FIELD OF INVENTION

The present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and a HMG-CoA reductase inhibitor.

Particularly, the present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and HMG-CoA reductase inhibitor, which is prepared by compression-coating technique.
More particularly, the present invention provides for a compression-coated oral solid dosage form comprising a combination of niacin and lovastatin.

BACKGROUND OF THE INVENTION

Niacin or nicotinic acid or 3-pyridinecarboxylic acid has been used for many years in the treatment of lipidemic disorders such as hyperlipidemia, hypercholesterolemia and atherosclerosis. This compound has long been known to exhibit the beneficial effects of reducing total cholesterol, low density lipoproteins or LDL cholesterol, triglycerides and apolipoprotein a [Lp(a)] in the human body, while increasing desirable high density lipoproteins or HDL cholesterol.

HMG-CoA reductase inhibitors have also been used for many years to treat hyperlipidemia. These compounds are known to exhibit beneficial effects of reducing total cholesterol and LDL-cholesterol in the human body, and elevating HDL-cholesterol levels in individuals.

However, both these types of drugs suffer from serious drawbacks which outweigh their advantages. For example, niacin administration, inter alia, suffers from the serious problem of cutaneous flushing, while HMG-CoA run the risk of inducing hepatotoxicity, myopathy and rhabdomyolysis, as reported widely m various literatures.

Based on this, there was a need to develop lipid-altering or hypolipidemic pharmaceuticals and methods of delivering said pharmaceuticals which would try to overcome albeit some of the drawbacks of the individual category of drugs and provide patients with balanced lipid alteration. This propagated into the development and marketing of the combination comprising niacin and HMG-CoA reductase inhibitors and among them is the combination comprising niacin and lovastatin.

Niacin and lovastatin combination is approved and marketed in the United States and other countries as Advicor .

There are several prior arts, as discussed below, which disclose and cover various compositions and processes for preparation of said combination of niacin and lovastatin.

U.S. Application No. 2005/0255158 disclose compositions comprising nicotinic acid and hydroxypropyl methylcellulose in the form of an extended or sustained release tablet or caplet coated with a coating comprising an HMG-CoA reductase inhibitor in immediate

U.S. Patent No. 6469035 also discloses sustained release compositions comprising nicotinic acid and/or nicotinic acid compounds which are preferably coated with an HMG-CoA reductase inhibitor for immediate release for oral administration.

PCT Publication No. WO 2007/069827 discloses coated bi-layer tablet comprising a sustained release layer containing nicotinic acid and its derivatives or mixtures thereof, together with a sustained release polymer and another fast release layer containing a HMG-CoA reductase inhibitor, a film- or layer- forming agent, a recrystallization inhibitor and a plasticizer.

PCT Publication No. WO 2008/146178 discloses tablet dosage form comprising a first layer comprising a tablet of one or more active pharmaceutical ingredients, wherein the tablet is inlayed in the first layer with one or more other pharmaceutically acceptable excipients; and a second layer comprising one or more active pharmaceutical ingredients and optionally other pharmaceutically acceptable excipients.

The present inventors hereby disclose a novel solid pharmaceutical composition in the form of tablet which is prepared by compression-coating technique. The compression coating makes the formulations easier to handle and less expensive to produce compared to film coated tablets. The processing and machinery used for compression coating are faster and can run at higher capacity than that used for film coating.

SUMMARY AND OBJECTIVES OF THE INVENTION

The present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and a HMG-CoA reductase inhibitor.

Particularly, the present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and HMG-CoA reductase inhibitor, which is prepared by compression-coating technique.

More particularly, the present invention provides for a compression-coated oral solid pharmaceutical composition comprising a combination of niacin and lovastatin.

In an embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin.

In an embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet prepared by compression-coating technique.

In an another embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet prepared by compression-coating technique, wherein niacin is present in an extended release form while lovastatin is present in an immediate release form.

In an another embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet prepared by compression-coating technique, wherein niacin is present in an immediate release form while lovastatin are present in an extended release form.

In an another embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet which is prepared by compression-coating technique, wherein both niacin and lovastatin are present in an immediate release form, in an another embodiment of the invention, there is provided an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet which is prepared by compression-coating technique, wherein both niacin and lovastatin are present in an extended release form.

In a further embodiment of the invention, there is provided a process of preparing an oral solid pharmaceutical composition comprising a combination of niacin and lovastatin prepared by compression-coating technique.

In a further embodiment of the invention, there is provided for the oral solid pharmaceutical composition comprising a combination of niacin and lovastatin in the form of tablet, prepared by compression-coating technique, wherein the in vitro dissolution release profile matches with the commercially available ADVICOR™.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and a HMG-CoA reductase inhibitor.

Particularly, the present invention relates to oral solid pharmaceutical compositions comprising a combination of niacin and HMG-CoA reductase inhibitor, which is prepared by compression-coating technique.

More particularly, the present invention provides for a compression-coated oral solid dosage form comprising a combination of niacin and lovastatin.

In the context of the present invention, the terms like "active" or "active ingredient" or "drug" or "drug substance" or "pharmacologically active agent" or "active substance" may be used interchangeably and synonymously for niacin or lovastatin or both.

The term "niacin" as used herein shall refer to nicotinic acid, 3-pyridinecarboxylic acid, vitamin B3, and all derivatives thereof in whatever form as is known in the art (including all pharmaceutically acceptable salts of any of the foregoing). Of these, niacin either alone or in combination with other nicotinic acid derivatives, can function as the niacin component of the combination drug of the invention.

The term "HMG-CoA reductase inhibitors" as used herein refers to include the family of statins. Examples of statins include fluvastatin, cerivasatin, mevastatin, pitavastatin, pravastatin, simvastatin, lovastatin, atorvastain, rosuvastatin, as well as any others which may be known in the art (including all pharmaceutically acceptable salts of any of the foregoing). Any of the foregoing, either alone or in combination, can function as the HMG-CoA reductase inhibitor component of the combination drug of the invention.

The term "compression-coating" as used here in refers to the technique of preparing a tablet dosage form, wherein a tablet is inlayed within an another tablet or it also refers to a solid core comprising the active ingredient, which solid core is substantially covered with a compression coating. It may be used interchangeably and synonymously for "press-coated", "inlay-tablets", "tablet-in-tablef and the like.

Pharmaceutical composition comprising combination of niacin and HMG-CoA reductase inhibitor can be formulated as pharmaceutical compositions for oral administration in the form of tablets, capsules, pills, powders, granules, particles, pellets, beads, or mini-tablets. Preferably the composition is in the form of tablets.

A preferred embodiment of the present invention comprises a solid oral pharmaceutical composition in the form of a tablet comprising an immediate release HMG-CoA reductase inhibitor component in one tablet (also called as over-coat) prepared by the technique of compression-coating over an extended release niacin component in an another tablet (also called as core tablet).

The core tablet comprises an active ingredient and any other pharmaceutically acceptable carriers or excipients. The excipients or carriers are selected from the group comprising rate-controlling ingredients, fillers/diluents, stabilizers, lubricants, glidants, colorants and other customary ingredients well known in the art. It may further include other components which are necessary to meet appropriate drug release characteristic and/or for manufacturing purposes, such as binders, surfactants, wetting agents and the likes.

The over-coat tablet surrounded/ covered over the core tablet comprises an active ingredient and any other pharmaceutically acceptable carriers or excipients. The excipients or carriers are selected from the group comprising diluents/fillers, binders, stabilizers, disintegrants, lubricants, ghdants, colorants and other customary ingredients well known in the art. It may further include other components which are necessary to meet appropriate drug release characteristic and/or for manufacturing purposes, such as surfactants, wetting agents, flavorants and the likes.

Rate-controlling ingredients are selected from the group consisting polymeric and non-polymeric substances. Polymeric substances may be selected from water-soluble and water-insoluble polymers. Water-soluble polymers are selected from the group consisting of cellulose and its derivatives, alginates.

polyols, polyethylene glycols, carbomer, carrageenans, pectins; chitosans; cyclodextrins; natural and synthetic gums, pyrrolidone derivatives and the likes. Water-insoluble polymers are selected from the group consisting of cellulose and its derivatives, methacrylates and its derivatives, shellac and the like. Non-polymeric substances may be selected from the group consisting of wax, stearic acid and its derivatives, cetyl alcohol, fatty acids and its derivatives, fats and lipids, and the like.

Fillers are selected from the group comprising microcrystalline cellulose (MCC), silicified MCC, lactose, starch, pre-gelatinized starch, mannitol, sorbitol, dextrates, dextrin, calcium carbonate, calcium sulfate, dibasic calcium phosphate dihydrate, tribasic calcium phosphate, magnesium carbonate, magnesium oxide and the like.

Binders are selected from the group comprising polyvinylpyrrolidone, cellulose derivatives such as hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, carboxy methyl cellulose sodium, starch and the likes.

Suitable disintegrants include sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, starch, calcium carboxymethlycellulose, croscarmellose sodium and the like.

Suitable lubricants include magnesium stearate, sodium stearate, calcium stearate, sodium stearyl fumarate, talc or silica and the like.

Stabilizers may be selected from the group comprising butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), propyl gallate, ascorbic acid, citric acid, edetate disodium and calcium metabisulphite, propyl gallate and combinations thereof.

A prefened embodiment of the present invention relates to a compression-coated tablet comprising a tablet core containing an effective amount of niacin and compression-coat comprising lovastatin surroxinded over the core tablet.

The extended release core tablet according to this invention, are prepared by forming a tablet-like matrix in which niacin is dispersed along with or within the rate-controlling ingredients and their mixture thereof, and/or granulating them suitably with the rate-controlling ingredients being solubilised in a suitable solvent system, to prepare the granules, compressing the granulates and other optional excipients into tablets and optionally coating this core tablet with a film/seal coat.

To form the tablet core, granulation techniques such as dry granulation or wet granulation is employed. In the dry granulation, the ingredients are blended in dry form, made denser by slugging or compaction and reduced to granules by grinding or milling, using suitable equipments. The ground particles or granules are then compressed into tablet form in conventional manner using lubricants, glidants, etc., which can take any of the conventional shapes, e.g., round, elongated, oval, etc.

The external-coat composition comprising lovastatin may be applied to the core by technique involving compressing-coating. The result is a layer of coating material comprising lovastatin around the core tablet. Since the coating is compressed around the core in a manner similar to that used to make a tablet, specialized tableting machinery is employed to compress the external coating over the core.

Depending on the principles of the compression-coating machinery, the core can be made in one tablet forming machine and then transferred to another tableting machine for application of the coat. The core may also be transferred to a compression-coating machine for the compression coating process. Alternatively the core can be made on one side of the machine, and instantaneously transferred to the other side of the machine for the application of compression coating. An example of this type of machinery is the Manesty DryCota tableting machine from Casburt Limited.

After the compression coating, the final solid dosage form includes the core tablet and the coating layer which covers or conceals the core tablet.

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

Example1

Brief Manufacturing Process:

Niacin Part:

1. Sift Niacin and lactose anhydrous through suitable mesh.

2. Disperse hydroxypropyl methylcellulose in water.

3. Granulate the blend of step 1 with the binder solution of step 2.

4. Dry the wet granules of step no.3 at suitable temperature.

5. Mill and sift the dried granules through a suitable mesh and blend.

6. Add the sifted stearic acid to the blend of step 5 and blend for suitable time.

Lovastatin Part:

7. Sift Lovastatin, lactose monohydrate, ascorbic acid, citric acid through a suitable sieve.

8. Dissolve BHA in IPA and add this solution slowly into the water.

9. Granulate the blend of step 7 with the solution of step 8.

10. Dry the wet granules of step no.9 at suitable temperature.

11. Mill and sift the dried granules through a suitable mesh.

12. Add the sifted magnesium stearate to the blend of step 11 and blend for suitable time.

13. Compress the blend of step 6 and blend of step 12 into a tablet in tablet in a compression-coating tablet machine.

Example 2

Brief Manufacturing Process:

Niacin Part:

1. Sift Niacin and Lactose anhydrous through suitable mesh.

2. Disperse hydroxypropyl methylcellulose in water.

3. Granulate the blend of step I with the binder solution of step 2.

4. Dry the wet granules of step no,3 at suitable temperature.

5. Mill and sift the dried granules through a suitable mesh and blend.

6. Add the sifted stearic acid to the blend of step 5 and blend for suitable time.

Lovastatin Part:

7. Sift Lovastatin, lactose monohydrate, ascorbic acid, citric acid through a suitable sieve.

8. Dissolve BHA in IPA and add this solution slowly into the water.

9. Granulate the blend of step 7 with the solution of step 8.

10. Dry the wet granules of step no.9 at suitable temperature.

11. Mill and sift the dried granules through a suitable mesh.

12. Add the sifted magnesium stearate to the blend of step 11 and blend for suitable time.

13. Compress the blend of step 6 and blend of step 12 into a tablet in tablet in a compression-coated tablet machine.

Dissolution Studies:

Dissolution studies were carried out as per the dissolution conditions given below:

For Niacin:

Media: Purified water.
Volume: 900ml,
Apparatus: USP Dissolution Apparatus Type I,
Rotational Speed: l00rpm

For Lovastatin:

Media: pH 7.0 phosphate buffer with 0.5% SLS,
Volume: 900ml,
Apparatus: USP Dissolution Apparatus Type I,
Rotational Speed: l00rpm

Media: pH 4.5 Acetate buffer with 0.1% SLS,
Volume: 900ml,
Apparatus: USP Dissolution Apparatus Type I,
Rotational Speed: 50rpm

Comparative dissolution profile of niacin /lovastatin l000/40mg tablets according to the present invention and the commercially available Advicor TM 1000/40mg tablets are shown in Table 1,2 & 3.

Table 1

Table 2

Table 3

CLAIM:

1. A compression-coated solid dosage form comprising a combination of an effective amount of nicotinic acid, and an effective amount of HMG-CoA reductase inhibitor, with one or more pharmaceutically acceptable excipient.

2. The compression-coated solid dosage form according to claim 1, wherein said HMG-CoA reductase inhibitor comprises a statin.

3. The compression-coated solid dosage form according to claim 2, wherein said statin is selected from the group comprising lovastatin, pravastatin, fluvastatin, atorvastatin, pitavastatin and simvastatin.

4. The compression-coated solid dosage form according to claim 3, wherein said statin is lovastatin.

5. The compression-coated solid dosage form according to claim 1, wherein said pharmaceutically acceptable excipient is selected from a group comprising fillers, diluents, binders, rate-controllmg polymers, stabilizers, lubricants, glidants, colorants and combinations thereof.

6. The compression-coated solid dosage form according to claim 1, wherein said solid dosage form is a tablet.

7. A compression coated tablet for once-a-day administration comprising;

a. an immediate release component containing about 40 mg of at least one HMG CoA reductase inhibitor; and

b. an extended release component containing about 1000 mg of niacin.

8. A process for preparing a compression-coated tablet comprising an effective amount of nicotinic acid and an effective amount of HMG-CoA reductase inhibitor; wherein said process comprises:

a. wet-granulating nicotinic acid and other pharmaceutically acceptable excipient with a binder solution to get granules;

b. drying, milling and lubricating said granules;

c. separately wet-granulating lovastatin and other pharmaceutically acceptable excipient with a binder solution to get granules;

d. drying, milling and lubricating said granules; and

e. compressing said granules obtained in (b) and (d) in a compression-coated tablet machine to get the said compression-coated tablet.