THE TREATMENT OF PAIN AND INFLAM MATION

Description

TECHNICAL FIELD

The present invention is related to pharmaceutical formulation comprising a non-steroidal anti-inflammatory agent (NSAIA) that selectively inhibits cyclooxygenase-2 (COX-2) and a H ₂ receptor antagonist in a single unit pharmaceutical dosage form.

BACKGROUND ART

It is well known that NSAIAs have the potential to cause gastrointestinal (Gl) side effects, such as gastric and duodenal ulcers, bleeding and perforation, oesophageal inflammation and strictures, and small bowel and colonic ulcers and strictures. NSAIAs exert most of their anti-inflammatory, analgesic and antipyretic activity and inhibit hormone-induced uterine contractions and certain types of cancer growth through inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Inhibition of COX-1 causes a number of side effects including inhibition of platelet aggregation associated with disorders of coagulation, and gastrointestinal toxicity with the possibility of ulcerations and of hemorrhage. It is believed that gastrointestinal toxicity is due to a decrease in the biosynthesis of prostaglandins which are cytoprotective of the gastric mucosa.

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. In the United States, it is estimated that some 2000 patients with rheumatoid arthritis and 20,000 patients with osteoarthritis die each year due to gastrointestinal side effects related to the use of COX inhibitors. In the UK, about 30% of the annual 4000 peptic ulcer-related deaths are attributable to COX inhibitors (Scrip 2162, p. 17). 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.

Selective COX-2 inhibitors are a type of NSAIA that directly targets COX-2 responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration. Although NSAIAs which are selective inhibitors of COX-2 have less gastrointestinal side effects, they still create compliance issues for the patients and can lead to treatment cessation.

There is a continuing need for analgesic medications to provide high efficacy pain relief while reducing the possibility of undesirable side effects. NSAIAs that are selective COX-2 inhibitors, including compounds such as etodolac, meloxicam, piroxicam, and nimesulide have anti-inflammatory actions and are effective on pain associated with the release of prostaglandins and other mediators of inflammation.

Measures which can be taken to decrease Gl side effects associated with NSAIA therapy, especially in case of high dose usage, long-term treatments, history of a gastrointestinal disease or sensitivity to develop disease,is to coadminister a prostaglandin analogue and/or gastroprotectant drug, e.g. misoprostol, an H2 blocker, e.g. ranitidine, or a proton pump inhibitor, e.g. omeprazole, with the NSAIA.

In cases where use of more than one medicine is needed, patient compliance is an important factor to be considered. According to the research, 50% of the patients fail to take medicines as prescribed and to fulfill the requirements of the treatment (Sabate, E. "Adherence to Long- Term Therapies: Evidence for Action". World Health Organization. Geneva, 2003. 212 pp.). Patients fail to take their medicines prescribed so as to include a complicated treatment regimen requiring use of more than one medicine due to the facts such as forgetfulness, busy lifestyle, different methods of the administration of the medicines, lack of suitable environment for taking medicines, misunderstanding of the disease or treatment, patient's perspective of the disease or treatment, side effects, depression, cognitive disorders and financial problems. In this case, combining the active components in a single dosage form will increase patient compliance to the treatment. In the state of the art there are disclosed binary combinations of NSAIAs as well as NSAIAs and gastroprotectants.

US patent no. US5204118 and US5417980 disclose combinations of NSAIA molecules with proton pump inhibitors (PPI) in order to balance gastric acid. PPIs can cause a decrease in bone density during long term use.

European patent no. EP 141 1900 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. US patent application no. US20070237820 Al relates to a solid oral dosage form comprising a first portion comprising an NSAID (preferably diclofenac), and a coating comprising an antiulcerative compound (preferably misoprostol); said coating at least partially surrounding said first NSAID portion.

US patent application no. US 20090233970 Al relates to a pharmaceutical composition for the treatment of pain and inflammation with reduced gastrointestinal irritation, the composition comprising at least one NSAID (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ranitidine). Above-mentioned patents relate to the combined use of NSAIDs (preferably aspirin, naproxen, diclofenac or ibuprofen) and gastroprotectants (preferably famotidine, proton pump inhibitors, misoprostol or ranitidine). There still exists a need in the state of the art for a combination formulation which includes an NSAID with a second agent to reduce the occurrence of gastro-intestinal side effects associated with NSAID treatment.

DISCLOSURE OF THE INVENTION

The present invention solves the problem described above by providing novel pharmaceutical formulations for treating inflammation and pain with reduced gastrointestinal side effects. It has surprisingly been found that when a NSAIA that selectively inhibits COX-2 has been combined with a H2 receptor antagonist 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. Accordingly, the present invention provides solutions to the above-mentioned problems, and demonstrates that inflammation and pain can be treated effectively by administering to a patient with inflammation and pain a pharmaceutical formulation comprising at least one NSAIA as defined herein that selectively inhibits COX-2 in combination with at least one H2 receptor antagonist as defined herein in a single unit pharmaceutical dosage form. The at least one NSAIA that used in the present invention that selectively inhibits COX-2 is selected from etodolac, meloxicam, piroxicam, and nimesulide. In a preferred embodiment, the pharmaceutical formulation comprises etodolac.

The at least one H2 receptor antagonist that used in the present invention is selected from selected from famotidine, cimetidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine. In a preferred embodiment, the pharmaceutical formulation comprises famotidine.

The novel pharmaceutical formulation of the present invention comprising at least one NSAIA as defined herein that selectively inhibits COX-2 in combination with at least one H2 receptor antagonist as defined herein in a pharmaceutically acceptable carrier is combined in a single unit pharmaceutical dosage form, for example a pill. The pharmaceutical formulation of the present invention is administered to a patient with inflammation and pain, in an amount and dosage regimen effective to treat the inflammation and pain.

Accordingly, it is an object of the present invention to provide a pharmaceutical formulation useful for treating inflammation and pain. Yet another object of the present invention is to provide a pharmaceutical formulation comprising at least one NSAIA that selectively inhibits COX-2 in combination with at least one H2 receptor antagonist in a pharmaceutically acceptable carrier wherein the NSAIA that selectively inhibits COX-2 is etodolac and H2 receptor antagonist is famotidine. Yet another object of the present invention is to provide a pharmaceutical formulation comprising at least one NSAIA that selectively inhibits COX-2 in combination with at least one H2 receptor antagonist in a pharmaceutically acceptable carrier, for use in the treatment of inflammation and pain, wherein the NSAIA that selectively inhibits COX-2 is etodolac and H2 receptor antagonist is famotidine.

Yet another object of the present invention is to provide a pharmaceutical formulation comprising at least one NSAIA that selectively inhibits COX-2 in combination with at least one H2 receptor antagonist in a pharmaceutically acceptable carrier, for use in the treatment of signs and symptoms caused by ankylosing spondylitis, rheumatoid arthritis and osteoarthritis with reduced gastrointestinal side effects.

DETAILED DESCRIPTION OF THE INVENTION

The pharmaceutical formulation of the present invention comprises at least one NSAIA ((Non Steroidal Anti-Inflammatory Agent also referred to as Non Steroidal Anti-Inflammatory Drug (NSAID)) that selectively inhibits cyclooxygenase-2 (COX-2) as defined herein in combination with at least one H2 receptor antagonist as defined herein, in a pharmaceutically acceptable carrier, in a single unit pharmaceutical dosage form. The pharmaceutical formulations of the present invention are useful in treating inflammation and pain, with reduced gastrointestinal side effects.

The pharmaceutical formulation: the first ingredient The NSAIA of the present invention is selected from a NSAIA that selectively inhibits COX-2 for their superiority, not to suppress gastric or duodenal prostaglandins, to have minimal hepatic or renal effects and to have favorable Gl tolerability while having a strong effect towards inflammation and pain.

The first ingredient comprises a NSAIA that selectively inhibits COX-2, preferably selected from, but is not limited to etodolac, meloxicam, piroxicam, and nimesulide. In a preferred embodiment, the first ingredient to be used as the first component in the present invention is etodolac. Etodolac is a NSAIA that selectively inhibits COX-2 it is used in the treatment of inflammation and pain. It possesses analgesic and antipyretic properties as well as anti-inflammatory activity. Its chemical structure is shown in Formula 1.

Formula 1

The chemical name of etodolac is l,8-diethyl-l,3,4,9-tetrahydropyrano (3,4-b) indol-l-yl acetic acid.

The pharmaceutical formulation: the second ingredient

In the pharmaceutical formulation of the present invention, a H ₂ receptor antagonist which functions as a gastroprotectant agent is used as the second ingredient. H ₂ receptor antagonists which function as gastroprotectant agents can be widely used and are known to one ordinary skilled in the art.

Among the H2 receptor antagonist which function as a gastroprotectant agent, those having excellent safety profile compared to other gastroprotective agents like proton pump inhibitors are preferable.

As to such H2-receptor antagonists which function as gastroprotectant agents at least one of famotidine, cimetidine, ranitidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine and famotidine is used. In a preferred embodiment, the second second ingredient to be used the second component in the present invention is famotidine. The reason why, the preferred embodiment of the present invention uses famotidine is because of it's ideal safety/efficacy ratio compared with the other gastroprotectant agents.

Famotidine is an H2-receptor antagonist used in the treatment of gastrointestinal diseases. It protects the gastric mucosa against irritation. Its chemical structure is shown in Formula 2.

Formula 2

The chemical name of famotidine is 3-(2-(diaminomcthyleneamino)thiazol-4-yl methylthio)- N-sulfamoyl propionamidine.

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

Dosage

Dosage of the drug used in the present invention is decided by considering the properties of each constituting drug to be combined, the properties of drugs being after combination and symptoms of the patient (existence of other diseases beside inflammation and pain). General outlines of the dosage can be applied by the following guidelines.

The first ingredient, for example etadolac: generally about 200-1200 mg, preferably 400 mg daily for acute pain, 800-1200 mg daily for inflammation-related diseases by oral administration in the form of tablet. The usual initial dose is about 200-400 mg daily for acute pain, 800-1200 mg daily for inflammation-related diseases by oral administration in the form of tablet. The second ingredient, for example famotidine: generally about 5 to 200 mg, preferably 20 to 40 mg daily by oral administration in the form of tablet or intravenous administration.

Generally, the weight ratio of the first ingredient to the second ingredient is between 30 to 1 and 5 to 1 selected in accordance with the above-mentioned guideline. In one embodiment of the present invention pharmaceutical composition comprises etodolac in an amount of 100-800 mg and famotidine in an amount of 10-80 mg.

In another embodiment of the present invention pharmaceutical composition according to claims 8 to 10, wherein the pharmaceutical composition comprises etodolac in an amount of 400 mg and famotidine in an amount of 20 mg. 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, that is why at least 30% of the etodolac and famotidine oral formulations of the present invention have to be released in the stomach before reaching the intestines.

Dosage forms of the drug may be administered once, twice or thrice a day. Generally, the weight ratio of the first ingredient to the second ingredient is selected in accordance with the following guidelines

Pharmaceutically Acceptable Carriers

Pharmaceutically acceptable carriers include diluents and excipients generally used in pharmaceutical preparations, such as fillers, extenders, binders, moisturizers, disintegrators, surfactants, and lubricants.

The pharmaceutical formulation of the present invention may be formulated as an ordinary pharmaceutical preparation , for example in the form of gel, cream, ointment, tablet, capsule, drop, pellet, granule, solution, suspension, syrup, powder, injectable suspension, injectable powder and injectable solution and the like. In a preferred embodiment, the pharmaceutical formulation of the present invention may be formulated as an oral dosage form, more preferably, in tablet form.

Oral dosage forms of the invention preferably in tablet form may comprise a pharmaceutically acceptable non-toxic inert carrier such as lactose, microcrystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose, dextrose and the like.

Oral dosage forms of the invention may optionally comprise suitable binders, lubricants, disintegrating agents, flavoring agents, sweetening agents, coloring agents and coating agents. Suitable binders of the invention may be selected from starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP (Polyvinylpyrrolidone), polyethylene glycols, waxes, sodium alginate, alcohols, water and the like. Suitable lubricants of the 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. Suitable disintegrating agents of the invention may be selected from starches, cellulose derivatives, PVP (Polyvinylpyrrolidone), crospovidone, clays, ion-exchange resins, alginic acid, sodium alginate and the like.

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

The present invention may comprise an injectable unit dosage form for intravenous, intramuscular or subcutaneous administration formulated as aqueous or non-aqueous solution or suspension, or as powder for injection, with suitable pharmaceutically acceptable non-toxic excipients. The present invention may also comprise extended, modified or controlled release (controlled, prolonged, sustained, immediate, timed, slow or fast release) tablet or capsule to provide the control of the release of the active components, preferably etodolac and/or famotidine in order to optimize the therapeutic effects and minimize the undesirable side effects.

The present invention also provides a combinatory tablet formulation of etodolac and famotidine with an instant or normal release profile, with at least 30% of etodolac and famotidine released in the stomach before reaching the intestines.

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 etodolac in combination with famotidine.

Table 1: Film Tablet Composition Example

Illustrative Film Tablet Weight (mg) / unit dose

Core

Etodolac 400.00

Famotidine 20.00

Lactose 230.00

Microcrystalline cellulose 132.00

Sodium starch glycolate 44.00

Colloidal silicon dioxide 2.20

PVP (K-30) 35.20

Magnesium stearate 8.80 Film Coating

Hidroxypropylmethyl cellulose 32.40

Titanium dioxide 14.70

PEG 400

2.90

Example 2

Preparation methods of the pharmaceutical compositions of the inventions

1. Preparation method wherein the active components are not directly mixed: At the first stage, a certain amount of Polyvinylpyrrolidone (K-30) is dissolved in purified water. Etodolac, remaining amount of Polyvinylpyrrolidone (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet-granulated with the Polyvinylpyrrolidone (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 Polyvinylpyrrolidone (K-30) is dissolved in purified water. Etodolac, famotidine, remaining amount of Polyvinylpyrrolidone (K-30), lactose, microcrystalline cellulose, sodium starch glycolate and colloidal silicon dioxide are mixed together. The obtained mixture is wet- granulated with the Polyvinylpyrrolidone (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 Chronic Back Pain 2 groups of patients (n=5 in each group) received etodolac 400 mg tablets alone and etodolac in combination with 20 mg famotidine tablet a single unit pharmaceutical dosage form, twice a day for chronic back pain for a period of 4 weeks. The group using the etodolac 400 mg tablets showed improvement in VAS pain score by 20%. The group using the etodolac 400 mg in combination with famotidine 20mg 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 etodolac 400 mg tablet were higher and 2 patients from the etodolac 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 400 mg etodolac in combination with 20mg famotidine in single unit pharmaceutical dosage form.

The extent of the invention should not be limited by the examples. The examples above are only given to illustrate the invention.