WO2001024778A1

WO2001024778A1 - Anti-inflammatory pharmaceutical formulations

Info

Publication number: WO2001024778A1
Application number: PCT/GB2000/003729
Authority: WO
Inventors: Austen John Woolfe
Original assignee: Norton Healthcare Ltd.
Priority date: 1999-10-01
Filing date: 2000-09-29
Publication date: 2001-04-12
Also published as: CA2387288A1; AU7537000A; JP2003510347A; EP1216030A1; KR20020063871A

Abstract

An oral pharmaceutical dosage form including a mixture of a delay release formulation of a non-steroidal anti-inflammatory drug (NSAID) and a mixture containing a prostaglandin and one or more excipients.

Description

ANTI- INFLAMMATORY PHARMACEUTICAL FORMULATIONS

This invention relates to pharmaceutical formulations of anti -inflammatory drugs, particularly non-steroidal anti- inflammatory drugs (NSAIDs) .

These NSAIDs are used for the treatment of inflammatory conditions such as osteoarthritis or rheumatoid arthritis. A side effect of the oral administration of NSAIDs particularly with long term usage, is a liability to ulcerogenic effects . NSAID induced ulcers in the stomach are potentially dangerous because few or no symptoms may be detected until significant damage has been caused. Certain prostaglandins , for example misoprostol have been shown to reduce and even prevent such ulcers .

Various patent applications relate to use of misoprostol with immediate release drugs, for example GB-A- 2135881 (Farmitalia Carlo Erba) , 091/16896 (G D Searle) , or where a gastric resistant coating is put over the NSAID in an attempt to reduce further gastric erosion due to release in the stomach of the NSAID, for example 091/16895, 091/16886 (G D Searle) .

There is an increasing use of sustained release preparations of NSAID drugs to reduce the number of doses required by the patient each day. Although the theory of such preparations is that the majority of the drug is released in the intestine rather than the stomach, in practice there is a significant occurrence of gastric problems. This may be due to release of small amounts of drug within the stomach.

The incorporation of misoprostol into such products to reduce the potential for such problems has not previously been disclosed. According to the present invention an oral pharmaceutical dosage form includes a mixture of a delay release formulation of a NSAID and a mixture containing one or more excipients and a prostaglandin, wherein the delay release NSAID formulation preferably comprises coated granules .

The prostaglandin mixture may be provided in the form of a powder which is mixed with the NSAID formulation within the dosage form.

The dosage form may comprise a tablet, capsule, granule or other commonly used configuration. However preferred dosage forms comprise a capsule containing multi-particulate granules of the NSAID formulation together with the powdered prostaglandin mixture. The NSAID granules preferably have coatings adapted to provide programmed release according to the position in the gastrointestinal tract. Use of such coated granules provides a more repeatable release along the gastrointestinal tract and may reduce gastric erosion because the small pellets or granules are easily moved and do not adhere readily to the folds of the gastric wall .

Granules for use in accordance with this invention may have a single slowly erodible coat or may comprise mixtures of granules with differing levels or types of coating adapted to provide a continuous or distributed release profile through the gastrointestinal tract . The delay afforded may range from a minimal delay to several hours, dependent on the pH of the gastrointestinal tract in the immediate vicinity.

The NSAID is preferably but not exclusively one of reasonably low weight per standard dose, that is 200 mg or below. Examples of suitable NSAIDs include tiaprofenic acid, piroxicam, flubiprofen, tenoxicam, meloxicam or similar molecules. Salts or other derivatives of these drugs may be employed in a conventional manner. Most preferably the drug is diclofenac sodium, ketoprofen or indomethacin. Mixtures may be used.

Drug delivery using capsules avoids a further compression step as may be necessary during tablet manufacture .

Granules, for example composed of diclofenac sodium and a methyl methacrylate (eg Eudragit L 30 D-55) may be prepared by blending the ingredients in a planetary mixer with slow addition of water to produce granules. In a preferred process very fine granules are produced to avoid a need for milling before compaction into tablets or incorporation into capsules. Use of granules with the dimension of 200 - 1000 μm, preferably 300 to 500 μm is particularly suitable. Tablets may be produced by coating these granules with a barrier coating material for example a cellulosic material such as hydroxypropylmethyl cellulose or hydroxypropyl cellulose. Tablets may be produced by coating these granules .

An alternative method of forming coated granules is by spraying a solution of Eudragit onto a bed of diclofenac sodium or other drug and any necessary excipients for example using a fluid bed coating apparatus. The process is preferably controlled to produce fine granules which do not require milling before incorporation into tablets or capsules .

The coating for the granules may include cellulose derivatives eg hydroxypropyl methyl cellulose, methacrylic acid and derivatives eg methyl methacrylates for example, Eudragrit^® (Rhom Pharm) , especially Eudragrit L or S . Other standard enteric coating materials may be used for example phthalates, eg cellulose acetate phthalate or preferably hydroxypropylacetate phthalate or polyvinylacetate phthalate. Mixtures of these and other materials may be used to produce delay release coated beads. Normally the coating will include plasticisers eg polyethylene glycol, triacetin or phthalate esters.

The prostaglandin component preferably contains misoprostol optionally together with one or more inert excipients. The prostaglandin is normally provided as a 1:10 or 1:100 dilution on an inert cellulose or other binder or filler. Especially useful material for this invention is hydroxypropyl methyl cellulose. The dosage of prostaglandin may be chosen to be suitable to prevent or reduce stomach ulceration caused by the NSAID. A suitable dose of misoprostol is between 10 - 50 μg preferably 50 - 200 μg per dosage form but this may be increased or decreased depending on the NSAID used.

Preferred dosage forms comprise capsules, preferably hard gelatin capsules.

Tablets where the prostaglandin is mixed with one or more binding agents may be bi-layer tablets wherein the NSAID is formed into a first layer and the prostaglandin is then compressed onto it. A tri- layer tablet with an inert intermediate barrier layer between the NSAID and prostaglandin layers may be employed.

In preferred embodiments of the invention, the potential for gastric erosion is reduced by ensuring that the prostaglandin is released before the NSAID. Any beads for immediate or rapid release are coated with an inert coating which defer solubility in gastric fluid, for example for a period of 30 minutes. Such materials include cellulose derivatives for example hydroxypropyl methyl cellulose, methyl or ethyl celluloses or other sealants eg Zein. Thin coatings of methacrylate derivatives eg polyhydroxymethacrylate or other materials such as hardened gelatine, waxes, starches or polyvinyl pyrrolidone may be used. Other portions of the granules may be coated with methacrylate derivatives, phthalate, for example hydroxypropyl methyl cellulose phthalate or similar materials to give an appropriate release profile as is well known in the art .

The invention is further described by means of example, but not in any limitative sense.

Example 1

The following formulation was mixed with water in a planetary mixer to make enteric coated granules :

diclofenac sodium 96.2%

Eudragit L 30 D-55 3.8%

The granules were dried and compacted into layered tablets having the following composition:

diclofenac-containing granules 26.0% microcrystalline cellulose 73.5% magnesium stearate 0.5%

The tablets were compared to a proprietary diclofenac- containing tablet available under the trade mark Arthrotec. Bioequivalence studies showed the release of diclofenac to be essentially similar.

Granules containing 35% diclofenac sodium ie 75 mg drug per dose were prepared. EXAMPLE 2

A two layer tablet was made as follows:

The following ingredients were mixed together:

Diclofenac sodium 75.95%

Eudragit 130-d55 (30% solid dispersion) 12.66%

Lactose (20 mesh) 11.4% Water

The mixture was blended, dried and milled to give diclofenac-containing granules. The granules (25%) were mixed with microcrystalline cellulose (Avicel pH 200 and pH 112) to give a total of 69%. Dry Eudragit 1100 powder (5%) and hydrogenated castor oil (1%) were added. The mixture was pressed into half tablets with a tablet weight of 400 mg.

A misoprostol layer was formed as follows:

A misoprostol dispersion (1:100) 6.7% was combined with microcrystalline cellulose (Avicel pH 112) 88.33%, croscarmelose sodium (4%) and hydrogenated castor oil to give a tablet weight of 300 mg . The combined bi- layered tablet had a total weight of 700 mg .

Dissolution properties were determined by exposure to acid medium for two hours followed by measurement of dissolution in alkaline buffer. The following results were obtained.

Claims

1. An oral pharmaceutical dosage form including a mixture of a delay release formulation of a non-steroidal anti-inflammatory drug (NSAID) and a mixture containing a prostaglandin and one or more excipients; wherein the NSAID formulation comprises coated granules.

2. A dosage form as claimed in claim 1, wherein the granules have a dimension of 200 - 1000 μm.

3. A dosage form as claimed in claim 2, wherein the granules have a dimension of 300 - 500 μm.

4. A dosage form as claimed in any preceding claim, wherein the prostaglandin is misoprostol.

5. A dosage form as claimed in any preceding claim, wherein the mixture is a powder comprising prostaglandin absorbed on an inert substance .

6. A dosage form as claimed in any preceding claim, comprising a capsule containing multi-particulate granules of the NSAID formulation together with the powdered prostoglandin mixture .

7. A dosage form as claimed in any preceding claim, comprising a mixture of granules with different levels or types of coating.

8. A dosage form as claimed in any preceding claim, wherein the NSAID is selected from the group consisting of tiaprofenic acid, piroxicam, flubiprofen, tenoxicam, meloxicam and salts and derivatives thereof.

9. A dosage from as claimed in claim 8, wherein the NSAID is selected from the group consisting of diclofenac sodium, ketoprofen and indomethacin and mixtures thereof.

10. A dosage form as claimed in any of claims 1 to 9, wherein the dosage of misoprostol is 50 to 200 μg per dosage form.

11. A dosage form as claimed in any preceding claim, wherein the granules have a coating of one or more compounds selected from the group consisting of: hydroxypropyl methyl cellulose, methacrylic acid and derivatives, methyl methacrylates, cellulose acetate phthalate, hydroxypropylacetate phthalate, polyvinylacetate phthalate and mixtures thereof .

12. A dosage form as claimed in claim 11, wherein the coating includes a plasticiser selected from the group consisting of: polyethylene glycol, triethyl acetate or phthalate esters .

13. A dosage form comprising a filled hard gelatin capsule containing a dosage form as claimed in any preceding claim.

14. A dosage form as claimed in any of claims 1 to 12, comprising a bi-layer or tri-layer tablet.

15. A dosage form as claimed in claim 14, wherein granules of the NSAID are coated with a coating selected from the group consisting of: hydroxypropyl methyl cellulose, methacrylic acid and derivatives, methyl methacrylates , cellulose acetate phthalate, hydroxypropylacetate phthalate, polyvinylacetate phthalate and mixtures thereof are compressed into a first layer and a second layer comprising the prostaglandin and excipients is compressed onto the first layer.