EP2464344A2

EP2464344A2 - Pharmaceutical tablet comprising rosuvastatin calcium

Info

Publication number: EP2464344A2
Application number: EP10739873A
Authority: EP
Inventors: Marta Vivancos
Original assignee: Synthon BV
Current assignee: Synthon BV
Priority date: 2009-08-13
Filing date: 2010-07-29
Publication date: 2012-06-20
Also published as: WO2011018185A2; EA201270269A1; WO2011018185A3; AU2010281913A1

Abstract

The invention relates to a tablet comprising: i) a compressed core, which comprises rosuvastatin calcium, a dibasic calcium phosphate, and at least one pharmaceutically acceptable excipient; and ii) moisture barrier layer around said core, which comprises a polyvinylalcohol, to a process for making the tablet and use in medicine.

Description

PHARMACEUTICAL TABLET COMPRISING ROSUVASTATIN

CALCIUM

The present invention relates to pharmaceutical tablets comprising the active agent rosuvastatin calcium.

Background of the Invention

Rosuvastatin, (3R,5S,6E)-7-(4-(4-fluorophenyl)-6-(l-methylethyl)-2- (methyl(methylsulfonyl)amino)-5-pyrimidinyl)-3,5-dihydroxy-6-heptenoic acid of the formula (I)

(I)

is a pharmaceutically active compound that acts as a competitive inhibitor of 3-hydroxy- 3-methylglutarylcoenzyme A reductase (HMG CoA reductase). The compound is purported to be useful in the treatment of hypercholesterolemia, hyperlipidemia, mixed dyslipidaemia and atherosclerosis. Rosuvastatin was disclosed in EP 521471 and US 5,260,440 (reissued as RE37,314) by Shionogi Seiyaku Kabushiki Kaisha. Rosuvastatin is marketed as a calcium salt by AstraZeneca under the brand name CRESTOR®.

EP 1223918 and US 6,316,460 indicate that rosuvastatin undergoes degradation under certain conditions, which can make formulating a stable pharmaceutical composition difficult. Specifically, EP 1223918/US 6,316,460 teach that the major degradation products are the corresponding (3R, 5S) lactone and an oxidation product, in which the hydroxy group adjacent to the carbon-carbon double bond is oxidized to a ketone. These patents purport to reduce these degradation products by the use of tribasic phosphate salts; e.g., tribasic calcium phosphate, tribasic magnesium phosphate or tribasic aluminium phosphate. Two examples show that a formulation comprising tribasic calcium phosphate has reduced levels of these degradation products in comparison to a composition comprising dibasic calcium phosphate. Specifically, Example 1 reports that a 2.5 mg direct compression tablet containing tribasic calcium phosphate developed only 0.50% lactone after 1 week at 7O⁰C under 80% humidity whereas replacement of the tribasic with dibasic calcium phosphate resulted in 15.61% lactone. In example 4, where tablets are compressed after wet granulation and fluid bed drying, replacement of the tribasic with dibasic calcium phosphate results in 28.15 % lactone after 1 week 7O⁰C at 80% humidity compared to 0.28 %. All of the tablets in these examples are uncoated.

These patents also disclose examples of tablets comprising rosuvastatin calcium and tribasic calcium phosphate, which are coated by a hydroxypropyl methylcellulose film coating. Comparative data, however, was not provided. The marketed CRESTOR® tablets apparently incorporated the invention of EP 1223918/US 6,316,460 and are film coated tablets which are purported to have the following composition:

a) in the core : rosuvastatin calcium

lactose monohydrate

microcrystalline cellulose

tribasic calcium phosphate

crospovidone

b) in the film coating : hydroxypropylmethylcellulose

lactose monohydrate

triacetin

titanium dioxide

iron oxide

It would be desirable to find alternative techniques for controlling the degradation issues associated with rosuvastatin.

Summary of the Invention

The present invention relates to a pharmaceutical tablet comprising rosuvastatin calcium and a dibasic calcium phosphate that is adequately protected by a suitable moisture barrier layer. Accordingly, a first aspect of the invention relates to a tablet comprising i) a compressed core, which comprises rosuvastatin calcium, a dibasic calcium phosphate, and at least one pharmaceutically acceptable excipient; and ii) moisture barrier layer around said core, which comprises a polyvinyl alcohol. The polyvinyl alcohol can be partially hydrolyzed. The barrier layer can contain other ingredients including pigments and dyes. Generally the barrier layer coating weight is from 2 to 7%, more typically 3 to 6% the weight of the compressed core. Although the compressed core contains a dibasic calcium phosphate, preferred tablets of the invention have stability that is similar or superior to the commercial CRESTOR® coated tablets.

Another aspect of the invention relates to a process for making a stable pharmaceutical tablet comprising rosuvastatin calcium which comprises:

a) compressing a tablet blend, which comprises rosuvastatin calcium, a dibasic calcium phosphate, and at least one pharmaceutically acceptable excipient, to form a compressed core; and

b) coating said compressed core with a moisture barrier layer comprising a polyvinyl alcohol.

Another aspect of the invention relates to the use acts as a competitive inhibitor of 3-hydroxy-3-methylglutarylcoenzyme A reductase (HMG CoA reductase) in medicine, such as in the treatment of hypercholesterolemia, hyperlipidemia, mixed dyslipidaemia and atherosclerosis

Detailed Description of the Invention

The present invention is based on the discovery that a sufficient moisture barrier layer around a rosuvastatin tablet can minimize degradation, especially the formation of the lactone degradation product. This moisture barrier layer can permit the use of dibasic calcium phosphate in forming a tablet with good storage stability, despite the admonition to avoid dibasic calcium phosphate shown in EP 1223918/US 6,316,460.

The moisture barrier layer used in the present invention generally contains a polyvinyl alcohol. As used herein, a polyvinyl alcohol includes hydrolyzed, such as partially hydrolyzed polyvinyl alcohol, as well as unhydrolyzed forms. The moisture barrier layer can contain, and typically does contain, additional excipients as is conventional in the art. Typically such excipients may include a plasticizer, a lubricant, a filler, and/or a colorant. Examples of such excipients include talc, lecithin, triacetin, xanthan gum, lactose monohydrate, titanium dioxide, and iron oxide. The polyvinyl alcohol generally accounts for at least 15% and more typically at least 20% of the moisture barrier layer, by weight.

In a preferred embodiment, the moisture barrier layer contains a colorant. A colorant can be useful in protecting the rosuvastatin from photodegradation. Colorant is used in a broad sense to embrace coloring materials as well as opacifiers and includes pigments and/or dyes. The dye can be in free form or associated with a substrate, i.e., in "lake" form. Typically one or more pigments, e.g., metal oxides such titanium dioxide and/or iron oxide(s), are contained in the moisture barrier layer, optionally with one or more dyes.

The moisture barrier layer can be formed from commercially available products such as Colorcon's OPADRY® II 85-series (a PVA-based coating) or OP ADR Y® amb (Aqueous Moisture Barrier); the latter being a preferred barrier material.

The moisture barrier layer is generally applied to a weight of 2 to 7%, preferably 3 to 6%, of the weight of the compressed core, e.g., the uncoated tablet.

Although the invention has been described in terms of a polyvinyl alcohol-based moisture barrier layer, it is contemplated that other sufficiently moisture proof coatings may also work in the invention. Such coatings include enteric coatings (e.g. coatings that contain enteroresistant polymers) and non-enteric coatings (e.g. enterosoluble coatings); the latter being preferred. Suitable polymers may include polymethacrylates and copolymers thereof, and polyvinylacetates including esters thereof such as

polyvinylacetate phthalates. Such polymers may be used instead of, or in addition to, polyvinyl alcohol in the moisture barrier layer. In this regard, hydroxypropyl

methylcellulose-based coatings generally provide insufficient moisture barrier resistance for purposes of the present invention and thus are not a suitable replacement for polyvinyl alcohol. Any of the above-mentioned polymers can be used in combination with polyvinyl alcohol.

The moisture barrier layer is coated on a compressed core that contains rosuvastatin calcium, a dibasic calcium phosphate, and at least one pharmaceutically acceptable excipient. The compressed core tablet typically contains from 1 to 100 mg of rosuvastatin calcium (expressed in terms of the weight of rosuvastatin base), particularly 5, 10, 15, 20, or 40 mg of rosuvastatin calcium. The conventional pharmaceutically acceptable dibasic calcium phosphate is either an anhydrate or a dihydrate. Either or both forms may be used in making the compositions of the present invention. Advantageously, however, the dibasic calcium phosphate is an anhydrous form, i.e. with a water content of 2 weight % or less.

Typically, the rosuvastatin calcium is present in an amount from 3 to 15 weight per cent and the dibasic calcium phosphate is present in an amount from 6 to 10 weight per cent, based on the total weight of the compressed core. More particularly, the ratio between the rosuvastatin calcium and the dibasic calcium phosphate is typically between 0.5:1 and 1.5: 1 by weight. The remaining excipients in the compressed core typically total from 75 to 89 weight per cent. Pharmaceutically acceptable excipients typically include binders, diluents or fillers, lubricants, and/or disintegrants. A particular excipient may act both as a binder and a diluent, or both as a binder and a disintegrant, etc. Examples of binders include polyvinylpyrrolidone, lactose, starch, modified starch, waxes, cellulose, and modified cellulose (methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose, or hydroxypropylmethyl cellulose). Examples of diluents include calcium phosphates, lactose, mannitol, sorbitol, xylitol, starch, a modified starch, cellulose, a modified cellulose, etc. Suitable lubricants include, for example, magnesium stearate, stearic acid, talc, calcium stearate, hydrogenated castor oil, sodium stearyl fumarate. Typical disintegrants include sodium starch glycolate and crosspovidone.

Additional conventional excipients include preservatives, colorants, flow conditioners, etc. The list of inert excipients presented above is not exhaustive; other suitable excipients may be found, e.g., in Handbook of Pharmaceutical Excipients edited by Arthur H. Kibbe, 3rd Edition, American Pharmaceutical Association.

In a typical preferred embodiment of the invention, the compressed core comprises rosuvastatin calcium; a dibasic calcium phosphate; a binder such as microcrystalline cellulose; a water-soluble diluent such as lactose (including lactose monohydrate), mannitol, sorbitol, or xylitol; a disintegrant such as crosspovidone; and a lubricant such as magnesium stearate.

Though not required, it is often advantageous that the total amount of water present in the compressed core prior to applying the moisture barrier layer, is less than 6.0%, measured as the loss on drying or by K. Fischer method. Additionally, while a pH- adjustor (i.e. an acid, a base and/or a salt thereof) can be present in the compressed core, it is an advantage of the invention that such an excipient is not required and is preferably omitted from the composition.

The tablets of the present invention can be made by conventional techniques known in the art. In general, the active substance and the excipients are formed into a tablet blend which is then compressed to form a tablet. This tablet serves as the compressed core of the present invention. The tablet blend can be made by any convenient method. For example, the active substance and at least one pharmaceutically acceptable excipient are, after optional sieving, blended together in one or more steps. After any blending step, the blend is optionally screened. Typically a lubricant such as magnesium stearate is added in the last blending step, as is common in the art, to form the final tablet blend; i.e., a powder blend that contains all the ingredients of the compressed core in a homogeneous mixture. The tablet blend is then compressed into a tablet which is then used as the compressed core of the present invention.

Alternatively, a wet granulation technique may be used in making the tablet blend. For example, the active substance and at least one excipient are, after optional sieving, blended together in a granulator and then granulated with a small volume of purified water. Typically the granulate includes a dibasic calcium phosphate as well as a diluent and/or binder. The granulate is dried and typically passed through a mill and/or sieved. Lubricant and, optionally, all or part of a disintegrant are blended with the granulate, and the obtained homogeneous mixture is compressed into tablets.

The tablets are subsequently coated with a polyvinyl alcohol-containing composition to form the moisture barrier layer. Optionally a sub-coat may be applied before forming the moisture barrier layer, but such a sub-coat is generally avoided in tablets of the invention. The coating of the tablet cores can be performed by any suitable technique including the conventional techniques of spray coating and pan coating.

Typically the coating step involves applying an aqueous or non-aqueous solution or suspension of polyvinyl alcohol and auxilliary excipients onto the tablets and drying to form a moisture barrier layer around a compressed core.

The tablets may be packed in a suitable package material, preferably in a blister package, to provide the final dosage form for administration of rosuvastatin by patients in need thereof.

The invention is further illustrated by some non-limiting examples.

Example 1

Rosuvastatin calcium tablet of 5 mg strength

Composition:

Opadry® AMB is a combination of Polyvinyl alcohol - part, hydrolyzed, Titanium dioxide, Talc, Lecithin (soya), Xanthan gum, iron oxide yellow

Process:

A pre-mixture of rosuvastatin calcium and microcrystalline cellulose (ratio 1 :5 aprox) was made in a tumbling blender. The pre-mixture was sieved through 0.5 mm mesh and also a part of the lactose (approx. half of the lactose) was sieved to drag the remainder of the drug substance. After the de-agglomeration step, the rest of the excipients were added to the blend, except Mg stearate, and mixed for 30 min in a free fall blender. Finally, Mg stearate was added and mixed for 5 min. The lubricated blend was compressed in a tablet press.

A 15 % ( w/w) suspension of Opadry® AMB Yellow in purified water was prepared. Tablet cores were transferred into t a standard perforated pan system and coated with the suspension of Opadry® AMB Yellow to a theoretical weight gain of 4%.

Examples 2-5

Rosuvastatin calcium tablets of 10, 15, 20 and 40 mg strengths

Composition:

' Opadry® AMB is a combination of Polyvinyl alcohol - part, hydrolyzed, Titanium dioxide, Talc, Lecithin (soya), Xanthan gum, iron oxide red, FD&C yellow #6/Sunset yellow FCF, Aluminium lake, iron oxide yellow.

Process:

A pre-mixture of rosuvastatin calcium and microcrystalline cellulose (ratio 1 :2 aprox) was made in a tumbling blender. The pre-mixture was sieved through 0.5 mm mesh and also a part of the lactose (approx. half of the lactose) was sieved to drag the remainder of the drug substance. After the de-agglomeration step, the rest of the excipients were added to the blend, except Mg stearate, and mixed for 30 min in a free fall blender. Finally, Mg stearate was added and mixed for 5 min. The lubricated blend was compressed in a tablet press.

A 15 % (w/w) suspension of Opadry® AMB Pink in purified water was prepared. Tablet cores were transferred into a standard perforated pan system and coated with the suspension of Opadry® AMB Pink to a theoretical weight gain of 4%.

Example 6

Rosuvastatin tablets were prepared containing dibasic calcium phosphate dihydrate and coated with various coatings; namely Opadry II 31 K32626 (HPMC-based coating same composition as CRESTOR®), Opadry AMB (moisture barrier coating system, based on PVA) and Opadry ns-g (based on CMC Na). Each coating was applied to achieve 4% weight gain. The tablet composition was as follows:

Opadry AMB

Opadry ns-g

The coated tablets were put in stability at 70°C/80% RH for two weeks, in open dish. The lactone content, both initially and at the conclusion of two weeks, is shown below as percentage of the active.

The use of polyvinyl alcohol (PVA), which is a superior moisture barrier to

hydroxypropyl methylcellulose (HPMC) and sodium carboxymethyl cellulose (CMC- Na), provided the best stability. Indeed, though dibasic, and not tribasic, calcium phosphate was used in the tablet core, the tablets showed lactone stability that was similar to, or even superior to, CRESTOR® when tested under similar conditions.

Each of the patents and patent applications mentioned above are incorporated herein by reference. The invention having been described it will be obvious that the same may be varied in many ways and all such modifications are contemplated as being within the scope of the invention as defined by the following claims.

Claims

CLAIMS 1. A tablet comprising :i) a compressed core, which comprises rosuvastatin calcium, a dibasic calcium phosphate, and at least one pharmaceutically acceptable excipient; and ii) moisture barrier layer around said core, which comprises a

polyvinylalcohol.

2. The tablet according to claim 1, wherein said barrier layer further comprises a pigment.

3. The tablet according to claims 1 and 2, wherein said polyvinylalcohol is partially hydrolyzed.

4. The tablet according to claims 1 - 3, wherein said barrier layer has a weight of 2-7%, preferably 3-6%, of the weight of the compressed core.

5. The tablet according to claims 1- 4, wherein said dibasic calcium phosphate is anhydrous.

6. The tablet according to claim 1 - 5, wherein said core further comprises a water-soluble diluent, such as lactose.

7. The tablet according to claims 1 - 6, wherein said core further comprises microcrystalline cellulose.

8. The tablet according to claims 1 - 7, wherein said dibasic calcium phosphate is present in said core in an amount from 6 to 10 weight %.

9. The tablet according to the claims 1-8, wherein the compressed core comprises less than 6.0 % of water.

10. The tablet according to the claims 1 - 9, wherein said rosuvastatin calcium is present in said core in an amount from 3 to 15 weight %.

1 1. The tablet according to the claims 1-10, wherein said core comprises from 1 to

100 mg of rosuvastatin, particularly 5, 10, 15, 20, or 40 mg of rosuvastatin.

12. A process for making a stable pharmaceutical tablet comprising rosuvastatin calcium which comprises:

b) coating said compressed core with a moisture barrier layer comprising a polyvinylalcohol.

13. The process according to claim 12, wherein said coating provides a moisture barrier layer having a weight of 2-7%, preferably 3-6%, of the weight of the compressed core.

14. The process according to claims 12 and 13, wherein said tablet blend comprises a water soluble diluent such as lactose, anhydrous dibasic calcium phosphate, and microcrystalline cellulose.

15. The tablet according to claim 1 - 1 1, for use in medicine.