GB2340038A - NSAID composition - Google Patents

Description

2340038 THERAPEUTIC AGENTS This invention relates to pharmaceutical

compositions comprising one or more substantially insoluble non-steroidal anti-inflammatory drugs, to uses thereof and to a process to make said composition.

The non-steroidal anti-inflammatory drugs, NSAIDs are well known medicaments with analgesic, anti-inflammatory and anti-pyretic properties.

Examples include ibuprofen, 2-(4-isobutylphenyl)propionic acid and flurbiprofen (2-(2-fluoro-4-biphenylyl)- propionic acid) which are usually sold in the form of the racernate (equal amounts of the S(+) and R(-) enantiomers). These active ingredients may also be in the form of the purified form of either enantiomer, especially the S(+)-enantiomer. These compounds are also available in salt form, for example the sodium or lysine salt. Racemic and S(+)-ibuprofen are available under prescription (eg Brufen (RTM) and Dexit 300mg (RTM)), primarily for the treatment of painful and anti-inflammatory disorders including rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, postoperative pain, post-parturn pain and soft tissue injuries, generally at doses of up to 3200mg per day. lbuprofen is also available as a non-prescription drug (eg Nurofen (RTM)), primarily for the treatment of symptoms of pain and fever including headache, migraine, rheumatic pain, muscular pain, backache, neuralgia, dysmenorrhoea, dental pain and colds and flu, generally at doses up to 1200mg per day. Compositions containing ibuprofen are usually provided in unit doses to give 200mg, 400mg, 600mg or 800mg ibuprofen. Flurbiprofen is currently available in the UK as a prescription drug under the trade name Froben (RTM) indicated for mild to moderate pain, headaches, dysmenorrhoea, post- operative pain, gout, back pain, pyrexia, rheumatoid disease, osteoarthritis, ankylosing spondylitits and acute muscoskeletal disorders, generally at doses up to 300mg per day. Other such NSAIDs include naproxen, ketoprofen, fenoprofen, indoprofen and fenbufen, eclotolac, diclofenac, piroxicam, mefanamic acid, 2 indomethacin and nabumetone and these vary in solubility from "sparingly soluble" to "practically insoluble" according to the definition in the British Pharmacopoeia.

In order to facilitate absorption it is desired that the active ingredients dissolve in the gastric and intestinal media. However, ibuprofen (as the racemic mixture or as a mixture enriched in one enantiomer or as the purified enantiomer) is very poorly soluble in water. Racemic ibuprofen is defined as having a solubility of less than 1 part in 10000 in water. Racemic flurbiprofen is defted as having a solubility of less than one part in 10000 in water. It is thus a problem to achieve solubilisation of these and the other substantially insoluble NSAIDs to ensure an adequate therapeutic effect is achieved quickly. The solubility of these substantially insoluble active ingredients increases as the pH of the aqueous medium rises. As the pH of the gastro-intestinal tract increases from the highly acidic medium in the stomach to the alkaline conditions found therein, the solubility of these active ingredients rise as they pass along the gastro-intestinal tract. However, it would be ari advantage to produce a form of the drug which dissolves more readily in acidic aqueous conditions.

It is therefore desired to provide a solid crystalline composition of the substantially insoluble NSAIDs which have improved solubility properties compared to the standard crystalline form of these drugs.

WO 93/25190 proposes that dispersible particles consisting essentially of a crystalline NSAID having a surface modifier adsorbed on the surface in an amount sufficient to maintain an effective average particle size of less than 400nm may exhibit reduced gastric irritation following oral administration and/or hastened onset. It is disclosed that this can be achieved by causing surface modifiers such as polymers, low molecular weight oligimers, natural products and surfactants to be adsorbed on the surface of the crystalline active ingredient. The tiny particle size may be achieved in a variety of ways although 3 in the specific Examples, illustrating the production of ibuprofen having a particle size in the range 253nm to 351 nm (0.253-0.351 pm), a pre-mix aqueous slurry of ibuprofen and the surface modifier is milled for a period ranging between 4 and 20 hours in order to produce an acceptable particle size.

US 5518738 proposes that pharmaceutical compositions comprising particles consisting essentially of an NSAID having polyvinylpyrrolidone adsorbed on the surface thereof in an.amount sufficient to maintain an average particle size of less than about a 1000nm (1pm), a hygroscopic sugar and sodium lauryl sulphate reduce gastric irritation and/or hasten the onset of action. The particles can be prepared by dispersing the NSAID in a liquid dispersion medium and applying mechanical means in the presence of grinding media to reduce the particle size of the NSAID. The particles can be reduced in size before or after the addition of the polyvinylpyrrolidone. The only drug specifically illustrated is naproxen and it is stated that the use of the hygroscopic sugar and sodium lauryl sulphate act synergistically as a combination of redispersants for the NSAID nahoparticles which is not achieved by the use of each of these components alone.

It is a particular problem to reduce the particle size of the NSAIDs, such as ibuprofen and flurbiprofen, to a few hundred nanometers. Racemic ibuprofen has a mean particle size of between 25,000 and 50,000nm and racemic flurbiprofen has a mean particle size of between 15,000 and 30,000nm, S(+)-ibuprofen has a even larger particle size of between 50,000 and 100,000nm. Although reduced particle sizes (eg down to 25,000nm) may be achieved by varying production process parameters, it remains a problem to reduce the particle size of a factor of 10 in accordance with the disclosures in

WO 93/25190 and US 5518738 above.

We have now found a form of the substantially insoluble NSAIDs which have improved solubility and which do not require the substantial reduction in 4 particle size as described in the prior art acknowledged above in order to. be effective. According to the invention, an improvement in the aqueous dissolution of the substantially insoluble NSAIDs may be achieved by surface treatment of these active ingredients with a suitable surfactant.

Accordingly, there is provided a solid crystalline composition having a mean particle size in the range 10-500pm comprising an NSAID, or a pharmaceutically acceptable salt thereof, having a solubility of less than 1 part per 100 parts water characterised by having at least one material selected from a pharmaceutically acceptable surfactant, poiyvinylpyrrolidone or polyethylene glycol adsorbed on the surface of the particle.

The crystalline composition according to the present invention has an improved solubility over the standard crystalline form of the subject NSAIDs.

As well as improved dissolution properties there may also be observed a more rapid absorption of the drug. Accordingly, reduced time to onset of therapeutic effects may be achieved. Furthermore, improvements may be seen in gastric tolerability. Additionally a reduction in the variation in dissolution performance between different batches can be achieved. Improvements are also obtained in formulation into dosage forms because reduced levels of the excipients, which are required to aid the dissolution of the drug are incorporated in the formulation.

The crystalline composition according to the present invention has an improved solubility compared to the normal crystalline form of each drug, ie without surface materials adsorbed thereon. Preferably the solubility is increased by a factor of greater than 10%, more preferably greater than 20% and most preferably greater than 50%.

The NSAIDs which are the subject of the invention have a solubility of less than 1 parts per 100 parts water. By the term "substantially insoluble" herein we mean that the NSAIDs have a solubility of less than one part per 100 parts water. This term includes the definitions of "sparingly soluble", "slightly soluble", "very slightly soluble" and "practically insoluble" as given in the British Pharmacopoeia. Preferably the NSAIDs used in accordance with the present invention have a solubility of less than 1 part per 1000 parts water, more preferably less than 1 part per 10,000 parts water. Preferred NSAIDs include ibuprofen, flurbiprofen, ketoprofen, naproxen, fenoprofen, indoprofen, fenbufen, edotolac, diclofenac, piroxicam, mefanamic acid, indomethacin and nabumetone. More preferred NSAIDs include ibuprofen, flurbiprofen, tial>rofenic acid, ketoprofen, naproxen, fenoprofen and indoprofen. More preferably, arylpropionic acids, particularly ibuprofen and flurbiprofen, are employed in accordance with the present invention. The salts of the NSAIDs include pharmaceutically acceptable salts such as sodium, potassium, lysine, arginine, meglumine, calcium, magnesium and aluminium salts. However, the advantages of the invention are more marked when the parent acid, which has a much a lower solubility, is present. Accordingly, preferably ibuprofen or flurbiprofen or an enantiomeric rich mixture thbreof are used in a composition according to the present invention, especially ibuprofen or flurbiprofen. Further preferred compositions contain either the R(-) or the S(+) enantiomer of ibuprofen or flurbiprofen, said enantiomers c onta ining less than 10% by weight of the undesired enantiomer.

Preferred anionic surfactants may be selected from sodium docusate and sodium lauryl sulphate. Preferred cationic surfactants may be selected from benzalkonium chloride, benzethonium chloride and cetrimide. Preferred non-ionic surfactants are glyceryl monooleate, polyoxyethylene alkyl ethers, polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters, sorbitan esters and polyvinyl alcohols. Polyvinyl pyrrolidone and polyethylene glycol may also be employed in accordance with the present invention. Most preferably, anionic surfactants such as sodium docusate and sodium lauryl sulphate are employed.

6 Suitably, the ratio of active ingredient to surfactant is 100,000:1 to 10:1 parts by weight, more preferably 50,000:1 to 1000:1 and most preferably 10,000: 1 to 5,000:1 parts by weight.

At least a portion of the surface of the particles of active ingredient contain the adsorbed material thereon. Preferably, this is one or more of an an ionic, cationic or non-ionic surfactant or polyvinyl pyrro lidone or polyethylene glycol.

Preferably, the solid composition consists essentially of an active ingredient as defted above and a surfactant. More preferably, the solid composition according to the present invention may comprise 95-100% particles of NSAID active ingredient having an anionic or non-ionic surfactant adsorbed thereon, preferably 99-100% and most preferably 99.5-100% particles of active ingredient having an anionic or non-ionic surfactant adsorbed thereon. Most preferably, the surfactant is the sole material adsorbed onto the surface of the active ingredient. In especially preferred compositions not more than two materials are adsorbed on the surface of the- NSAID, most preferably, just a single material such as a surfactant.

The particle size of the composition according to the present invention varies according to the nature of the active ingredient. Preferably, the particle sizes are in the range 10-250pm. Preferred particle sizes for ibuprofen are in the range 10 to 200pm, most preferably 20 to 50pm. Preferred particle sizes for flurbiprofen are in the range 10 to 1 OOpm, most preferably 15 to 30pm.

The composition may be prepared according to known methods for surface adsorption of surfactants in which the substantially insoluble NSAID is combined with the surfactant, preferably in a liquid medium, and optionally washed and dried. For example, the active ingredient may be dispersed in a solution of the adsorbed material (eg the surfactant) and agitated for a period before filtration to collect the composition and drying. Preferably, the active 7 ingredient is dispersed with sonication in the aqueous solution of the surfactant at 30C and is held at that temperature with agitation for at least 24 hours. Filtration with a water wash is used to collect the composition, which is dried at an appropriate temperature.

The solid composition may be formulated by known techniques into pharmaceutical dosage forms, for example into tablets, capsules, liquid preparations, topical preparations, parenteral preparations, anal and vaginal preparations. These have been widely disclosed in the art. Thus, the standard form of these arylpropionic NSAIDs may be replaced in such formulations by the composition according to the present invention, but with reduced levels of solubility enhancing agents.

The solid crystalline composition according to the present invention is useful in all therapeutic areas where treatment by arylproplonic acids has been proposed. Typical treatments include the relief of painful conditions, including headache, migraine, dysmennhoreoea, post-operative pain, post-partum pain, dental pain, cancer pain, gout, back pain, muscular pain, neuralgia, sprains and strains and other soft tissue injuries, pyrexia, colds and flu, rheumatoid disease, osteoarthritis, arthritic disease, ankylosing spondylitis and acute musco-skeletal disorders.

Unit dosages are usually administered a according to the therapeutic treatment desired and will be within the knowledge of any prescribing physician (as evidenced by MIMS) or pharmacist as appropriate or as indicated on a leaflet to the patient. Usually the daily dosage will be between 5 and 3200mg divided into multiple daily unit doses.

The invention may be illustrated by the following non-limiting Example.

Preparation 8 A 2M solution of docusate sodium is saturated with ibuprofen. 150ml of this solution at 300C in a stoppered flask is held and a further portion of ibuprofen (10g) added and dispersed in the solution by sonication for at least one minute. The flask is immersed in a shaking water bath at 300C for 24 hours. The ibuprofen is recovered by filtration and washed with about 50ml of deionised water. The recovered crystals are dried in an oven at 50C.

Anale of Contact Measurement The angle of contact is a measure of the wettability of a surface and where that surface is a pure substance a measure of its wettability. C ompacts of treated and untreated ibuprofen are formed in a cylindrical die lubricated with magnesium stearate using flat faced punches. The angle of contact is measured on the compacts using the technique of Heertjes and Kossen (1967).

Dissolution Measurement 200mg of treated of untreated ibuprofen is loosely filled into a hard gelatin capsule and the dissolution rate of the ibuprofen is measured at 37C in 900ml of pH 6 buffer, using the USP XXIII method two apparatus operating at 50 rpm, sampling every 5 minutes up to 20 minutes and every 10 minutes thereafter up to 1 hour.

Tablet

The crystalline ibuprofen having sodium docusate adsorbed thereon prepared as described above is mixed with calcium phosphate and granulated with a solution of polyvinylpyrrolidone in isopropyl alcohol. The granules are dried, sieved and then blended with croscarmellose sodium and compressed into tablets.

There may also be formed a tablet by dry mixing the crystalline ibuprofen having sodium docusate adsorbed thereon with microcrystalline cellulose, colloidal silicon dioxide, sodium starch glycolate and stearic acid and directly compressing the formulation into tablets.

claims 1. A solid crystalline composition having a mean particle size in the range 10-500pm comprising an NSAID, or a pharmaceutically acceptable salt thereof, having a solubility of less than 1 part per 100 parts water characterised by 5 having at least one material selected from a pharmaceutically acceptable surfactant, polyvinylpyrrolidone or polyethylene glycol adsorbed on the surface of the particle.

2. A formulation composing a composition as claimed in claim I together with a carder.

lo 3. The use of a composition as claimed in claim 1 in the treatment of conditions including symptoms of inflammation, pain and/or fever.