slow release granules and slow release beads can be compacted together to form the core.

The coating can be applied to the core by various methods. For example

compression coating, spray coating, fluid bed coating etc.

Compression coating is applied on core by compressing the coating mixture on the core. Spray coating is applied on core by spraying the dispersion of coating mixture on the core. Such dispersion can be made by dispersing the coating mixture in a suitable solvent. In fluid bed coating, the coating solution is sprayed onto a fluidized bed of tablets.

The coating mixture comprises a material which forms gel upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. The non limiting examples of such materials include alginates, gums, ionic synthetic or semi-synthetic polymers or combinations thereof. The additional materials may be used in coating to facilitate the application of the coating on the core or to improve the physical properties of the coating or both. The examples of such other materials include but not limited to film formers, diluents, lubricants, compression aid, surfactants, preservatives, plasticizers, opacifying agents, coloring agents or any combinations thereof. The particular choice of such material from the available variety at the time of coating should be based on suitability of such material with respect to present invention. Such suitability factors for example include the compatibility and interaction of the said material with pharmaceutical agent and other materials of core or coating and may include the further assistance of such material in controlling the release rate of pharmaceutical agent from coating etc.

An additional seal coat between the core and gel forming coating can be optionally introduced to maintain the integrity of the core. For example, the seal coat helps in maintaining the integrity of core especially if the core contains plurality of individual units giving slow release of pharmaceutical agent. Also, seal coat may be applied to make the core surface smooth so as to achieve easy and effective application of gel forming coating on it.

In third embodiment, a composition giving controlled release of pharmaceutical agent in two phases comprises a matrix core containing the pharmaceutical agent in controlled release form, a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

Such composition preferably prepared by preparing matrix core comprising a pharmaceutical agent, release retarding polymer, diluent and lubricant. Preferably, the amounts of pharmaceutical agent, release retarding polymer, diluent and lubricant suitable for incorporation in matrix core are from about 5 to about 75%, from about 5 to about 95%, from about 0 to about 90% and from about 0.05 to about 2% of the composition respectively. These materials are mixed to form a blend and followed by compressing this blended material to form core using suitable punch.

Suitable release retarding polymer for use in above matrix core includes without any limitation, hydroxypropylmethyl cellulose, hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, xanthan gum, carragenen, poly(ethy!ene oxide) polymers, carbomer, alginates, glyceryl - monostearate, glyceryl behenate, polyethylene glycol monostearate, triglycerides, carnauba wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, beeswax, ion-exchange resins or any combination thereof. Suitable diluent for use in above matrix core includes without limitation, microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, starch, pregelatinized starch, dicalcium phosphate or any combination thereof.

Suitable lubricant for use in above matrix core includes without limitation, magnesium stearate, talc, stearic acid, silicon dioxide, glycerly behenate, calcium stearate, sodium stearyl fumarate or any combination thereof.

The prepared core is applied with a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5. Preferably, such coating is sprayed on core by preparing its dispersion in suitable solvent. More preferably, core is sprayed with coating comprising dispersion of sodium alginate in water. Suitably said dispersion is coated to obtain from about 5 to 25 % weight gain of the core.

Optionally a seal coat can be applied on core prior to coating it with gel forming coating material as described above. It makes the core surface smoother and thus, it may facilitate the further application of gel forming coating. Preferably, the seal coat is applied on matrix core to obtain 0.5% to 5% weight gain.

Seal coat preferably comprises the material selected from cellulose ether polymers and polyvinyl alcohol-polyethylene glycol graft copolymer.

Hereinafter the present invention will be explained more specifically with referring to the examples, which do not limit the scope of invention.

Example 1:

Preparation of Lamotrigine controlled release composition giving release in two phases.

Materials for matrix core preparation:

The percentage weights given below are calculated with respect to the total weight of final composition.

Procedure: Sift the above ingredients except magnesium stearate through 40 mesh and mix in a blender for 20 minutes. Sift magnesium stearate through 60 mesh and mix with above blended material for three minutes. Compress this finally mixed blend on 9 mm circular punches to form cores.

A seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain 0.5 to 5 % weight gain.

After applying seal coat, further coat these cores with sodium alginate. For coating, disperse sodium alginate in water and coat the core with this solution in a tablet coating pan up to 10% weight gain. Optionally, plasticizer can be added with sodium alginate in this dispersion. Prepared tablets were subjected to dissolution testing. Two dissolution media were used for this test. The dissolution test for first two hours was carried out in an acidic medium of acid buffer pH 1.2 which corresponds to gastric environment and after 2 hours this acidic medium was replaced with phosphate buffer of pH 6.8 which corresponds to intestinal environment. The dissolution data is given below.

The release in first 2 hrs shows the leaky enteric behaviour of sodium alginate coating. This coating started loosing its integrity in phosphate buffer as mentioned above. The graphical representation for above dissolution profile is shown in figure 1. From the above data it is apparent that the release of lamotrigine in gastric similar environment was slower than in intestinal similar environment.

Example 2:

Materials for matrix core preparation:

The percentage weights given below are calculated with respect to the total of final composition. Sr. No. Ingredients % w w

1 Lamotrigine 7.17

(pharmaceutical agent)

2 Hypromellose (viscocity: 3000 to 5600 cps) 21.50

(release retarding polymer)

3 Lactose monohydrate 56.90

(diluent)

4 Magnesium stearate 0.43

(lubricant)

Procedure: By following the similar procedure as shown in example 1 , prepare the final mixed blend for matrix core. Compress this finally mixed blend on 8.8 mm circular punches to form matrix cores.

A seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain about 1.72 % weight gain.

After applying the seal coat, further coat these cores with sodium alginate to obtain about 12.28% weight gain.

Prepared tablets were subjected to exactly similar dissolution testing as shown in example 1. The dissolution data is given below.

From above data it is apparent that the release of lamotrigine in gastric similar environment was slower than in intestinal similar environment. The graphical representation for dissolution profile is shown in figure 2.

Example 3:

Materials for matrix core preparation:

Procedure: Dissolve low viscosity grade hypromellose in water and granulate pharmaceutical agent using this solution. After drying and then sifting through appropriate mesh, add these granules to the remaining ingredients which are sifted through 40 mesh (except magnesium stearate) and mix in a blender for 20 minutes. Sift magnesium stearate through 60 mesh and add it to above mixture and further blend the mixture. Compress this final mixture on 10 mm circular punches to form cores.

A seal coat of hydroxypropyl methyl cellulose is applied on the prepared cores to obtain 1.72 % weight gain.

After applying seal coat, further coat these cores with sodium alginate. For coating, disperse sodium alginate in water and coat the core with this solution in a tablet coating pan to obtain up to 12.28% weight gain.

From above data it is apparent that the release of lamotrigine in gastric similar environment was slower than in intestinal similar environment. The graphical representation for dissolution profile is shown in figure 3.

Claims

We claim:

1. A composition giving controlled release of pharmaceutical agent in two phases comprising

(a) a core containing a pharmaceutical agent in controlled release form, and

(b) a coating surrounding the said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

2. The composition as claimed in claim 1, further comprising an optional seal coat between the core and the coating.

3. The composition as claimed in claim 1, wherein the core is selected from a matrix core having release retarding polymers therein and a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of the pharmaceutical agent individually.

4. The composition as claimed in claim 1, wherein the core is a matrix core having release retarding polymers therein.

5. The composition as claimed in claim 4, wherein the release retarding polymer used in matrix core is selected from hydrophilic polymers, hydrophobic polymers, gelling polymers, ionic polymers, swellable polymers and any combinations thereof.

6. The composition as claimed in claim 5, wherein the hydrophobic polymers include lipids, fatty acids, waxes and their chemical modifications.

7. The composition as claimed in claim 4 and 5, wherein the release retarding polymer comprises a polymer selected from hydroxypropyimethyl cellulose, hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, xanthan gum, carragenen, poly(ethylene oxide) polymers, carbomer, alginates, glyceryl monostearate, glyceryl behenate, polyethylene glycol monostearate, triglycerides, carnauba wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, beeswax, ion-exchange resins or any combination thereof.

8. The composition as claimed in claim 1, wherein said core is a core formed by compacting together the plurality of pharmaceutical agent containing units giving slow release of the pharmaceutical agent individually.

9. The composition as claimed in claim 8, wherein the plurality of pharmaceutical agent containing units are selected from granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules and any combinations thereof.

10. The composition as claimed in claim 1, wherein a coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which . dissolves and/or looses its integrity above pH 5.

1 1. The composition as claimed in claim 10, wherein said material is selected form alginates, gums, ionic synthetic polymers, ionic semi-synthetic polymers and any combination thereof.

12. The composition as claimed in claim 1 1, wherein said material is sodium alginate.

13. The composition as claimed in claim 1 1 and 12, wherein the coating further comprises a material selected from film formers, diluents, lubricants, compression aid, surfactants, preservatives, plasticizers, opacifying agents, coloring agents or any combinations thereof.

14. A method for preparing a composition giving controlled release of pharmaceutical agent in two phases comprises preparing a core containing a pharmaceutical agent in controlled release form and applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

15. The method of claim 14, further comprising applying an optional seal coat between the core and the coating.

16. The method of claim 14, wherein preparing the core containing the

pharmaceutical agent in controlled release form comprises preparing a matrix core having release retarding polymers therein.

17. The method of claim 16, wherein matrix core is prepared by a method selected from direct compression method, dry granulation method and wet granulation method.

18. The method of claim 14, wherein preparing the core containing the

pharmaceutical agent in controlled release form comprises compacting together the plurality of pharmaceutical agent containing units giving slow release of the pharmaceutical agent individually.

19. The method of claim 18, wherein the plurality of pharmaceutical agent containing units are selected from granules, beads, spherules, mini-tablets, pharmaceutical agent coated particles, micro-capsules and any combinations thereof.

20. The method of claim 18 and 19, wherein the methods for preparation of pharmaceutical agent containing units comprises granulation for preparing granules, spray coating onto non-pareil seeds for preparing beads, spheronization for preparing spherules, fluid bed coating or granulation for preparing polymer coated

pharmaceutical agent particles, microencapsulation methods for preparing microcapsules.

21. The method of claim 14, wherein the coating is applied on core by a method selected from compression coating, spray coating and fluid bed coating.

22. A composition giving controlled release of pharmaceutical agent in two phases comprising a matrix core containing a pharmaceutical agent in controlled release form, and a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

23. The composition of claim 22, wherein the matrix core containing a

pharmaceutical agent in controlled release form comprises a pharmaceutical agent, a release retarding polymer, a diluent and a lubricant.

24. The composition of claim 23, wherein the release retarding polymer comprises hydroxypropylmethyl cellulose, Hydroxy propyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, sodium carboxy methyl cellulose, xanthan gum, carragenen, poly(ethylene oxide) polymers, carbomer, alginates, glyceryl monostearate, glyceryl behenate, polyethylene glycol monostearate, triglycerides, carnauba wax, stearyl alcohol, cetyl alcohol, cetostearyl alcohol, stearic acid, beeswax, ion-exchange resins or any combination thereof.

25. The composition of claim 23, wherein the diluent comprises microcrystalline cellulose, silicified microcrystalline cellulose, lactose, mannitol, sorbitol, starch, pregelatinized starch, dicalcium phosphate or any combination thereof.

26. The composition of claim 23, wherein the lubricant comprises magnesium stearate, talc, stearic acid, silicon dioxide, glycerly behenate, calcium stearate, sodium stearyl fumarate or any combination thereof.

27. The composition of claim 23, wherein the amounts of pharmaceutical agent, release retarding polymer, diluent and lubricant suitable for incorporation in matrix core are from about 5% to about 75%, from about 5% to about 95%, from about 0% to about 90% and from about 0.05% to about 2% of the weight of composition respectively.

28. The composition of claim 23, wherein the pharmaceutical agent is lamotrigine, the release retarding polymer is hydroxypropylmethyl cellulose, the diluent is microcrystalline cellulose and the lubricant is magnesium stearate.

29. The composition of claim 23, wherein the pharmaceutical agent is lamotrigine, the release retarding polymer is hydroxypropylmethyl cellulose, the diluent is lactose and the lubricant is magnesium stearate.

30. The composition of claim 22, wherein a coating comprises a material which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

31. The composition of claim 30, wherein said material comprises sodium alginate.

32. The composition of claim 31 , wherein the said material further comprises a material selected from film formers, diluents, lubricants, compression aid, surfactants, preservatives, plasticizers, opacifying agents, coloring agents or any combinations thereof.

33. The composition of claim 22, wherein the composition is prepared by a method comprising preparing a matrix core containing a pharmaceutical agent in controlled release form and applying on said core a coating which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5.

34. The composition of claim 33, wherein preparing a matrix core comprises mixing core materials to form a blend followed by compressing this blend to form matrix core.

35. The composition of claim 34, wherein mixing core materials refers to mixing pharmaceutical agent, release retarding polymer, diluent and lubricant.

36. The composition of claim 33, wherein the coating is applied with spray coating technique.

37. The composition of claim 36, wherein the coating is applied by spraying dispersion comprising sodium alginate on the matrix core.

38. The composition of claim 37, wherein the coating is applied by spraying aqueous dispersion comprising sodium alginate on the matrix core.

39. The composition of claim 37 and 38, wherein the dispersion further comprises a material selected from film formers, diluents, lubricants, compression aid, surfactants, preservatives, plasticizers, opacifying agents, coloring agents or any combinations thereof.

40. The composition of claim 33, 38 and 39 wherein said coating is applied to obtain from about 5% to 25% final weight gain of the core.

41. The composition of claim 22, further comprising an optional seal coat between the core and the coating.

42. The composition of claim 41, wherein the seal coating is applied on the core prior to coating it with gel forming coating material.

43. A composition giving controlled release of pharmaceutical agent in two phases comprising a matrix core containing a pharmaceutical agent in controlled release form, and a coating surrounding said core which forms gel structure upon contact with water or gastrointestinal fluid and which dissolves and/or looses its integrity above pH 5, wherein

(i) the matrix core comprises

(a) lamotrigine or salts thereof from about 5% to about 75%,

(b) hydropropylmethyl cellulose from about 5% to about 95%,

(c) diluent selected from microcrystalline cellulose and lactose monohydrate from about 0% to about 90% and

(d) magnesium stearate from about 0.05% to about 2% of the composition respectively; and

(ii) the coating material comprises sodium alginate.

44. The composition of claim 43, further comprising an optional seal coat between the matrix core and the coating.

45. The composition of claim 43 and 44, wherein

(i) the matrix core comprises

(a) about 8.33% lamotrigine or salts thereof,

(b) about 25.25% hydropropylmethyl cellulose,

(c) about 65.92% macrocrystalline cellulose and

(d) about 0.50% magnesium stearate of the composition respectively,

(ii) the seal coat comprises hydropropylmethyl cellulose and

(Hi) the coating material comprises sodium alginate.

46. The composition of claim 43 and 44, wherein

(i) the matrix core comprises

(a) about 7.15% lamotrigine or salts thereof,

(b) about 21.50% hydropropylmethyl cellulose,

(c) about 56.90% lactose monohydrate and

(d) about 0.45% magnesium stearate of the composition respectively,

(ii) the seal coat comprises hydropropylmethyl cellulose and

(iii) the coating material comprises sodium alginate.

47. The composition of claim 43 and 44, wherein

(i) the matrix core comprises

(a) about 49.15% lamotrigine or salts thereof,

(b) about 8.60% hydropropylmethyl cellulose as release retarding polymer,

(c) about 26.1 1% lactose monohydrate and

(d) about 0.45% magnesium stearate of the composition respectively, (ii) the seal coat comprises hydropropylmethyl cellulose and

(iii) the coating material comprises sodium alginate.

48. The composition of claim 47, wherein the matrix core further comprises a binding agent.

49. The composition of claim 44, 45, 46 and 47, wherein seal coat is applied on matrix core to obtain 0.5% to 5% weight gain.

50. The composition of claim 43, 45, 46, 47 and 49, wherein coating comprising sodium alginate is applied to obtain up to 25% weight gain.