| WO2012173581A1 | 2012-12-20 | |||
| WO2008027963A2 | 2008-03-06 | |||
| WO2002098352A2 | 2002-12-12 | |||
| WO2018004498A1 | 2018-01-04 | |||
| WO2005076987A2 | 2005-08-25 |
| US20140186439A1 | 2014-07-03 | |||
| EP1411900B1 | 2010-07-21 | |||
| US20090233970A1 | 2009-09-17 | |||
| US20070237820A1 | 2007-10-11 | |||
| EP0814839B1 | 2003-06-04 |
"Comprehensive Toxicology.", 2010, ELSEVIER, pages: 159 - 161
| CLA1MS 1. An instant release pharmaceutical formulation for oral use comprising: (i) a selective COX-2 inhibitor NSA1D or a pharmaceutically acceptable salt thereof; (ii) an H2 receptor antagonist or a pharmaceutically acceptable salt thereof; (in) one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 5 mg to 90 mg or in an amount from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D. 2. The instant release pharmaceutical formulation according to claim 1, wherein said selective COX-2 inhibitor NSA1D is selected from etodolac, meloxicam and piroxicam, or a pharmaceutically acceptable salt thereof. 3. The instant release pharmaceutical formulation according to claim 1 or 2, wherein the selective COX-2 inhibitor NSA1D is etodolac or meloxicam. 4. The instant release pharmaceutical formulation according to anyone of claims 1 to 3, wherein the selective COX-2 inhibitor NSA1D is etodolac. 5. The instant release pharmaceutical formulation according to anyone of claims 1 to 4, wherein said H2 receptor antagonist is selected from famotidine, cimetidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine, or a pharmaceutically acceptable salt thereof. 6. The instant release pharmaceutical formulation according to anyone of claims 1 to 5, wherein the H2 receptor antagonist is famotidine. 7. The instant release pharmaceutical formulation according to anyone of claims 1 to 5, wherein the selective COX-2 inhibitor NSA1D is etodolac or meloxicam, and the H2 receptor antagonist is famotidine. 8. The instant release pharmaceutical formulation according to anyone of claims 1 to 7, wherein the composition is in the form of a unit dose pack of powder for dissolving or suspending in water. 9. The instant release pharmaceutical formulation according to anyone of claims 1 to 7, wherein the composition is in the form of an instant release tablet. 10. The instant release pharmaceutical formulation according to anyone of claims 1 to 7, wherein the composition is in the form of an instant release capsule. 11. The instant release pharmaceutical formulation according to anyone of claims 1 to 10, comprising selective COX-2 inhibitor NSA1D or pharmaceutically acceptable salt thereof in an amount of from 7.5 to 800 mg. 12. The instant release pharmaceutical formulation according to anyone of claims 1 to 11, comprising etodolac or pharmaceutically acceptable salt thereof in an amount from 200 to 800 mg. 13. The instant release pharmaceutical formulation according to anyone of claims 1 to 12, comprising etodolac or pharmaceutically acceptable salt thereof in an amount of 200, 300, 400, 500 or 600 mg. 14. The instant release pharmaceutical formulation according to anyone of claims 1 to 13, comprising meloxicam or pharmaceutically acceptable salt thereof, in an amount from 5 to 30 mg. 15. The instant release pharmaceutical formulation according to anyone of claims 1 to 14, comprising meloxicam or pharmaceutically acceptable salt thereof in an amount of 7.5 or 15 mg. 16. The instant release pharmaceutical formulation according to anyone of claims 1 to 15, comprising H2 receptor antagonist in an amount from 5 to 80 mg. 17. The instant release pharmaceutical formulation according to anyone of claims 1 to 16, comprising H2 receptor antagonist in an amount from 10 to 60 mg. 18. The instant release pharmaceutical formulation according to anyone of claims 1 to 17, comprising H2 receptor antagonist in an amount from 10 to 40 mg. 19. The instant release pharmaceutical formulation according to anyone of claims 1 to 18, comprising H2 receptor antagonist in an amount of 10, 20 or 40 mg, wherein the H2 receptor antagonist is famotidine. 20. The instant release pharmaceutical formulation according to anyone of claims 1 to 19, wherein at least 25% of the selective COX-2 inhibitor NSA1D and at least 25% of the H2 receptor antagonist is released before reaching the intestines. 21. An instant release pharmaceutical formulation according to anyone of claims 1 to 20, wherein the H2 receptor antagonist increases the Cmax of selective COX-2 inhibitor NSA1D by at least 3%. 22. An instant release pharmaceutical formulation according to anyone of claims 1 to 21, wherein the H2 receptor antagonist increases the Cmax of selective COX-2 inhibitor NSA1D by at least 10%. 23. An instant release pharmaceutical formulation according to anyone of claims 1 to 22, wherein the H2 receptor antagonist creates an AUC at least 10% higher than selective COX-2 inhibitor NSA1D administered alone. 24. An instant release pharmaceutical formulation according to anyone of claims 1 to 23, wherein the H2 receptor antagonist creates a Tmax of less than about 2 hours for etodolac. 25. An instant release pharmaceutical formulation according to anyone of claims 1 to 24, wherein the H2 receptor antagonist creates a Cmax of higher than 2700 ng/ml for etodolac. 26. An instant release pharmaceutical formulation according to anyone of claims 1 to 23, wherein the H2 receptor antagonist creates a Cmax of higher than 1600 ng/ml for meloxicam. 27. An instant release pharmaceutical formulation according to anyone of claims 1 to 26 for use in the treatment of inflammation or pain. 28. An instant release pharmaceutical formulation for use according to claim 27, wherein inflammation or pain caused by muscular or skeletal system diseases. 29. An instant release pharmaceutical formulation for use according to claim 27 or 28, wherein inflammation or pain is caused by chronic polyarthritis, ankylosing spondilytis, osteoarthritis, gout attacks, extra-articular rheumatism, post-traumatic and postoperative pain, and dysmenorrhea. 30. An instant release pharmaceutical formulation according to anyone of claims 1 to 26, for use in a method of treating a human subject in need of a fast pain relief or fast relief from an inflammatory or pyretic condition. 31. A method for obtaining a Tmax of a selective COX-2 inhibitor NSA1D in a human patient between about 80 and 240 minutes after administrating said selective COX-2 inhibitor NSA1D to said patient, comprising orally administering the selective COX-2 inhibitor NSA1D formulation to said patient, wherein said selective COX-2 inhibitor NSA1D formulation comprises etodolac or a pharmaceutically acceptable salt thereof together with an H2 receptor antagonist, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D. 32. A method for obtaining a Cmax of a selective COX-2 inhibitor NSA1D in a human patient higher than 1600 ng/ml after administrating said selective COX-2 inhibitor NSA1D to said patient, comprising orally administering the selective COX-2 inhibitor NSA1D formulation to said patient, wherein said selective COX-2 inhibitor NSA1D formulation comprises meloxicam or a pharmaceutically acceptable salt thereof together with an H2 receptor antagonist, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D. |
ANTAGONISTS FOR FAST TREATMENT OF PAIN AND INFLAMMATION
TECHN1CAL F1ELD
The present invention is relates to pharmaceutical combinations comprising a selective COX-2 inhibitor as a NSA1D and a H2 receptor antagonist, to oral dosage forms comprising such combinations and to processes for the preparation thereof
BACKGROUND ART lt is well known that NSAlDs have the potential to cause gastrointestinal (GI) side effects, such as gastric and duodenal ulcers, bleeding and perforation, esophageal 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 lnhibition of COX-1 is also responsible, in part, for gastrointestinal side effects, which are the most frequent side effects of NSAlDs.
Gwaltney-Brant S.M. reports that non-selective COX inhibitors have other contributors to their gastrointestinal side effects, which are the carboxylic acid group in compounds, such as aspirin, ibuprofen and the acidic enolic group in oxicams, such as piroxicam (Charlene A.M., editor. Comprehensive Toxicology. 2nd ed. Elsevier; Oxford, UK: 2010. pp. 159-161). These acidic groups cause local irritation upon oral administration, which can lead to the clinically observed gastrointestinal side effects either independently or in tandem with inhibition of the COX-1 enzyme. ln a report, Lanas et al. (2011) have concluded that more than 90% of the treated patients with osteoarthritis are at increased Gl risk, with 60% of them at high risk.
Selective COX-2 inhibitors are a proven, commonly prescribed NSAIDs that has analgesic, anti-inflammatory, and antipyretic properties, and has been shown to be effective in treating a variety of acute and chronic pain and inflammatory conditions.
Selective COX-2 inhibitor NSAlDs are a type of NSA1D that directly targets COX-2 responsible for inflammation and pain. Targeting selectivity for COX-2 reduces the risk of peptic ulceration. Although NSAlDs which are selective inhibitors of COX-2 tend to have less gastro-intestinal 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. NSAlDs that are selective COX- 2 inhibitors, including compounds such as etodolac, meloxicam, piroxicam, and nimesulide have anti-inflammatoiy actions and are effective on pain associated with the release of prostaglandins and other mediators of inflammation. Another important issue related to the use of selective COX-2 inhibitors is the time of onset and duration of action lt is desirable to obtain a rapid onset of action and long duration of analgesic effect for an efficient pain management. Attempts are therefore still being made in order to enhance the rate of absorption of selective COX-2 inhibitor NSAlDs and to provide an earlier onset of the therapeutic effect whilst increasing the long term effect of these NSAlDs as well.
Due to the fact that NSAlDs can cause Gl 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 Gl side effects is needed. To reduce the risk of serious Gl adverse effects associated with long-term use of selective COX-2 inhibitor NSAIDs, combination therapies based binary combinations of selective COX-2 inhibitors with gastro protective agents such as prostaglandin analogs or proton pump inhibitors were developed.
US patent application US 2014186439 A1 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 B1 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 NSA1D (preferably aspirin or naproxen) and a barrier coating surrounding the inner core of said NSA1D, which might create manufacturing difficulties, stability issues.
US patent application no. US 20090233970 A1 relates to co-administration of a NSA1D 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 NSA1D (preferably naproxen or ibuprofen); and at least one acid blocking agent (preferably ranitidine).
US patent application US 20070237820 A1 relates to a solid oral dosage form comprising a first portion comprising an NSA1D (preferably selective COX-2 inhibitor); and a coating comprising an anti-ulcerative compound (preferably misoprostol); said coating at least partially surrounding said first NSA1D portion. The pharmaceutical dosage described therein creates manufacturing difficulties. European patent EP 0814839 B1 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 NSA1D (preferably ibuprofen, selective COX-2 inhibitor sodium, piroxicam or naproxen) and optionally pharmaceutically acceptable excipients are compressed together. lnternational patent application WO 2005076987 A2 relates to a pharmaceutical composition comprising at least one proton pump inhibitor (preferably omeprazole), at least one NSA1D and at least one buffering agent.
The use of a proton pump inhibitors as described above might create secondary complications due to long term use of the PPls.
Therefore a particular need exists for a composition giving fast and long duration of pain relief with decreased side effects.
The aim of the present invention to provide an instant release pharmaceutical formulation comprising at least one NSA1D, that is COX-2 selective and at least one H2 receptor antagonist as a gastro protective agent to reduce the occurrence of gastro intestinal side effects and at the same time providing an efficient pain management.
Another aim of the present invention is to provide an instant release pharmaceutical formulation of a NSA1D that is a selective COX-2 inhibitor in combination with an H2 receptor antagonist as a gastro protective agent, having a three-fold advantage in a synergistic manner decreasing the side effects while inducing an increase in the blood concentration of the NSA1D in a shorter time compared to the mono administration of the said NSA1D whilst also increasing it’s long term potency.
BR1EF DESCRIPTION OF THE INVENTION
The present invention provides instant release pharmaceutical formulations for oral use comprising a selective COX-2 inhibitor NSA1D or a pharmaceutically acceptable salt thereof; an H2 receptor antagonist or a pharmaceutically acceptable salt thereof; one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 5 mg to 90 mg or in an amount from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D. The pharmaceutical composition comprising said two active ingredients provides numerous advantages over either ingredient alone including: a significant reduction in the time of onset of action, pain relief over extended periods of time and reduced side effects. ln one embodiment pharmaceutical formulation comprising a selective COX-2 inhibitor NSA1D is selected from etodolac, meloxicam and piroxicam, or a pharmaceutically acceptable salt thereof. ln one embodiment pharmaceutical formulation comprising an H2 receptor antagonist is selected from famotidine, cimetidine, ebrotidine, pabutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine and oxmetidine, or a pharmaceutically acceptable salt thereof. ln one embodiment pharmaceutical formulation comprising etodolac or meloxicam, and famotidine.
Furthermore, the present invention provides the use of pharmaceutical formulation comprising a combination of selective COX-2 inhibitor NSA1D and an H2 receptor antagonist for the treatment of inflammation and pain ln one embodiment said
combination is used for the treatment of inflammation and pain caused by muscular or skeletal system diseases ln another embodiment said combination is used for the treatment of inflammation and pain caused by chronic polyarthritis, ankylosing spondilytis, osteoarthritis, gout attacks, extra-articular rheumatism, post-traumatic and postoperative pain, or dysmenorrhea.
The present invention further provides a method for obtaining a Tmax of a selective COX-2 inhibitor NSA1D in a human patient between about 80 and 240 minutes after administrating said selective COX-2 inhibitor NSA1D to said patient, comprising orally administering the selective COX-2 inhibitor NSA1D formulation to said patient, wherein said selective COX-2 inhibitor NSA1D formulation comprises etodolac or a pharmaceutically acceptable salt thereof together with an H2 receptor antagonist, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D.
The present invention further provides a method for obtaining a Cmax of a selective COX-2 inhibitor NSA1D in a human patient higher than 1600 ng/ml after administrating said selective COX-2 inhibitor NSA1D to said patient, comprising orally administering the selective COX-2 inhibitor NSA1D formulation to said patient, wherein said selective COX- 2 inhibitor NSA1D formulation comprises meloxicam or a pharmaceutically acceptable salt thereof together with an H2 receptor antagonist, and one or more pharmaceutically acceptable excipients, wherein said H2 receptor antagonist is present in an amount of from 2 to 300% by weight based on the weight of the selective COX-2 inhibitor NSA1D.
DETA1LED DESCRIPTION OF THE INVENTION
The present invention provides an instant release pharmaceutical formulation comprising a) a selective COX-2 inhibitor NSA1D, and b) at least one H2 receptor antagonist as a gastro protective agent. The instant release pharmaceutical formulation of the present invention has the benefit of diminishing the gastrointestinal side effects associated with the selective COX-2 inhibitor NSAlDs. Furthermore, the combination of an H2 receptor antagonist, preferably famotidine with the selective COX-2 inhibitor NSA1D, preferably etadolac or meloxicam surprisingly increases the permeability and the rate of absorption of the selective COX-2 inhibitor NSA1D. ln other words, said combinations increase Cmax and AUC values and decrease Tmax of the selective COX-2 inhibitor NSA1D.
For the purposes of the present invention Tmax means the amount of time that a drug is present at the maximum concentration in serum; Cmax is the peak serum concentration of a drug; and AUC (the area under the curve) represents the area under the plasma concentration curve, also called the plasma concentration-time profile, a measure of total systemic exposure to the drug. The fact that H2 receptor antagonist creates this synergistic effect when coupled with selective COX-2 inhibitor NSA1D has a threefold advantage which has never attained before; 1: higher concentration of selective COX-2 inhibitor NSA1D in blood, 2: in a shorter period of time compared with the traditional selective COX-2 inhibitor NSA1D tablets or capsules, 3: protection of the gastric mucosa due to the gastroprotective properties of H2 receptor antagonist. This will create a new treatment modality with fast onset of action whilst maintaining the long acting effect of the COX-2 inhibitor NSA1D, without the unwanted Gl side effects. The selective COX-2 inhibitor NSA1D used in the present invention is a COX-2 selective inhibitor which by definition has more affinity for COX-2 compared to COX-1. Other NSAlDs do not necessarily share the same mechanism of action. COX-2 selective inhibitor NSA1DS also have a longer half-life compared to equipotent COX inhibitor NSAlDs. Thus they have the advantage of having a longer time period of effectiveness (longer half-life) but have the disadvantage to take effect later, having a delayed Tmax. They posses analgesic and antipyretic properties as well as anti-inflammatoiy activity. ln one embodiment of the present invention the instant release pharmaceutical formulation comprises a selective COX-2 inhibitor NSA1D selected from etodolac, meloxicam, and piroxicam.
The chemical structure of etodolac is shown in Formula 1.
Formula 1 The chemical structure of meloxicam is shown in Formula 2.
Formula 2 The chemical structure of piroxicam is shown in Formula 3.
Formula 3 ln one embodiment, the selective COX-2 inhibitor NSA1D is in the form of a free acid or in the form of a salt. ln one preferred embodiment of the present invention, the selective COX-2 inhibitor NSA1D is etodolac or meloxicam. ln most preferred embodiment of the present invention, the selective COX-2 inhibitor NSA1D is etodolac. The chemical name of etodolac is 2-(l,8-diethyl-4,9-dihydro-3H- pyrano [3,4-b] indol- 1-yl) acetic acid. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises at least one H2 receptor antagonist selected from famotidine, pibutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine, and oxmetidine. ln one preferred embodiment of the present invention, the H2 receptor antagonist is famotidine, or pharmaceutically acceptable salt thereof.
Famotidine is an H2-receptor antagonist used in the treatment of gastrointestinal diseases lt protects the gastric mucosa against irritation, thus it is used in the treatment of gastrointestinal diseases lts chemical structure is shown in Formula 5.
Formula 5
The chemical name of famotidine is 3-(2-(diaminomcthyleneamino)thiazol-4-yl methylthio) - N -sulfamoylpropionamidine. ln one preferred embodiment of the present invention the instant release pharmaceutical formulation comprises etodolac and famotidine lt has now been found that said combination provides the most efficient etodolac treatment when a fast onset of action and over an extended period of time pain relief or antipyretic/anti - inflammatoiy effect with decreased Gl side effects is needed. The reason why this combination can be stated as the most efficient etodolac treatment is that the results obtained in the current study demonstrate a superior, surprising effect with Cmax over 2700 ng/ml, a Tmax below 240 minutes and an AUC over 1900 h.ng/ml. ln another preferred embodiment of the present invention the instant release pharmaceutical formulation comprises meloxicam and famotidine lt has also been found that said combination provides the most efficient meloxicam treatment when a fast onset of action and over an extended period of time pain relief or antipyretic/anti - inflammatoiy effect with decreased Gl side effects is needed. The reason why this combination can be stated as the most efficient meloxicam treatment is that the results obtained in the current study demonstrate a superior, surprising effect with Cmax over 1600 ng/ml and an AUC over 8000 h.ng/ml.
These results clearly demonstrate the synergistic effect between selective COX-2 inhibitor NSAIDs and H2 receptor antagonists. Thus the present invention provides an analgesic and antipyretic/anti-inflammatory effect with a fast and extended period of time and reduced risk of developing gastrointestinal side effects ln other words, the present invention is able to provide a longer period of therapeutic effect due to the slow elimination of selective COX-2 inhibitor NSA1D as evidenced by its high AUC value despite its instant release and fast onset of action.
The instant release pharmaceutical formulation of the present invention is synergistically effective for the treatment of painful inflammatory or pyretic conditions. The instant release pharmaceutical formulation of the present invention would also allow for relatively safe administration of high doses of COX-2 inhibitor NSA1D and long administration duration, which would be especially important for patients who have acute pain attacks in a period shorter than 6 months but also for patients who have pain and inflammation related problems over a long period of time.
The combination of the present invention can be administered in various dosage forms and strength in pharmaceutically effective amount. An instant release pharmaceutical formulation of the present invention may be in the form of a tablet, capsule pellet, granule, tablet in tablet, tablet in capsule, powder or in coated tablet form, preferably being in tablet, capsule or powder form lt is important for the tablets or capsules to have an instant or immediate release profile in the gastrointestinal system. Powder form can be a pack of powder for dissolving or suspending in water. Suitable dosages can be selected according to the condition to be treated. Dosage of the selective COX-2 inhibitor NSA1D used in the combination of 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, etodolac: 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.
First ingredient, meloxicam: generally about 5-15 mg for acute pain, preferably up to 15 mg daily for inflammation related diseases by oral administration in the form of a capsule or tablet.. The usual initial dose is about 7.5-15 mg daily for acute pain, 15 mg daily for inflammation-related diseases by oral administration in the form of a capsule or tablet.
First ingredient, piroxicam: generally about 5-20 mg for acute pain, preferably up to 20 mg daily for inflammation related diseases. The usual initial dose is about 10-20 mg daily for acute pain, 20 mg daily for inflammation-related diseases by oral administration in the form of a capsule or tablet.
The pharmaceutical dosage form of the present invention may comprise active components in the form of a racemic mixture, or in the form of substantially pure enantiomers or salts of enantiomers thereof. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises from 7.5 to 800 mg of the selective COX-2 inhibitor NSA1D or pharmaceutically acceptable salt thereof. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises from 200 to 800 mg, more preferably 200, 300, 400, 500 or 600 mg of etodolac or pharmaceutically acceptable salt thereof. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises from 5 to 30 mg, preferably 7.5 or 15 mg of meloxicam or pharmaceutically acceptable salt thereof. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises from 5 to 90 mg, preferably from 10 to 60 mg, more preferably from 10 to 40 mg, the most preferably 10, 20 or 40 mg of H2 receptor antagonist. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises from 2 to 300%, preferably 3 to 200% by weight of H2 receptor antagonist based on the weight of the selective COX-2 inhibitor NSA1D. ln one embodiment of the present invention the ratio of selective COX-2 inhibitor NSA1D, preferably meloxicam or piroxicam to the H2 receptor antagonist can be from about 1 to 2 or from about 1 to 1.5 or from about 1 to 1.333 by weight. ln one embodiment of the present invention, a ratio of H2 receptor antagonist to selective COX-2 inhibitor NSA1D, preferably etodolac can be from about 0.025 to 1 or from about 0.05 to lor from about 0.1 to 1 by weight. ln one preferred embodiment, the instant release pharmaceutical formulation of the present invention comprises a selective COX-2 inhibitor NSA1D selected from etodolac, meloxicam and piroxicam, or pharmaceutically acceptable salt thereof, in combination with H2 receptor antagonist selected from famotidine, pibutidine, lafutidine, loxtidine, nizatidine, roxatidine, tiotidine, niperotidine, and oxmetidine or pharmaceutically acceptable salt thereof, in which H2 receptor antagonist is present in an amount of from 5 mg to 50 mg. ln one embodiment of the present invention the instant release pharmaceutical formulation of the present invention is in the form of an instant release tablet. ln one embodiment of the present invention the instant release pharmaceutical formulation of the present invention is in the form of an instant release capsule. ln one embodiment an instant release pharmaceutical formulation of the present invention further comprises at least one pharmaceutically acceptable excipient such as a carrier.
Oral dosage forms of the present invention may comprise suitable diluents, binders, lubricants, disintegrating agents, surfactants, sweetening agents, coloring agents and coating agents.
Examples of pharmaceutically acceptable diluents include, but not limited to, magnesium stearate, lactose, microciystalline cellulose, starch, pre-gelatinized starch, calcium phosphate, calcium sulfate, calcium carbonate, mannitol, sorbitol, xylitol, sucrose, maltose, fructose and dextrose.
Examples of pharmaceutically acceptable binders include, but not limited to, starches, natural sugars, corn sweeteners, natural and synthetic gums, cellulose derivatives, gelatin, PVP, polyethylene glycol, waxes, sodium alginate, alcohols and water.
Examples of pharmaceutically acceptable lubricants include, but not limited to metallic stearates, metallic lauiyl sulfates, fatty acids, fatty acid esters, fatty alcohols, paraffins, hydrogenated vegetable oils, polyethylene glycols, boric acid, sodium benzoate, sodium acetate, sodium chloride and talk. Examples of pharmaceutically acceptable disintegrating agents include, but not limited to, starches, cellulose derivatives, PVP, crospovidone, clays, ion-exchange resins, alginic acid and sodium alginate .
Examples of pharmaceutically acceptable surfactants include, but not limited to 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, and poloxamers. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises etodolac and famotidine wherein the Tmax of etodolac is between 60 and 240 minutes, preferably between 90 and 240 minutes and more preferably between 90 and 180 minutes. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises etodolac and famotidine wherein the Tmax of etodolac is less thanl20 minutes. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises etodolac and famotidine wherein the Cmax of of etodolac is between 2700 and 2800 ng/ml. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises etodolac and famotidine wherein the AUC of etodolac after 12 hours of administration is between 18,800 and 19,500 h.ng/ml. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises etodolac and famotidine wherein famotidine increases the Cmax of etodolac by at least 3%, preferably by 10%. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises meloxicam and famotidine wherein the Cmax of of meloxicam is between 1600 and 1800 ng/ml. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises meloxicam and famotidine wherein the AUC of meloxicam after 12 hours of administration is between 7,800 and 8,500 h.ng/ml. ln another embodiment of the present invention, the instant release pharmaceutical formulation comprises meloxicam and famotidine wherein famotidine increases the Cmax of meloxicam by at least 3%, preferably by 10%. ln one embodiment of the present invention, the instant release pharmaceutical formulation comprises meloxicam and famotidine wherein the Tmax of meloxicam is less than 180 minutes. ln one embodiment, an oral instant release pharmaceutical formulation of the present invention has an instant or immediate release profile, with at least 25% of the selective COX-2 inhibitor NSA1D and at least 25% of H2 receptor antagonist released before reaching the intestines. lt will be by the way evident to any skilled in this art that the present formulations can also be used as instant or immediate release layers of multilayered release pharmaceutical formulations containing selective COX-2 inhibitor NSAlDs, preferably etodolac or meloxicam and at least one H2 receptor antagonist, preferably famotidine said formulations are therefore a further object of the present invention. ln one embodiment, the instant release pharmaceutical formulation of the present invention is synergistically effective for the treatment of painful inflammatory or pyretic conditions. ln one preferred embodiment, the instant release pharmaceutical formulation of the present invention is synergistically effective for the treatment of inflammation or pain caused by muscular or skeletal system disease. ln another preferred embodiment, the instant release pharmaceutical formulation s of the present invention is synergistically effective for the treatment of inflammation or pain caused by chronic polyarthritis, ankylosing spondilytis, osteoarthritis, gout attacks, extra-articular rheumatism, post-traumatic and postoperative pain, and dysmenorrhea. EXAMPLES
The present invention will be explained in more detail by illustrating Examples and studies. Example 1
Table 1 provides the contents of an embodiment of the present invention. The composition is in the form of a film coated tablet of meloxicam in combination with famotidine. Table 1 Film coated tablet of meloxicam in combination with famotidine
Example 2
Preparation methods of the pharmaceutical compositions comprising meloxicam in combination with famotidine
1. Preparation method wherein the active components are not directly mixed:
At the first stage, a certain amount of PVP (K-30) is dissolved in purified water. Meloxicam , 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 passed 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. Meloxicam, 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 passed 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. Example 3
Table 2 provides the contents an embodiment of the present invention. The composition is in the form of a film coated tablet of etodolac in combination with famotidine. Table 2 Film coated tablet of etodolac in combination with famotidine
Example 4
Preparation methods of the pharmaceutical compositions comprising etodolac in combination with famotidine
1. Preparation method wherein the active components are not directly mixed:
At the first stage, a certain amount of PVP (K-30) is dissolved in purified water. Etodolac, 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.
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. Etodolac, 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.
DETA1LS OF THE STUDY PROV1NG THE SYNERGEST1C EFFECT BETWEEN SELECT1VE COX-2 INHIBITOR NSA1D AND H2 RECEPTOR ANTAGON1ST
Example 6
Experimental procedure to compare the pharmacokinetic properties of etodolac alone and etodolac in combination with famotidine
The primary objective of this experimental study was to compare the pharmacokinetic properties of etodolac in combination with famotidine ln this experimental study, the aim was to observe how the addition of famotidine would change the pharmacokinetic properties of etodolac when etodolac is given alone or in combination with famotidine.
Animals
Male Wistar rats (240-260 g) were maintained in an air conditioned quarters at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 10 %. Food and water were allowed ad libitum. The animals were acclimatized to the facilities for five days, and then fasted with free access to water for 12 h prior to the experiment. All these animals were housed under similar conditions. Drug Administration
Bioavailability and pharmacokinetics of etodolac were studied in two different groups; the first group was administered etodolac alone and the second group was administered a combination of etodolac and famotidine following an oral administration of 10 mg/kg etodolac, 0.5 mg/kg. The ratio of etodolac to famotidine was 20 to 1; equal to 400 mg etodolac and 20 mg famotidine in human dosing.
Six male and/or female rats per group were lavaged with 10 mg/kg Selective COX-2 inhibitor etodolac and a combination of etodolac and famotidine. Blood (0.2 ml) was taken from the tail vein prior to administration of test substances (0 h) and blood was taken after 0.083, 0.167, 0.25, 0.5, 1, 2, 4, 8 and 12h respectively.
Extraction of Blood Samples
Blood samples were collected in tubes containing %5 Na2-EDTA and kept on ice until dichloromethane was added and they were centrifuged at 7000 x g for 5 min at 4°C and supernatants were collected for HPLC analysis. Results
Table 3. Blood Concentrations of Etodolac
Figure 1 shows the effects of famotidine on blood concentrations of etodolac. Table 4. Pharmacokinetic Parameters of Etodolac in Blood
Evaluation of the Results
Table 3 shows the Cmax and Tmax values of etodolac and etodolac + famotidine. As it can be seen there is an evident increase in the Cmax values of etodolac when it is used in combination with famotidine. The Cmax of etodolac when used as a single active ingredient is 2624 ng/ml, whereas it is 2786 ng/ml when used in combination with famotidine. Similarly, Tmax values in Table 3 also show that combinations of the present invention provide a faster pain relief compared to etodolac alone. Tmax of etodolac when used as a single active ingredient is 4 hours, whereas it is 2 hours when used in combination with famotidine. ln addition to Table 3, Table 4 provides 12 hour AUC values of etodolac. The combination of etodolac + famotidine has a higher AUC value compared to etodolac alone, meaning this combination provides a long duration of pain and inflammation relief.
The surprising results prove the pharmacokinetic superiority of a selective COX-2 inhibitor NSA1D and H2 receptor antagonist combination especially when pharmacokinetic parameters are concerned. Furthermore in a 12 hour period after the oral administration of the combination of the present invention, surprisingly there isn’t a fast decrease of the blood concentration, instead the addition of famotidine creates therapeutically effective blood concentrations throughout the 12 hour period as evidenced by the higher than normal AUC.
Example 7 Experimental procedure to compare the pharmacokinetic properties of meloxicam alone and meloxicam in combination with famotidine
The primary objective of this experimental study was to compare the pharmacokinetic properties of meloxicam in combination with famotidine ln this experimental study, the aim was to observe how the addition of famotidine would change the pharmacokinetic properties of meloxicam when meloxicam is given alone or in combination with famotidine.
Animals
Male Wistar rats (240-260 g) were maintained in an air conditioned quarters at a temperature of 22 ± 2 °C and a relative humidity of 50 ± 10 %. Food and water were allowed ad libitum. The animals were acclimatized to the facilities for five days, and then fasted with free access to water for 12 h prior to the experiment. All these animals were housed under similar conditions.
Drug Administration
Bioavailability and pharmacokinetics of meloxicam were studied in two different groups; the first group was administered meloxicam alone and the second group was administered a combination of meloxicam and famotidine. Following an oral administration of 1.5 mg/kg meloxicam, 2 mg/kg famotidine. The ratio of meloxicam to famotidine was 1 to 1.33 ; equal to 15 mg meloxicam and 20 mg famotidine in human dosing. Six male and/or female rats per group were lavaged with 1,5 mg/kg Selective COX-2 inhibitor meloxicam and a combination of meloxicam and famotidine. Blood (0.2 ml) was taken from the tail vein prior to administration of test substances (0 h) and blood was taken after, 0.16, 0.5, 1, 1.5, 2,3 4,5,6, 8 and lOh respectively. Extraction of Blood Samples
Blood samples were collected in tubes containing %5 Na2-EDTA and kept on ice until dichloromethane was added and they were centrifuged at 7000 x g for 5 min at 4°C and supernatants were collected for HPLC analysis. Results
Table 5. Blood Concentrations of Meloxicam
Figure 2 shows the effects of famotidine on blood concentrations of meloxicam. Table 6. Pharmacokinetic Parameters of Meloxicam in Blood
Evaluation of the Results
Table 5 shows the Cmax and Tmax values of meloxicam and meloxicam ± famotidine. As it can be seen there is an evident increase in the Cmax values of meloxicam when it is used in combination with famotidine. The Cmax of meloxicam when used as a single active ingredient is 1554 ng/ml, whereas it is 1735 ng/ml when used in combination with famotidine. ln addition to Table 5, Table 6 provides 10 hour AUC values of meloxicam. The combination of meloxicam ± famotidine has a higher AUC value compared to meloxicam alone, meaning this combination provides a long duration of pain and inflammation relief. Even though meloxicam alone and meloxicam ± famotidine have the same Tmax, the meloxicam ± famotidine has higher blood concentrations of meloxicam at the 2nd hour, which is comparable to the concentration at 3rd hour of meloxicam alone, meaning that the extent of absorption was much higher.
The surprising results detailed below demonstrate the pharmacokinetic superiority of a selective COX-2 and famotidine combination especially when pharmacokinetic parameters are concerned. Furthermore in a 10 hour period after the oral administration of the combination of the present invention, surprisingly there isn’t a fast decrease of the blood concentration, instead the addition of famotidine creates therapeutically effective blood concentrations throughout the 10 hour period as evidenced by the higher than normal AUC. lt has to be understood that the above-described various types of compositions, dosage forms and/or modes of applications, described in the examples above are only illustrative of preferred embodiments of the present invention. Numerous modifications and alternative arrangements may be devised by those skilled in the art without departing from the spirit and scope of the present invention.
Next Patent: METAL DETECTOR CAPABLE OF VISUALIZING THE TARGET SHAPE