WO2004091587A1

WO2004091587A1 - Multiple release anti-diabetic drugs and process of production thereof

Info

Publication number: WO2004091587A1
Application number: PCT/IN2003/000311
Authority: WO
Inventors: Ramachandran Thembalath; Yatish Kumar Bansal; Vaishali Manish Tawde; Vinod Kumar TIWARI; Vivek Kamlakar Jadhav
Original assignee: Ipca Laboratories Limited
Priority date: 2003-04-17
Filing date: 2003-09-17
Publication date: 2004-10-28

Abstract

The present invention relates to a process for dual release combination of pharmaceutical active ingredients, more particularly, anti-diabetic drugs, where in one of the active ingredients is homogenously dispersed throughout a rate controlling polymer matrix and the release of the drug is controlled by diffusion through the matrix.

Description

MULTIPLE RELEASE ANTI-DIABETIC DRUGS AND PROCESS OF PRODUCTION THEREOF

Related Applications

This application claims priority from India National patent application serial NO.383/MUM/2003, filed 17 April 03.

Field of the Invention

The invention relates to the field of medicine and pharmacology. More specifically, the invention relates to a pharmaceutical composition comprising at least two different pharmaceutically active ingredients, the release profile of a first active ingredient being different from the release profile of a second active ingredient. The pharmaceutical composition ofthe invention is particularly indicated in the treatment of diabetes.

Background and Prior Art

It is well known in the pharmaceutical field to provide delivery systems for the controlled release of pharmaceutically active ingredients. Such systems allow for the delivery after administration of a pharmaceutical dose sustained over a period of time. As well as direct pharmacological benefits of such sustained release, it is generally thought that patient compliance with the treatment protocol is also improved as a result of a diminished need for repetitive administration. WO-A-02/28383 for example discloses a delivery system for chiral pharmaceutical agents. In fact, much attention in this field has focussed on the delivery of chiral compounds, which often exhibit different pharmacokinetic properties among other pharmacological differences.

Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors. Ofthe several known types of diabetes mellitus, the two major types are type I (insulin-dependent diabetes mellitus; IDDM) and type II (non- insulin-dependent diabetes mellitus; NIDDM).

Type II diabetes mellitus is a common disease increasingly affecting people worldwide. While type II diabetes affects less than 10% ofthe population in developed countries, the prevalence ofthe disease is growing faster among the Asian population, especially Asian immigrants. Antidiabetic drugs have therefore become an area of immense interest and attention for the research community throughout the world.

First line therapy in both type I and type II diabetes involves dietary control and, especially in the case of type II diabetes, increased exercise routine. If patients with type II diabetes have not achieved suitable control within about three months after dietary modification and increased physical activity, then oral hypoglycemic drugs may be indicated. The two major classes of such drugs are sulfonylureas and biguanides. Sulfonylureas act mainly by increasing endogenous insulin secretion. Biguanides act chiefly by decreasing hepatic gluconeogeneis and increasing peripheral utilization of glucose. Metformin (N, N - dimethyl imidocarbonimidic diamide) is a typical biguanide and is an active ingredient used in oral hypoglycemic drugs for the treatment of type II diabetes mellitus in humans and other mammals. It is typically administered in the form of a pharmaceutically acceptable salt, usually a hydrochloride salt. Metformin is not chemically or pharmacologically related to any other class of hypoglycemic agents. Unless otherwise indicated, this specification will use "metformin" to mean metformin and pharmaceutically acceptable salts thereof. Metformin is often indicated for patients who are not effectively treated with a sulfonylurea drug independently. Metformin hydrochloride is a white to off-white crystalline compound having the molecular formula C-_tHπNs.HCl (molecular wt. 165.63) and is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. Metformin can exert its hypoglycemic effect even in the absence of insulin, particularly in patients who are not effectively treated with sulfonylureas.

Metformin is not chemically related to sulfonylurea, but it is routinely used in combination with a sulfonylurea and shows synergistic properties in some cases. Other biguanides such as phenformin and buformin can also be used in combination with metformin.

Glimepiride is an oral blood glucose lowering drug of the sulfonylurea class. Chemically, glimepiride is identified as l-[[p-[2-(3-ethyl-4-methyl-2-oxo-3-pyrroline-l- carboxamido)ethyl]phenyl]sulfonyl]-3-(trans-4-methylcyclohexyl)urea. Glimepiride is a white to yellowish-white crystalline odorless powder having the molecular formula C₂₄H₃₄N θ₅S (molecular wt 490.62) and is practically insoluble in water.

US Patent 6031004 describes a method for the treatment of diabetes employing metformin hydrochloride and other salts by themselves or in combination with another anti-diabetic agent (e.g. a hypoglycemic agent such as glyburide, glipizide, glimepiride, acarbose, miglitol, troglitazone or insulin). The dosage is disclosed as an oral tablet form. Metformin salts of dibasic acids that are equivalent to metformin hydrochloride are also described.

US Patent 6475521 discloses a biphasic controlled release system for high solubility pharmaceuticals. A metformin hydrochloride salt or a salt of metformin with a dibasic acid is used in combination with another hypoglycemic agent, for example a sulfonylurea such as glyburide, glimepiride, glipizide, gliclazide or chlorpropamide, for the treatment of diabetes. The combination of active agents with a suitable excipient (a hydrophilic and/or hydrophobic polymer) is said to provide controlled release and an extended biphasic release delivery system.

US Patent 6524618 describes an extended-release matrix formulation capable of being directly compressed into tablets comprising metformin hydrochloride blended with specific excipients in the form of a free flowing powder. Metformin hydrochloride is also used in combination with another anti-diabetic agents selected from the group consisting of sulfonylureas (eg. glimepiride, glipyride, glipizide, glyburide, and gliciazide), α- glucosidaze inhibitors and glitazones as well as combinations of two or more of the foregoing anti-diabetic agents.

WO-A-02094285 describes orally administered galenic preparations (such as tablets, capsules, powders and the like), which consist of biguanide, preferably metformin and at least one other hypoglycemic active agent (glibenclamide, pioglitazone hydrochloride, rosiglitazone maleate, nateglinide, glipizide, glimepiride). This capsule-shaped tablet consists of a core based on metformin further coated with a film that enables prolonged release in vivo of metformin. Optionally the capsule may be coated with the said at least one other hypoglycemic active agent and may allow for the prolonged release of the agent.

Although single dose combination preparations with active agents are known in the prior art for the treatment of diabetes, the combination agents are generally released simultaneously either at administration or over a period of time. Such preparations, although convenient, may not be as effective for treatment as two separately administered doses of individual active agents and this may be for a number of reasons. For example, one agent may require a slower release profile in relation to another agent in order to be effective. It may also be the case that both agents have similar modes of pharmacological action and the action of one or both may therefore be inhibited by simultaneous release with the other because both are competing for the same or similar receptor. Summary ofthe Invention

It is an object of the invention to provide an improved pharmaceutical composition, in particular for the treatment of diabetes. It is a further object ofthe invention to overcome or ameliorate one of more of the problems associated with the prior art pharmaceutical preparations. It is also an object of the present invention to provide a pharmaceutical preparation comprising two or more active ingredients, at least two of the active ingredients having different release profiles. Furthermore, it is also an object of the present invention to provide a pharmaceutical preparation comprising two or more active ingredients that act synergistically against a disease or condition.

According to the present invention there is provided a pharmaceutical composition comprising a matrix material having first pharmaceutically active agent dispersed therein, the dispersion of the first agent within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition with respect to the release profile of a second pharmaceutically active agent provided in the composition outside ofthe matrix material.

Detailed Description

The first pharmaceutically active agent and the second pharmaceutically active agent may, in one preferred composition according to the invention, be independently indicated in the treatment of diabetes. Preferably, the first pharmaceutically active agent and the second pharmaceutically active agent are selected from respectively different classes of chemical compound.

The first and second active agents in the composition may be selected to exhibit a synergistic effect for treatment of a disease or a condition, such as diabetes.

In one preferred composition according to the invention, the first pharmaceutically active agent is a biguanide compound, preferably metformin.

In another preferred composition according to the invention, the second pharmaceutically active agent is a sulfonylurea compound, preferably glimepiride.

The matrix material is preferably a polymeric material or mixture of polymeric materials and is preferably insoluble or only sparingly soluble in water. Preferably the matrix material has the capacity to absorb water from its surrounding environment and to swell on such absorption. Preferred polymeric materials include carbomers, such as carbomer 971, cellulosic polymers and alkyl cellulosic polymers such as methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl methyl cellulose phthalate and mixtures of two or more thereof. Hydroxypropyl methyl cellulose is especially preferred, preferably with a viscosity in the range of 15000 - 100000 cps. Combinations of carbomers with cellulosic polymers are also particularly suitable as the matrix material.

Preferably, the matrix material is biodegradable. The polymer ofthe matrix material may account for 15-25% or 15-20% ofthe total mass ofthe pharmaceutical composition

Preferably, the first pharmaceutically active agent is dispersed substantially homogenously throughout the matrix material.

On administration ofthe pharmaceutical composition ofthe invention, it is preferred that the release profile ofthe second pharmaceutically active agent be such that release ofthe second agent begins only a short time, for example in less than about 30 minutes, preferably less than about 15 minutes and most preferably less than about 5 minutes after administration. Release of the second agent may begin substantially immediately after administration. Release of the first pharmaceutically active agent is delayed relative to the second agent, and may also be extended to take place over a longer timescale with respect to the second agent.

The second active agent, sulfonylurea for example, may conveniently be provided in combination with a solubilising agent to provide a predetermined substantially immediate release on administration of the composition. Sodium lauryl sulphate is one preferred solubilising agent, which may suitably be present in an amount of from 0.2-2% ofthe total mass ofthe composition.

The second active agent may be therefore provided in combination with an effective amount of one or more immediate release excipients selected, for example, from one or more of: sodium starch glycolate, sodium lauryl sulphate, croscarmellose sodium and betacyclodextrin.

The pharmaceutical composition ofthe invention is suitably provided in a tablet form for oral administration and is preferably provided as a layered tablet, with a first layer comprising the matrix material and the first pharmaceutically active agent (optionally in combination with other exipients, colourants, binders, diluents, disintegrants, fillers, lubricants, glidants, taste-masking agents and the like) and a second layer comprising the second pharmaceutically active agent (optionally in combination with other exipients, colourants, diluents, disintegrants, binders, fillers, lubricants, glidants, taste-masking agents and the like).

The first active agent may suitably be present in the first layer in an amount ranging from 500 mg to 850 mg. The second active agent may suitably be present in the second layer in an amount ranging from 1 mg to 5 mg.

When a binding agent is present in the composition, preferred binding agents (for combination with the first active agent) include polyvinylpyrrolidone, starch or mixtures thereof. When present, polyvinylpyrrolidone preferably has a grade varying from 10 - 120. The percentage of binding agent, when present, is preferably from 1-10% of the total mass ofthe composition.

When a diluent is present in the compositon, preferred diluents (provided in combination with the second active agent) include micro crystalline cellulose, starch and lactose. Such diluents, when used, may suitably be present in an amount of from 5-10% of the total mass of the composition. Also, preferred diluents (provided in combination with first or second active agents) include microcrystalline cellulose, dicalcium phosphate or mixtures thereof. Such diluents may suitably be present in an amount of from 10 - 20 % ofthe total mass ofthe composition.

When a disintegrant is present in the composition, preferrred disintegrants (provided in combination with the second active agent) include sodium starch glycolate and croscarmellose sodium. Such disintegrants may suitably be present in an amount of from 0.2-2% ofthe total mass ofthe composition.

When a lubricant is present in the composition, a preferred lubricant (for combination with the first active agent) is magnesium stearate. Such lubricants may suitably be present in an amount of from 0.01-0.02% ofthe total mass ofthe preparation.

When a glidant is present in the composition, a preferred glidant (provided in combination with first or second active agents) is colloidal silicon dioxide. Such glidants may suitably be present in an amount of from 1-2% ofthe total mass ofthe composition.

Accordingly, the invention provides a pharmaceutical preparation in tablet form comprising two or more active ingredients with pre-determined release profiles, at least one active ingredient having a release profile that differs substantially from the release profile of another ofthe other active ingredient. Preferred pharmaceutical compositions ofthe invention will: provide immediate release of sulfonylurea by using a solubilizing agent in an effective manner in a first layer; use a combination of two specific hydroxypropyl methyl cellulose and/or carbomer polymers in a second layer to aid effective release of the drug over a specific period of time independent of pH affects; provide a two drug combination therapy having a synergistic effect over control of blood glucose in diabetic patients; allow reduced frequency of drug dosing and hence improve patient compliance; maintain a steady drug concentration in the blood circulation with the help of a sustained release layer; and minimize incidence and severity of adverse side effects.

The present invention therefore relates to a pharmaceutical composition adapted for dual release at different rates of combined pharmaceutical active agents, for example agents having anti-diabetic activity, in which at least one ofthe active ingredients is, preferably homogenously, dispersed throughout a rate controlling polymer matrix, release of the at least one active ingredient being controlled by diffusion through the matrix, and in which at least one other active agent is provided in the composition in a form available for rapid release in vivo.

In accordance with present invention there is provided a pharmaceutical preparation in tablet form comprising two or more active ingredients with pre-determined release profiles, at least one active ingredient having a release profile that differs substantially from the release profile of at least one other active ingredient. Each active ingredient may be disposed in a discrete layer within the tablet. Additionally, the at least two release profiles may comprise an extended release profile and an immediate release profile. The present invention also relates to the pharmaceutical preparation of a bi-layer tablet suitable for oral administration. Each tablet is preferably made up of immediate release compartment and extended release compartment. The immediate release compartment may comprise a compressed blend of an active agent and one or more polymers with some super disintegrant and solubilisers. The extended release compartment may comprise biodegradable/non-biodegradable or hydrophilic /hydrophobic polymers which have swelling properties within which an active ingredient is suitably blended and this allows prolonged release of active substance within the second layer.

When the extended release compartment is in contact with the immediate release compartment it provides a dose sufficient to exceed the metabolic capacity of the body and maintains the therapeutic levels.

The invention is not limited as to the nature of the active ingredients. Each layer may contain a different active ingredient. The first layer may contain up to 50-80% of the active substance ofthe total weight ofthe first layer. The second layer may contain up to 3-10% by weight ofthe active ingredient.

Drug efficacy generally depends on the ability ofthe drug to reach its target in sufficient quantities, to maintain desired therapeutic levels for a fixed (desired) time period.

Metformin and glimepiride are two active ingredients for anti-diabetic drugs that are used to treat diabetic patients (human beings). The use ofthe core formulation involving both the active ingredients is advantageous to patients and physicians because both medicaments are synergistic to each other in the body when used in the management of blood glucose control. I.e.: diabetes.

In one pharmaceutical composition of the invention, the matrix material polymer is associated to the biguanide by forming a core within the preparation to provide a predetermined delay in the time period ofthe release ofthe biguanide.

The compartmentalized (two compartments or more) delivery of active ingredients in the intestinal tract is facilitated by the product formulation, taking into account the physical & physiological conditions in the human GI tract and also the travelling time of the pharmaceutical preparation through the intestinal tract.

In the dual compartment delivery, the immediate release ingredient releases within 45 minutes in acidic pH (stomach), and the extended release ingredient releases within 10 hrs at a different pH.

Orally administered drugs have to overcome several obstacles to reach their desired targets. Before orally administered drugs enter the general circulation ofthe human body they are absorbed into the capillaries and veins ofthe GI tract and are transported by the portal vein to the liver. The pH and enzymatic activities found in the GI tract fluids may inactivate the drug or cause the drug to dissolve poorly. Thus the amount of drugs in the blood stream is significantly lower than the amount administered. This metabolic elimination ofthe given dose results in bioavailability.

Formulations capable of immediate and sustained release are suitable for once daily administration.

In a preferred embodiment the pharmaceutical formulation is as follows:

(a) Lower Layer

Approximately 55 to 60% of active ingredient Release retardant polymer A 5 - 25% Release retardant polymer B 5 - 25% Binding agent 2 - 10% Diluents 0- 10% Non-aqueous vehicle q.s.

(b) Upper Layer

Approximately 0.5-1% of active ingredient Diluents 70- 90 % Disintegrants 0.5 - 5 % Solubilizers 0.2 - 0.3% Colour 0.2 - 0.4% Binding agent 3 - 5 % Non-aqueous/aqueous vehicle q.s.

The tablets ofthe invention are prepared by a method including the steps of granulation, followed by compression.

Accordingly, the present invention further provides a method for forming a tablet-form pharmaceutical composition comprising: providing a first pulverulent component comprising a first pharmaceutically active agent and a matrix material; providing a second pulverulent component comprising a second pharmaceutically active agent; and compressing the first and second pulverulent components together as discrete layers to form a tablet-form pharmaceutical composition having a first layer comprising the matrix material having the first pharmaceutically active agent dispersed therein, the dispersion ofthe first agent within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition with respect to the release profile of the second pharmaceutically active agent provided in the composition as a second discrete layer.

More precisely, the method of preparation, which is the subject of invention comprises the steps of: a) preparing granules of a first active substance from a pulverulent mixture of the said first active substance and one or more biodegradable inert polymeric materials, and optionally one or more additives suitable for the prolonged release ofthe said first active substance; b) preparing granules of second active substance from a pulverulent mixture of the said second active substance, a disintegrating agent, a solubilising agent, optionally one or more additives such as binding agent and polymers for the preparation ofthe immediate release ofthe second active substance; and c) combining, by compressing, in a manner known per se the two types of granules obtained in steps a) and b) above so as to obtain tablets in which the lower layer, affording prolonged release, results from the compression of granules obtained in step a) and in which the upper layer, affording immediate release, results from the compression ofthe granules in step b).

The first step (a) is designed to provide granules based on the first active substance, which will lead , through compression, to the lower layer, designated as the prolonged release layer. The constituents of this layer are those of the biodegradable inert polymeric matrix defined above. The second step (b) is designed to provide granules based on a different active substance, which will lead, through compression, to the upper layer, designated the immediate release layer. Step c) leads to successive compression of the granules obtained in the preceding steps a) and b) to form a tablet.

Steps a) and b) involve the granulation of powder of amorphous or crystallized particles. This granulation may be carried out by a wet granulation method.

The compression step is suitably achieved using 19 x 9 mm flat bevelled capsule shaped punches. The method of granulation comprises five essential steps:

1) Dry mixing of its various constituents, 2) wetting, 3) granulation process, 4) drying and then, 5) sizing.

The dry mixing consists of mixing the pulverulent excipients entering into the composition of the granules. The wetting consists in adding to the pulverulent mixture, various constituents, an aqueous solution of binder or hydroalcoholic solution of binder or alcoholic solution of binder. The granulation procedure is carried out by kneading in a planetary or a rapid type mixer granulator. The drying procedure is carried out in a fluidised bed dryer or tray dryer to achieve desired loss on drying. Sizing is done in multimill by using suitable size distribution ofthe granules.

In accordance with a further aspect ofthe present invention, there is provided a process for producing a multi-layered pharmaceutical product with an immediate release and controlled release of two or more active ingredients comprising the steps of: a) producing a core comprising at least one or more polymers which absorbs water and swells, selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, carbomer, hydroxypropyl methyl cellulose phthalate; and b) inserting a lower layer comprising a biguanide and upper layer comprising a sulfonylurea.

The invention will now be more particularly described with reference to the following Figures and Examples in which: Description of Drawings

Figure 1 is a graph illustrating the results of the in vitro release of metformin over 12 hours from a pharmaceutical preparation produced in Example 1; and

Figure 2 is a graph illustrating the results of the in vitro release of metformin over 12 hours from a pharmaceutical preparation produced in Examples 2, 3 and 4.

Example 1

A pharmaceutical preparation was produced with two active ingredients (metformin and glimepiride), each of which was held in a separate layer in the tablet.

Lower Layer:

The lower layer was produced from the following components:

The components, except magnesium stearate were mixed together in a blender and then granulated, using a paste containing polyvinylpyrrolidone. The granules were dried, screened to obtain suitable particle size distribution and mixed with hydroxypropyl methyl cellulose. When the mixture was effectively blended, magnesium stearate was mixed with the powder.

Upper Layer:

The upper layer was produced from the following components:

The components except magnesium stearate, part of the sodium lauryl sulphate and colloidal silicon dioxide, were mixed together and were granulated using a paste containing polyvinylpyrrolidone and the granules were dried and screened, to obtain a suitable size distribution and mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. After this had been effectively blended, magnesium stearate was mixed in with the powder.

The resultant bi-layer tablets, each contained 500mg of metformin hydrochloride and 1 mg of glimepiride. Each tablet weighed 1150mg and contained 890mg of lower layer and 260mg of upper layer and were 19 9 mm in dimension. The tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.

When these tablets were tested for in vitro dissolution, following results were obtained:

The results in this table are illustrated in Figure 1 and show that whilst the upper layer (which contained the glimepiride) had almost immediate release profile of just over 90% within 45 minutes, compared to the lower layer (which contained the metformin) had a much slower release profile of over 8 hours to achieve the same level of release.

Example 2

Lower Layer:

The lower layer was produced from the following components:

The components, except magnesium stearate were mixed together in a blender and then granulated, using a paste containing polyvinlypyrrolidone. The granules were dried and screened to obtain suitable particle size distribution and mixed with hydroxypropyl methyl cellulose. When this had been effectively blended, magnesium stearate was mixed with the powder. Upper Layer:

The upper layer was produced from the following components:

The components except magnesium stearate, part of the sodium lauryl sulphate and colloidal silicon dioxide, were mixed together and were granulated using a paste containing polyvinylpyrrolidone. The granules were dried and screened, to obtain a suitable size distribution and mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate was mixed with the powder.

Each bi-layer tablet contained 500mg of metformin hydrochloride and 1 mg of glimepiride. Each tablet weighed 1130mg and containing 900mg of lower layer and 230mg of upper layer and were 19 x 9 mm in dimension. The tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.

When the tablets were tested for in vitro dissolution, the following results were obtained:

Example 3

Lower Layer:

The lower layer was produced from the following components:

[052] The components, except magnesium stearate were mixed together in a blender and then granulated, using a paste containing polyvinylpyrrolidone.. The granules were dried and screened to obtain suitable particle size distribution and were then mixed with hydroxypropyl methyl cellulose. When this has been effectively blended, magnesium stearate was mixed with the powder.

Upper Layer:

The upper layer was produced from the following components:

The components except magnesium stearate, part of the sodium lauryl sulphate and the colloidal silicon dioxide, were mixed together and were granulated using a paste containing Starch and the granules were dried and screened, to obtain a suitable size distribution. The mixture was then mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate were mixed with the powder.

Each bi-layer tablets contains 500mg of metformin hydrochloride and 1 mg of glimepiride.

Each tablet weighs HOOmg and contains 900mg of lower layer and 200mg of upper layer and is 19 x 9 mm in dimension. The tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer were added and the press operated again.

When these tablets are tested for in vitro dissolution, following results were obtained:

Example 4

Lower Layer:

The lower layer was produced from the following components:

The components, except magnesium stearate were mixed together in a blender and then granulated, using a paste containing polyvinylpyrrolidone. The granules were dried, screened to obtain suitable particle size distribution and mixed with hydroxypropyl methyl cellulose. When this had been effectively blended, magnesium stearate was mixed with the powder.

Upper Layer:

The upper layer was produced from the following components:

The components except magnesium stearate, part of the sodium lauryl sulphate and colloidal silicon dioxide, were mixed together and were granulated using a paste containing starch and the granules were dried and screened , to obtain a suitable size distribution. The mixture is mixed with colloidal silicon dioxide and croscarmellose sodium in a blender. When this has been effectively blended, magnesium stearate were mixed with the powder. The bi-layer tablets each contained 500mg of metformin hydrochloride and 1 mg of glimepiride.

Each tabled weighed llOOmg and contained 900mg of lower layer and 200mg of upper layer and were 19 x 9 mm in dimension. The tablets were produced on a tablet press by a two stage pressing procedure, thereby tablets of lower layer were formed in the press and then the upper layer was added and the press operated again.

The results of the experiments conducted in Examples 2 to 4 are illustrated in Figure 2 and show that whilst the upper layers (which contained the glimepiride) had an almost immediate release profile of approximately 98% within 45 minutes. This is in contrast with the release profile ofthe lower layer (which contained the metformin) which had a much slower release profile of over 8 hours to achieve a similar level of release by using HPMC and carbomer.

Claims

1. A pharmaceutical composition comprising a matrix material having first pharmaceutically active agent dispersed therein, the dispersion ofthe first agent within the matrix material being effective to delay the release profile of the first agent on administration of the pharmaceutical composition with respect to the release profile of a second pharmaceutically active agent provided in the composition outside ofthe matrix material

2. A pharmaceutical composition according to claim 1, wherein the first pharmaceutically active agent and the second pharmaceutically active agent are each independently indicated in the treatment of diabetes

3. A pharmaceutical composition according to claim 1 or claim 2, wherein the first pharmaceutically active agent and the second pharmaceutically active agent are selected from respectively different classes of chemical compound

4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the first pharmaceutically active agent is a biguanide compound

5. A pharmaceutical composition according to claim 4, wherein the biguanide compound is metformin

6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the second pharmaceutically active agent is a sulfonylurea compound

7. A pharmaceutical composition according to claim 6, wherein the sulfonylurea compound is glimepiride

8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the matrix material is a polymeric material or mixture of polymeric materials having the capacity to absorb water from its surrounding environment and to swell on such absorption

9. A pharmaceutical composition according to claim 8 wherein the matrix material is selected from carbomers, cellulosic polymers, alkyl cellulosic polymers and mixtures of two or more thereof

10. A pharmaceutical composition according to claim 9, wherein the matrix material comprises a carbomer, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxy propyl cellulose, hydroxypropyl methyl cellulose or mixtures of two or more thereof

11. A pharmaceutical composition according to claim 10, wherein the matrix material comprises a combination of a carbomer with a cellulosic polymer

12. A pharmaceutical composition according to any one of claims 1 to 11, wherein the first pharmaceutically active agent is dispersed substantially homogenously throughout the matrix material

13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the dispersion of the first agent within the matrix material is effective to extend the release profile of the first agent on administration of the pharmaceutical composition with respect to the release profile of a second pharmaceutically active agent

14. A pharmaceutical composition according to any one of claims 1 to 13, provided in the form of a layered tablet, with a first layer comprising the matrix material and the first pharmaceutically active agent and a second layer comprising the second pharmaceutically active agent

15. A pharmaceutical composition according to any one of claims 1 to 14, wherein one or both ofthe first and second active agents are provided in combination with one or more pharmaceutical adjuvants selected from excipients, colourants, binders, diluents, fillers, solubilising agents, disintegrants, lubricants, glidants and taste-masking agents

16. A pharmaceutical composition according to any one of claims 1 to 15, wherein the first and second active agents in the composition are selected to exhibit a synergistic effect for treatment of a disease or a condition

17. A pharmaceutical composition according to any one of claims 1 to 16, wherein the second active agent is provided in combination with a solubilising agent to provide a predetermined substantially immediate release on administration ofthe composition

18. A method for forming a tablet-form pharmaceutical composition comprising: providing a first pulverulent component comprising a first pharmaceutically active agent and a matrix material; providing a second pulverulent component comprising a second pharmaceutically active agent; and compressing the first and second pulverulent components together as discrete layers to form a tablet-form pharmaceutical composition according to any one of claims 1 to 17.