DESCRIPTION

TECHNICAL FIELD

The present invention is related to stable pharmaceutical formulations comprising nonsteroidal anti-inflammatory drugs (NSAlDs) which are dual COX-1 and COX-2 inhibitors, and gastro protective agents in a single unit pharmaceutical dosage form.

BACKGROUND ART

NSAlDs are drugs with analgesic, antipyretic and anti -inflammatory effects that extensively used worldwide. NSAlDs are classified based on their chemical structure or mechanism of action.

Several NSAID classifications include: salicylates, p-amino phenol derivative, propionic acid derivatives, carboxylic acid derivatives, enolic acid derivatives, fenamic acid derivatives, and sulphonanilides.

It is well known that NSAlDs have the potential to cause gastrointestinal (GI) side effects, such as gastric and duodenal ulcers, bleeding and perforation, oesophageal inflammation and strictures, and small bowel and colonic ulcers and strictures.

Laine L. (Semin. Arthritis Rheumatism. 2002;32:25-32) reports that NSAlDs exert their pharmacological action by inhibiting the synthesis of prostaglandins (PGs) by non- selectively blocking cyclooxygenases 1 and 2 (COX-1 and COX-2) or by selectively blocking COX-2. Inhibition of COX-1 is also responsible, in part, for gastrointestinal side effects, which are the most frequent side effects of NSAIDs.

Inhibition of COX-1 causes a number of side effects including gastrointestinal toxicity with the possibility of ulcerations and of hemorrhage. A high incidence of side effects has historically been associated with chronic use of classic cyclooxygenase inhibitors, all of which are about equipotent for COX-1 or COX-2 or which are COX-1 selective. COX inhibitors cause gastrointestinal and renal toxicity due to the inhibition of synthesis of homeostatic prostaglandins responsible for epithelial mucus and renal blood flow, respectively.

Dual COX-1 and COX-2 inhibitors are a type of NSAIDs that target COX-1 and COX-2 responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration. Selective inhibitors of COX-2 have less gastrointestinal side effects but have more cardiovascular side effects. Dual COX inhibitors create compliance issues mainly due to GI side effects, for the patients and can lead to treatment cessation.

Therefore a formulation having a COX-1 and COX-2 inhibitory effect with reduced gastro intestinal side effects would create big difference in the treatment of pain and inflammation.

Due to the fact that NSAIDs can cause GI ulceration, bleeding and perforation, especially in case of high dose usage, long-term treatments, history of a gastrointestinal disease or sensitivity to develop disease, additional use of gastro protective agent drugs for reducing GI side effects is needed. There have been binary combinations of NSAIDs and gastro protective agents in single unit dosage forms disclosed in the state of the art.

US patent application US 2014186439 relates to a new stable pharmaceutical composition comprising the combination of ibuprofen and famotidine with at least one pharmaceutically acceptable excipient, wherein said combination is in solid form which is stable over time.

European patent EP 1411900 Bl relates to a multi-layer tablet suitable for oral administration comprising an outer layer of an acid inhibitor (H2 -receptor antagonist, preferably famotidine, or proton pump inhibitor), an inner core of an NSAID (preferably aspirin or naproxen) and a barrier coating surrounding the inner core of said NSAID, which might create manufacturing difficulties, stability issues.

US patent application US 20090233970 Al relates to co-administration of a NSAID and acid blocking agent for the treatment of pain and inflammation with reduced gastrointestinal irritation. The application discloses that the two components can be administered in the same dosage form as a pharmaceutical composition comprising at least one NSAID (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ranitidine).

US patent application US 20070237820 Al relates to a solid oral dosage form comprising a first portion comprising an NSAID (preferably diclofenac); and a coating comprising an anti-ulcerative compound (preferably misoprostol); said coating at least partially surrounding said first NSAID portion. The pharmaceutical dosage described therein creates manufacturing difficulties.

European patent EP 0814839 Bl relates to a multiple unit tablet wherein a proton pump inhibitor (preferably omeprazole, esomeprazole, lansoprazole or pantoprazole) in the form of individually enteric coating layered pellets, at least one NSAID (preferably ibuprofen, diclofenac sodium, piroxicam or naproxen) and optionally pharmaceutically acceptable excipients are compressed together. International patent application WO 2005076987 A2 relates to a pharmaceutical composition comprising at least one proton pump inhibitor (preferably omeprazole), at least one NSAID and at least one buffering agent.

In the state of the art, as mentioned above, disclosures relate to the combined use of NSAIDs (preferably aspirin, naproxen, diclofenac sodium, ibuprofen or piroxicam) and gastro protective agents (preferably misoprostol, ranitidine, omeprazole, esomeprazole, lansoprazole or pantoprazole). Aim of the present invention is to provide a single unit pharmaceutical dosage form comprising at least one NSAID with dual COX-1 and COX-2 inhibitory effect, and a second agent to reduce the occurrence of gastro intestinal side effects.

DETAILED DESCRIPTION OF THE INVENTION

The single unit pharmaceutical dosage form of the present invention comprises at least one propionic acid derivative NSAID that inhibits both COX-1 and COX-2, in combination with at least one H2 receptor antagonist as a gastro protective agent. The single unit pharmaceutical dosage form of the present invention is useful in the treatment of inflammation and pain with reduced gastrointestinal side effects. The term "single unit dosage form" as used herein refers to a single entity for drug administration. For example, a single tablet or capsule combining both propionic acid derivative NSAID that inhibits both COX-1 and COX-2, and H2 receptor antagonist.

In one embodiment of the present invention, the propionic acid derivative NSAID that inhibits both COX-1 and COX-2 is selected from naproxen, dexibuprofen, and dexketoprofen, and pharmaceutically acceptable salts and combinations thereof. In one preferred embodiment of the present invention, the propionic acid derivative NSAID that inhibits both COX-1 and COX-2 is selected from naproxen and dexketoprofen, and pharmaceutically acceptable salts and combinations thereof.

In another preferred embodiment of the present invention, the propionic acid derivative NSAID that inhibits both COX-1 and COX-2 is dexketoprofen.

Dexketoprofen is the S-(+) enantiomer of the well known NSAID and reversible COX inhibitor, ketoprofen, with the chemical name S-(+)-2-(3-benzoylphenyl)propionic acid. Dexketoprofen is used in the treatment of inflammation and pain. It possesses analgesic as well as anti-inflammatory activity.

Dexketoprofen was first disclosed in the WO89/04658. Dexketoprofen has a superior effect towards inflammation and pain, and faster onset of action. It has similar gastrointestinal and cardiovascular side effects as compared with other NSAIDs and administration of a smaller amount by weight for comparable or higher efficacy is possible. Although it has a solid efficacy, the ulcerogenic properties and gastro intestinal side effects are to a large extent relates to dexketoprofen's inhibition of COX-1 in the gastric mucosa.

In another preferred embodiment of the present invention, the propionic acid derivative NSAID that inhibits both COX-1 and COX-2 is dexketoprofen trometamol.

W094/11332 relates to a specific salt of dexketoprofen i.e. dexketoprofen tromethamine (trometamol) salt as shown in Formula 1.

Formula 1

In the single unit pharmaceutical dosage form of the present invention, a H2 receptor antagonist is used as a gastro protectant agent. When propionic acid derivative NSAID that inhibits both COX-1 and COX-2 is combined with a H2 receptor antagonist as a gastro protective agent in a single unit pharmaceutical dosage form, the efficacy of the pain treatment has increased due to increased patient compliance caused by the diminished side effects. Furthermore higher doses and/or longer administration periods of propionic acid derivative NSAID that inhibits COX-1 and COX-2 can also be attained due to the diminished side-effects.

In one embodiment of the present invention, H2 receptor antagonist is selected from famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine, and pharmaceutically acceptable salts and combinations thereof.

The H2 -receptor antagonist used in the present invention may be either in free form or in the form of a pharmaceutically acceptable salt thereof.

In one preferred embodiment of the present invention, H2 receptor antagonist is famotidine, or pharmaceutically acceptable salts or combinations thereof.

Famotidine is a H2 -receptor antagonist used in the treatment of gastrointestinal diseases. Famotidine provides a superior treatment to current therapies as it limits the gastrointestinal side effects that will happen in a prophylactic manner, therefore creating fewer complications from efficient NSAID use in a long term. Famotidine protects the gastric mucosa against irritation. Famotidine has an ideal safety/efficacy ratio which makes it preferably used in the present invention. Its chemical structure is shown in Formula 2.

Formula 2

"Famotidine" is 3-[2-(diaminomcthyleneamino)thiazol-4-yl methylthio)- N- sulfamoylpropionamidine including the polymorphic forms designated Form A and Form B (see, e.g. US Pat. Nos. 5,128,477 and 5,120,850) and their mixtures, as well as pharmaceutically acceptable salts thereof. Famotidine can be prepared using art-known methods, such as the method described in U.S. Pat. No. 4,283,408. Famotidine's properties have been described in the medical literature (see e.g., Echizen et al., 1991, Clinical Pharmacokinetics 21:178-94).

The single unit pharmaceutical dosage form of the present invention used in the treatment of inflammation and pain can reduce the gastrointestinal side effects induced by propionic acid derivative NSAID that inhibits both COX-1 and COX-2 thanks to the presence of the H2 receptor antagonist as a gastro protective agent.

In one preferred embodiment of the present invention the single unit pharmaceutical dosage form comprising propionic acid derivative NSAID that inhibits both COX-1 and COX- 2, in combination with at least one H2 receptor antagonist as a gastro protective agent is provided for use in a method for the treatment of inflammation or pain with reduced gastro intestinal side effects.

In one preferred embodiment, the single unit pharmaceutical dosage forms of the present invention is useful for the treatment of inflammation or pain of mild to moderate intensity originated by different causes and related to different diseases such as muscular or skeletal system diseases, dysmenorrhoea, toothache, dental pain and headache. Suitable dosages of propionic acid derivative NSAID that inhibits both COX-1 and COX-2 and H2 receptor antagonist as a gastro protective agent in a single unit dosage form of the present invention can be selected according to the condition to be treated, as well as to the properties of each constituting drug to be combined and the properties of drugs being after combination.

In one embodiment a single unit pharmaceutical dosage form of the present invention further comprises at least one pharmaceutically acceptable carrier. In one embodiment of the present invention, the single unit pharmaceutical dosage form comprises propionic acid derivative NSAID that inhibits COX-1 and COX-2, in an amount from about 12.5 to 550 mg.

In one preferred embodiment, an oral single unit pharmaceutical dosage form comprises naproxen in an amount of 550 mg.

In another embodiment, the single unit pharmaceutical dosage form of the present invention comprises propionic acid derivative NSAID that inhibits COX-1 and COX-2, in an amount from about 25 to 75 mg.

In another embodiment, the single unit pharmaceutical dosage form of the present invention comprises propionic acid derivative NSAID that inhibits COX-1 and COX-2 in an amount from about 25 to 50 mg. In one preferred embodiment, an oral single unit pharmaceutical dosage form of the present invention comprises dexketoprofen in an amount of 50 mg. In one embodiment of the present invention, the single unit pharmaceutical dosage form comprises H2 receptor antagonist in an amount from about 5 to 200 mg.

In another embodiment the single unit pharmaceutical dosage form of the present invention comprises H2 receptor antagonist in an amount from about 10 to 80 mg.

In one embodiment of the present invention, the single unit pharmaceutical dosage form comprises dexketoprofen in an amount of about 25-75 mg and famotidine in an amount of about 10-80 mg.

In another embodiment of the single unit pharmaceutical dosage form of the present invention comprises dexketoprofen in an amount of about 50 mg and famotidine in an amount of about 20 mg.

In accordance with the above embodiments, generally the ratio of the propionic acid derivative NSAID that inhibits COX-1 and COX-2 to the H2 receptor antagonist is generally between 1.25 to 2.5, 3.75 to 1, and 1.875 to 1 by weight.

The single unit pharmaceutical dosage form of the present invention may be an oral dosage form. This oral dosage form may be tablet, capsule, pellet, granule, tablet in tablet, tablet in capsule, or coated tablet, preferably being in tablet or capsule form.

The single unit pharmaceutical dosage form may also be in the form of gel, cream, ointment, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution and the like. In one embodiment the present invention may comprise an injectable single unit pharmaceutical dosage forms for intravenous, intramuscular or subcutaneous administration formulated as aqueous or non-aqueous solution or suspension, or as powder for injection, with suitable pharmaceutically acceptable excipients. The usual dose of the single unit pharmaceutical dosage of the present invention is 25 to 50 mg of propionic acid derivative NSAID that inhibits both COX-1 and COX-2 daily for acute pain and 75 mg of propionic acid derivative NSAID that inhibits both COX-1 and COX-2 daily for inflammation-related diseases by oral administration in the form of tablet.

The usual dose of the single unit pharmaceutical dosage of the present invention is 20 to 80 mg of H2 receptor antagonist daily by oral administration in the form of tablet or intravenous administration. Dosage forms of the drug may be administered once, twice or thrice a day.

In one embodiment of the present invention for a faster onset of action, it is important for the tablets or capsules to have an immediate or at least normal release profile in the gastrointestinal system. Accordingly at least 25% of propionic acid derivative NSAID that inhibits COX-1 and COX-2, and 25% of H2 receptor antagonist in the oral formulations have to be released in the stomach before reaching the intestines.

In one embodiment, an oral single unit pharmaceutical dosage form of the present invention has an instant or normal release profile, with at least 25% of propionic acid derivative NSAID that inhibits COX-1 and COX-2, and at least 25% of H2 receptor antagonist released in the stomach before reaching the intestines.

In another embodiment at least 6.5 mg of propionic acid derivative NSAID that inhibits COX-1 and COX-2 is released in the stomach before reaching the intestines.

In another embodiment at least 5 mg of H2 receptor antagonist released in the stomach before reaching the intestines. In one embodiment of the single unit pharmaceutical dosage of the present invention is in the form of a combinatory tablet comprising dexketoprofen in combination with famotidine with an instant or normal release profile, with at least 25 % of dexketoprofen and 25% of famotidine released in the stomach before reaching the intestines.

In another embodiment, the single unit pharmaceutical dosage of the present invention comprises modified release (controlled, delayed, extended, prolonged sustained, timed release, slow or fast release) profile in order to provide the control of the release of the active components and in order to optimize the therapeutic effects and to minimize the undesirable side effects. In one embodiment a single unit pharmaceutical dosage form of the present invention further comprises at least one pharmaceutically acceptable excipient such as binder, lubricant, diluent, disintegrant etc.

Oral dosage forms of the present invention may comprise suitable diluents, binders, fillers, lubricants, extenders, moisturizers, disintegrating agents, surfactants, sweetening agents, coloring agents and coating agents.

Pharmaceutically acceptable diluents of the present invention may be selected from magnesium stearate lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like.

Pharmaceutically acceptable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycols, waxes, sodium alginate, alcohols, water and the like.

Pharmaceutically acceptable lubricants of the present invention may be selected from metallic stearates, metallic lauryl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride, talk and the like.

Pharmaceutically acceptable disintegrating agents of the present invention may be selected from starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like.

Pharmaceutically acceptable surfactants of the present invention may be selected from sulfates, sulfonates, phosphates, carboxylates, primary-secondary-tertiary amines, quaternary ammonium compounds, fatty alcohols, sugar esters of fatty acids, glycerides of fatty acids, polyoxy ethylene glycol alkyl ethers, polisorbates, sorbitan alkyl esters, poloxamers and the like.

Pharmaceutically acceptable coating agents of the present invention may be selected from hydroxypropylmethylcellulose as a film coating agent, PEG 400 as a plasticizer, titanium dioxide and iron oxide as coloring agents.

EXAMPLES

The present invention will be explained more in detail by illustrating Examples. Example 1:

Table 1 below provides the contents of an example composition in the form of a film coated tablet of dexketoprofen in combination with famotidine. Table 1: Film Tablet Composition

Example 2 Preparation processes of the single unit pharmaceutical dosage of the present invention

1. Preparation process wherein the active components are not directly mixed:

At the first stage, a certain amount of PVP (K-30) is dissolved in purified water. Dexketoprofen, remaining amount of PVP (K-30), lactose, micro crystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet-granulated with the PVP (K-30) solution. Granules so-obtained are dried and pass through the dry granulator.

At the second stage, famotidine is added to the granules obtained in the first stage. Suitable mixing is applied. Final mixture is obtained by the addition of magnesium stearate to the mixture. After the tablets are pressed, they are film-coated.

2. Preparation method wherein the active components are directly mixed:

A certain amount of PVP (K-30) is dissolved in purified water. Dexketoprofen, famotidine, remaining amount of PVP (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet- granulated with the PVP (K-30) solution. Granules so-obtained are dried and pass through the dry granulator. Final mixture is obtained by the addition of magnesium stearate to the mixture. After the tablets are pressed, they are film-coated.

Tablets prepared by the processes of the invention have not met any stability problems during long term stability studies performed at 25 ± 2 °C and 60 ± 5 % RH across a 0-, 3- and 6-month follow-up period; and accelerated stability studies performed at 40 ± 2 °C and 75 ± 5 % RH across a 0-, 3- and 6-month follow-up period.

Example 3

Treatment of Patients with acute Pain caused by injury 2 groups of patients (n=6 in each group) received dexketoprofen 25mg tablets alone and dexketoprofen in combination with 20 mg famotidine tablet unit pharmaceutical dosage form, two times a day for chronic back pain for a period of 4 weeks. The group using the dexketoprofen 25 mg tablets twice a day showed improvement in VAS pain score by 20%. The group using the dexketoprofen25 mg in combination with famotidine 20 mg tablet showed improvement in VAS pain score by 25 %. Although the VAS pain score improvement was similar in both groups, there was a significant difference between the groups for the safety parameters. The gastro intestinal side effects reported with the group using dexketoprofen 25 mg tablet were higher and 2 patients from the mono dexketoprofen therapy group had to stop using the medication due to gastro intestinal complications. No gastro intestinal side effects other than mild esophageal reflux were reported in the group using 25 mg dexketoprofen in combination with 20 mg famotidine twice a day.

The examples of pharmaceutical formulations and preparation methods of the invention given above are only given to illustrate the invention. The extent of the invention should not be limited by the examples.