MXPA06009501A - Compostions comprising glycosaminoglycan and nonsteroidal anti-inflammatory drug - Google Patents
Compostions comprising glycosaminoglycan and nonsteroidal anti-inflammatory drugInfo
- Publication number
- MXPA06009501A MXPA06009501A MXPA/A/2006/009501A MXPA06009501A MXPA06009501A MX PA06009501 A MXPA06009501 A MX PA06009501A MX PA06009501 A MXPA06009501 A MX PA06009501A MX PA06009501 A MXPA06009501 A MX PA06009501A
- Authority
- MX
- Mexico
- Prior art keywords
- salts
- inflammatory drug
- glycosaminoglycan
- steroidal anti
- agents
- Prior art date
Links
- 229940021182 non-steroidal anti-inflammatory drugs Drugs 0.000 title claims abstract description 51
- 239000000041 non-steroidal anti-inflammatory agent Substances 0.000 title claims abstract description 37
- 229920002683 Glycosaminoglycan Polymers 0.000 title claims abstract description 27
- 239000000203 mixture Substances 0.000 claims abstract description 48
- 150000003839 salts Chemical class 0.000 claims abstract description 44
- 239000011780 sodium chloride Substances 0.000 claims abstract description 44
- 229920001287 Chondroitin sulfate Polymers 0.000 claims abstract description 35
- KXKPYJOVDUMHGS-OSRGNVMNSA-N Chondroitin sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](OS(O)(=O)=O)[C@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](C(O)=O)O1 KXKPYJOVDUMHGS-OSRGNVMNSA-N 0.000 claims abstract description 35
- 230000002496 gastric Effects 0.000 claims abstract description 22
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 15
- 239000000546 pharmaceutic aid Substances 0.000 claims abstract description 14
- 231100000419 toxicity Toxicity 0.000 claims abstract description 13
- 230000001988 toxicity Effects 0.000 claims abstract description 13
- 238000004519 manufacturing process Methods 0.000 claims abstract description 5
- 229940059329 chondroitin sulfate Drugs 0.000 claims description 34
- 239000003826 tablet Substances 0.000 claims description 19
- 229960001259 diclofenac Drugs 0.000 claims description 11
- DCOPUUMXTXDBNB-UHFFFAOYSA-N diclofenac Chemical compound OC(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl DCOPUUMXTXDBNB-UHFFFAOYSA-N 0.000 claims description 11
- 230000002178 gastroprotective Effects 0.000 claims description 9
- 239000000725 suspension Substances 0.000 claims description 7
- HYWYRSMBCFDLJT-UHFFFAOYSA-N Nimesulide Chemical compound CS(=O)(=O)NC1=CC=C([N+]([O-])=O)C=C1OC1=CC=CC=C1 HYWYRSMBCFDLJT-UHFFFAOYSA-N 0.000 claims description 6
- -1 disintegrators Substances 0.000 claims description 6
- 229960000965 nimesulide Drugs 0.000 claims description 6
- 239000002775 capsule Substances 0.000 claims description 5
- 239000011248 coating agent Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 4
- 239000000499 gel Substances 0.000 claims description 4
- 230000002335 preservative Effects 0.000 claims description 4
- 239000003755 preservative agent Substances 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- RZEKVGVHFLEQIL-UHFFFAOYSA-N Celecoxib Chemical compound C1=CC(C)=CC=C1C1=CC(C(F)(F)F)=NN1C1=CC=C(S(N)(=O)=O)C=C1 RZEKVGVHFLEQIL-UHFFFAOYSA-N 0.000 claims description 2
- MNJVRJDLRVPLFE-UHFFFAOYSA-N Etoricoxib Chemical compound C1=NC(C)=CC=C1C1=NC=C(Cl)C=C1C1=CC=C(S(C)(=O)=O)C=C1 MNJVRJDLRVPLFE-UHFFFAOYSA-N 0.000 claims description 2
- SYTBZMRGLBWNTM-UHFFFAOYSA-N Flurbiprofen Chemical compound FC1=CC(C(C(O)=O)C)=CC=C1C1=CC=CC=C1 SYTBZMRGLBWNTM-UHFFFAOYSA-N 0.000 claims description 2
- HEFNNWSXXWATRW-UHFFFAOYSA-N Ibuprofen Chemical compound CC(C)CC1=CC=C(C(C)C(O)=O)C=C1 HEFNNWSXXWATRW-UHFFFAOYSA-N 0.000 claims description 2
- ZRVUJXDFFKFLMG-UHFFFAOYSA-N Ilacox Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=NC=C(C)S1 ZRVUJXDFFKFLMG-UHFFFAOYSA-N 0.000 claims description 2
- OZWKMVRBQXNZKK-UHFFFAOYSA-N Ketorolac Chemical compound OC(=O)C1CCN2C1=CC=C2C(=O)C1=CC=CC=C1 OZWKMVRBQXNZKK-UHFFFAOYSA-N 0.000 claims description 2
- UAWXGRJVZSAUSZ-UHFFFAOYSA-N Licofelone Chemical compound OC(=O)CC=1N2CC(C)(C)CC2=C(C=2C=CC=CC=2)C=1C1=CC=C(Cl)C=C1 UAWXGRJVZSAUSZ-UHFFFAOYSA-N 0.000 claims description 2
- 229950003488 Licofelone Drugs 0.000 claims description 2
- HYYBABOKPJLUIN-UHFFFAOYSA-N Mefenamic acid Chemical compound CC1=CC=CC(NC=2C(=CC=CC=2)C(O)=O)=C1C HYYBABOKPJLUIN-UHFFFAOYSA-N 0.000 claims description 2
- CMWTZPSULFXXJA-VIFPVBQESA-N Naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 claims description 2
- QYSPLQLAKJAUJT-UHFFFAOYSA-N Piroxicam Chemical compound OC=1C2=CC=CC=C2S(=O)(=O)N(C)C=1C(=O)NC1=CC=CC=N1 QYSPLQLAKJAUJT-UHFFFAOYSA-N 0.000 claims description 2
- RZJQGNCSTQAWON-UHFFFAOYSA-N Rofecoxib Chemical compound C1=CC(S(=O)(=O)C)=CC=C1C1=C(C=2C=CC=CC=2)C(=O)OC1 RZJQGNCSTQAWON-UHFFFAOYSA-N 0.000 claims description 2
- 239000000443 aerosol Substances 0.000 claims description 2
- 230000000181 anti-adherence Effects 0.000 claims description 2
- 239000003911 antiadherent Substances 0.000 claims description 2
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- 239000004067 bulking agent Substances 0.000 claims description 2
- 229960000590 celecoxib Drugs 0.000 claims description 2
- 239000002738 chelating agent Substances 0.000 claims description 2
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- 230000003111 delayed Effects 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- 239000006185 dispersion Substances 0.000 claims description 2
- 239000003995 emulsifying agent Substances 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 229960004945 etoricoxib Drugs 0.000 claims description 2
- 239000000945 filler Substances 0.000 claims description 2
- 239000000796 flavoring agent Substances 0.000 claims description 2
- 229960002390 flurbiprofen Drugs 0.000 claims description 2
- 235000013355 food flavoring agent Nutrition 0.000 claims description 2
- 230000004927 fusion Effects 0.000 claims description 2
- 229960001680 ibuprofen Drugs 0.000 claims description 2
- 229960004752 ketorolac Drugs 0.000 claims description 2
- 239000000314 lubricant Substances 0.000 claims description 2
- 229960000994 lumiracoxib Drugs 0.000 claims description 2
- KHPKQFYUPIUARC-UHFFFAOYSA-N lumiracoxib Chemical compound OC(=O)CC1=CC(C)=CC=C1NC1=C(F)C=CC=C1Cl KHPKQFYUPIUARC-UHFFFAOYSA-N 0.000 claims description 2
- 229960003464 mefenamic acid Drugs 0.000 claims description 2
- 229960001929 meloxicam Drugs 0.000 claims description 2
- 229960002009 naproxen Drugs 0.000 claims description 2
- 239000002674 ointment Substances 0.000 claims description 2
- 239000006186 oral dosage form Substances 0.000 claims description 2
- 239000003002 pH adjusting agent Substances 0.000 claims description 2
- 229960004662 parecoxib Drugs 0.000 claims description 2
- TZRHLKRLEZJVIJ-UHFFFAOYSA-N parecoxib Chemical compound C1=CC(S(=O)(=O)NC(=O)CC)=CC=C1C1=C(C)ON=C1C1=CC=CC=C1 TZRHLKRLEZJVIJ-UHFFFAOYSA-N 0.000 claims description 2
- 239000006201 parenteral dosage form Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229960002702 piroxicam Drugs 0.000 claims description 2
- 239000004014 plasticizer Substances 0.000 claims description 2
- 229920000642 polymer Polymers 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 230000002685 pulmonary Effects 0.000 claims description 2
- 230000000541 pulsatile Effects 0.000 claims description 2
- 229960000371 rofecoxib Drugs 0.000 claims description 2
- 239000000243 solution Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000007921 spray Substances 0.000 claims description 2
- 239000003381 stabilizer Substances 0.000 claims description 2
- 239000000375 suspending agent Substances 0.000 claims description 2
- 230000002459 sustained Effects 0.000 claims description 2
- 239000006208 topical dosage form Substances 0.000 claims description 2
- 229960002004 valdecoxib Drugs 0.000 claims description 2
- LNPDTQAFDNKSHK-UHFFFAOYSA-N valdecoxib Chemical compound CC=1ON=C(C=2C=CC=CC=2)C=1C1=CC=C(S(N)(=O)=O)C=C1 LNPDTQAFDNKSHK-UHFFFAOYSA-N 0.000 claims description 2
- 239000003981 vehicle Substances 0.000 claims description 2
- DKYWVDODHFEZIM-UHFFFAOYSA-N Ketoprofen Chemical compound OC(=O)C(C)C1=CC=CC(C(=O)C=2C=CC=CC=2)=C1 DKYWVDODHFEZIM-UHFFFAOYSA-N 0.000 claims 1
- 229960000991 ketoprofen Drugs 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 7
- DLGJWSVWTWEWBJ-HGGSSLSASA-N Chondroitin Chemical compound CC(O)=N[C@@H]1[C@H](O)O[C@H](CO)[C@H](O)[C@@H]1OC1[C@H](O)[C@H](O)C=C(C(O)=O)O1 DLGJWSVWTWEWBJ-HGGSSLSASA-N 0.000 abstract description 6
- 229920002567 Chondroitin Polymers 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 241000124008 Mammalia Species 0.000 abstract description 2
- CGIGDMFJXJATDK-UHFFFAOYSA-N Indometacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 27
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- 229940075614 colloidal silicon dioxide Drugs 0.000 description 12
- 239000002808 molecular sieve Substances 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 239000000454 talc Substances 0.000 description 12
- 235000012222 talc Nutrition 0.000 description 12
- 229910052623 talc Inorganic materials 0.000 description 12
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 description 11
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 11
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 11
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- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 description 10
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- JEIPFZHSYJVQDO-UHFFFAOYSA-N Iron(III) oxide Chemical compound O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 6
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- 150000003431 steroids Chemical class 0.000 description 6
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- 208000007107 Stomach Ulcer Diseases 0.000 description 5
- 229920000045 Dermatan sulfate Polymers 0.000 description 4
- AVJBPWGFOQAPRH-FWMKGIEWSA-L Dermatan sulfate Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@H](OS([O-])(=O)=O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@H](C([O-])=O)O1 AVJBPWGFOQAPRH-FWMKGIEWSA-L 0.000 description 4
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- KPHWPUGNDIVLNH-UHFFFAOYSA-M diclofenac sodium Chemical compound [Na+].[O-]C(=O)CC1=CC=CC=C1NC1=C(Cl)C=CC=C1Cl KPHWPUGNDIVLNH-UHFFFAOYSA-M 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N iso-propanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
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- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitric oxide Chemical compound O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 2
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Abstract
Pharmaceutical compositions comprising of glycosaminoglycan or salts thereof, preferably chondroitin or salts thereof, more preferably chondroitin sulphate, and nonsteroidal anti-inflammatory drug(s) or salts thereof, optionally with pharmaceutically acceptable excipient(s) are described. The compositions of the present invention provide gastrosparing effect in conditions where nonsteroidal anti-inflammatory drug(s) or their salts are used, particularly in mammals. Also provided are process for the manufacture of such novel compositions and method to minimize the nonsteroidal anti-inflammatory drug(s) induced gastric toxicity.
Description
NOVEL COMPOSITIONS COMPRISING GLYCOSAMINOGLYCAN AND AN NON-STEROID ANTI-INFLAMMATORY DRUG
FIELD OF THE INVENTION
The present invention relates to novel pharmaceutical compositions comprising glycosaminoglycan or salts thereof, preferably chondroitin or salts thereof, more preferably chondroitin sulfate and the non-steroidal anti-infiamatory drug (s) or salts thereof, optionally with pharmaceutically acceptable excipient (s). The compositions of the present invention provide the gastroprotective effect in conditions wherein the non-steroidal anti-inflammatory drug (s) or their salts are used, particularly in mammals. The present invention also provides methods for the manufacture of said novel compositions and the method for minimizing gastric toxicity induced by the non-steroidal anti-inflammatory drug (s).
BACKGROUND OF THE INVENTION
Glycosaminoglycans are a type of large unbranched polysaccharide molecules. These are the main structural components of cartilage and are also found in the cornea of the eye.
Examples of common glycosaminoglycans include keratan sulfate, chondroitin sulfate, dermatan sulfate, heparin sulfate and hyaluronan. Chondroitin sulfate is a sulfated glycosaminoglycan consisting of a repeating chain of glycosaminoglycan molecules. It is a linear sulphate polysaccharide constructed of two or three classes of monosaccharides mainly N-acetylgalactosamine, L-iduronic acid, and D-glucuronic acid. It is present in various connective tissues, including cartilage, skin, blood vessels, and bones (Hardingham and Fosang, 1992). It is the main constituent of proteoglycan of articular cartilage and plays an important role in the elasticity and function of articular cartilage (Hardingham and Bayliss, 1992). It has been used clinically as a condoprotective agent for the treatment of osteoarthritis. Chondroitin sulfate is currently marketed and therapeutically prescribed for neurodynia, lumbago, and arthrodynia as a protective agent of cartilage. Hori et al. Demonstrated the therapeutic efficacy of chondroitin sulfate in the protection of digestive mucosa against the animal model of inflammatory bowel disease (Hori et al., 2001). Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used in the administration of pain and inflammation. They are among the most commonly prescribed drugs in the world but their therapeutic defects are limited by their adverse effects on the gastrointestinal tract (Kulkarni and Varghese, 1998, Kulkarni and others, 2000). The NSAIDs act through the non-selective inhibition of the cyclooxygenase (COX) enzyme thus blocking the release of prostaglandins. Two COX isoforms have been identified, mainly COX.1 and COX-2. COX-1 is constitutive and involves maintenance functions such as mucus secretion and renal blood flow; while COX-2 is inducible through inflammatory pain stimulation (Kulkarni et al., 2000). Classical NSAIDs inhibit both COX isoforms thereby blocking the useful gastric prostaglandins released by gastric COX-1 leading to gastrointestinal side effects on the scale of dyspepsia for lifethreatening gastrointestinal bleeding and potentially perforation of gastro-duodenal ulcers (García Rodríguez and Jick, 1994; Langman et al., 1994). Several attempts have been made to develop NSAIDs with reduced gastrointestinal side effects that have led to the development of several types of NSAIDs such as selective COX-2 inhibitors (Brideau et al., 1999), nitric oxide releasing NSAIDs (Takeuchi et al., 1998). ), NSAIDs preassociated with zwitterionic phospholipids (Wallace and Chin, 1997), and formation of NSAID complexes with divalent metal ions (Dendrinu-Samara and others, 1998). Of these attempts, the main method has been to develop safe NSAIDs on the basis of a COX-1 hypothesis. There is still an unmet need to develop new combination products or new methods to minimize gastric toxicity induced by NSAID (s). No composition in the art has been reported where chondroitin or chondroitin salts, especially chondroitin sulfate, are used in combination with NSAID (s) to minimize gastric toxicity induced by NSAID (s). The present invention provides novel pharmaceutical compositions comprising glycosaminoglycan or salts thereof, such as chondroitin sulfate and the non-steroidal anti-inflammatory drug (s).
OBJECT OF THE INVENTION
It is an object of the present invention to provide a novel pharmaceutical composition comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients, wherein said composition provides a gastroprotective effect and minimizes gastric toxicity induced by the administration of the non-steroidal anti-inflammatory drug. It is an object of the present invention to provide a novel pharmaceutical composition comprising glycosaminoglycan or salts thereof, preferably chondroitin or salts thereof, more preferably chondroitin sulfate, and at least one non-steroidal anti-inflammatory drug or salts thereof, optionally with pharmaceutically acceptable excipients, wherein said composition provides a gastroprotective effect and minimizes gastric toxicity induced by the administration of the non-steroidal anti-inflammatory drug. It is another object of the present invention to provide a method for preparing said pharmaceutical composition comprising admixing glycosaminoglycan or salts thereof with at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients and formulating them in a suitable dosage form. It is a further object of the present invention to provide a method that provides a gastroprotective effect and minimizes gastric toxicity induced by the administration of the non-steroidal anti-inflammatory drug, through the administration of a pharmaceutical composition comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides novel compositions comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients. The composition provides a gastroprotective effect and minimizes gastric toxicity induced by the administration of the non-steroidal anti-inflammatory drug. In one embodiment, the invention provides novel pharmaceutical compositions comprising chondroitin or salts thereof, preferably chondroitin sulfate and the non-steroidal anti-inflammatory drug (s) or salts thereof, optionally with pharmaceutically acceptable excipient (s). In one embodiment of the present invention, the ratio of glycosaminoglycan or salts thereof and the non-steroidal drug-inflammatory or salts thereof in the composition is 100: 1 to 1: 100. In one embodiment of the present invention, the pharmaceutically acceptable excipients are selected from a group comprising but not limited to diluents, disintegrators, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti-oxidants, binders, pH regulators, lubricants, anti-adherents, coating agents, preservatives, emulsifiers, suspending agents, release control agents, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, chelating agents, and the like; used either alone or in combination thereof. The pharmaceutical compositions of the present invention can be administered in the form of conventional pharmaceutical compositions, and can be formulated by means known in the art. The compositions of the present invention may be formulated as oral dosage forms, such as tablets, pills, capsules, gels, finely divided powders, dispersions, suspensions, solutions, emulsions, etc .; the pulmonary and nasal dosage form such as sprays, aerosols, etc .; topical dosage forms such as gels, ointments, creams, etc .; parenteral dosage forms; controlled release formulations; fast fusion formulations, lyophilized formulations, delayed release formulations, sustained release formulations, extended release formulations, pulsatile release formulations, and mixed and controlled immediate release formulations. In one embodiment, the composition of the present invention is provided to be taken orally through a pediatric suspension, capsule, or tablet. In another embodiment, the present invention also provides a method for minimizing gastric toxicity induced by the non-steroidal anti-inflammatory drug (s). In one embodiment of the present invention, the compositions comprise glycosaminoglycan or salts thereof and the anti-inflammatory drug (s) steroid (s) or salts thereof which are intended to reduce the incidence of dyspepsia, heartburn, ulcers with bleeding and other gastrointestinal complications associated with the use of the non-steroidal anti-inflammatory drug (s). In yet another embodiment, the present invention also provides methods for the manufacture of analgesic and / or antiinflammatory compositions comprising glycosaminoglycan, preferably chondroitin sulfate or salts thereof and the anti-inflammatory drug (s). no steroid (s) or salts thereof. The process for preparing said pharmaceutical compositions comprises mixing glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients and formulating in a suitable dosage form. The novel pharmaceutical compositions of the present invention are also intended to ensure greater acceptance by the patient and promise a potential to reduce gastric toxicity associated with the use of the non-steroidal anti-inflammatory drug (s) (s). ). In addition, the novel pharmaceutical compositions of the present invention are not expected to alter the pharmacodynamic profile of either glycosaminoglycan or the non-steroidal anti-inflammatory drug (s). In one embodiment, the non-steroidal anti-inflammatory drug (s) of the present invention includes, but is not limited to, ndometacin, flurbiprofen, naproxen, diclofenac, ketorolac, mefenamic acid, ibuprofen. , cetoprofen, meloxicam, piroxicam, nimesulide, celecoxib, rofecoxib, etoricoxib, parecoxib, valdecoxib, lumiracoxib, licofelone, and the like, or salts thereof. Examples of glycosaminoglycans that can be used include keratan sulfate, chondroitin sulfate, dermatan sulfate, heparin sulfate and hyaluronan. Through careful experimentation, the inventors have found that among the non-steroidal anti-inflammatory drugs (NSAIDs), indomethacin and diclofenac produced severe gastric damage in the stomach. The present invention surprisingly found that the combination of chondroitin sulfate with indomethacin or diclofenac significantly attenuated ulcerations and gastric perforations induced per se of indomethacin or diclofenac in rats; in this way an unexpected gastric protection was produced through the minimization of gastric toxicity induced by NSAIDs.
Determination of biological activity
Acute pustular ulcers induced by NSAIDs in rats The gastroprotective effect of chondroitin sulfate was studied in acute gastric ulcers induced by rat NSAIDs. The NSAIDs used by the study are free acid of indomethacin and diclofenac.
Acute gastric ulcers induced by indomethacin in rats The unexpected gastroprotective effect observed of chondroitin sulfate is shown through the conducted test e? rats Wistar rats of either sex were procured from the Central Animal House facilities of Panacea Bistec Ltd., India. The animals kept fasting during the night and those who weighed between 150-170 grams at the time of the test were used. All animals were dosed sequentially through the oral route with 0.5% suspension of carboxymethylcellulose (CMC) of indomethacin and / or chondroitin sulfate solutions in distilled water. A dosage volume of 10 ml / kg was used for each solution or sequential suspension. The ulcers were induced as described by Chan et al. (1995). Briefly, the animals that fasted overnight were administered orally 20 mg / kg indomethacin on the day of the experiment. Chondroitin sulfate was administered at a dose of 50 or 100 mg / kg, 15 minutes before the administration of ndometacin. The animals were sacrificed after 4 hours of indomethacin administration. The stomach was opened along the greater curvature and washed under running water. The number of ulcers was identified using 10X magnifying glasses, counted, multiplied by their respective score, and added up for each animal. The average score as an ulcer index in each group was calculated and compared with the indomethacin group.
Ulcer score: Size (longest diameter) Score Ulcers < 1 mm Ulcer 1 - 3 mm Ulcer > 3 mm 10 The results of the study are presented in Table 1.
TABLE 1 Effect of chondroitin sulfate on gastric ulcers induced by indomethacin in rats
All values are expressed as mean ± S. E. M. (Error
Standard of the Media). n (No. of rats) = 6-9 in each treatment group; * p < 0.05 as compared to control (vehicle) (test t); ap < 0.05 as compared to treatments per se (ANOVA followed by Dunnett's test). Individual oral administration of indomethacin of 20 mg / kg produced severe gastric damage (red color, bleeding ulcers and mucus layer disruption) in fasting animals with an ulcer score of 66.25 + 15.8 when compared with the value of control of 2.25 ± 0.48. Oral coadministration of chondroitin sulfate 50 mg / kg or 100 mg / kg with indomethacin 20 mg / kg showed unexpected gastroprotection with ulcer scores of 23.0 ± 8.04 and 6.0 ± 3.07, respectively. Also the extent of gastroprotection was dose dependent as was evident from the ulcer index values for 50 and 100 mg / kg of chondroitin sulfate administered together with 20 mg / kg of indomethacin (Table 1).
Acute gastric ulcers induced by diclofenac in rats Wistar rats of either sex were used that fasted overnight and weighed 170 - 200 g at the time of testing. All animals were dosed sequentially through the oral route with 0.5% suspension of diclofenac free acid carboxymethyl cellulose and / or chondroitin sulfate solutions in distilled water. A dosage volume of 10 ml / kg was used for each solution or sequential suspension. All doses were coded and the test was carried out under a code not known to the observer. The ulcers were induced as described by Chan et al. (1995). Briefly, the animals that fasted overnight were weighed and randomly divided into 4 groups. Three groups of animals were administered orally with 10 mg / kg of diclofenac-free acid and the last group received an equivalent volume of vehicle only on the day of the experiment. Two groups of animals received chondroitin sulfate at a dose of 50 or 100 mg / kg, 15 minutes before the administration of diclofenac-free acid. Animals were sacrificed 4 hours after diclofenac-free acid administration; the stomach opened along the greater curvature and was washed under running water. The number of ulcers identified using 10X magnifying glasses was counted, multiplied by the respective score and added for each animal. The average score as the ulcer index in each group was calculated as mentioned below.
Ulcer score: Size (longest diameter) Score Ulcers < 1 mm 1 Ulcer 1 - 3 mm 5 Ulcers > 3 mm 10 The results of the study are presented in Table 2.
TABLE 2 Effect of chondroitin sulfate on gastric ulcers induced by diclofenac in rats
All values are expressed as mean ± S. E. M. (Standard Error of the Mean). n = 5-7 in each treatment; * p < 0.05 as compared to the control vehicle; ap < 0.05 as compared to diclofenac control. Individual oral administration of diclofenac-free acid of 100 mg / kg produced severe gastric damage (redness, bleeding ulcers and disruption of the mucus layer) in fasted animals compared to the control animals (Table 1). Oral administration of chondroitin sulfate of 50 mg / kg or 100 mg / kg 15 minutes before the administration of diclofenac-free acid 100 mg / kg showed a gastroprotection as evidenced by a significant reduction in the ulcer index as compared to the control of diclofenac-free acid (Table 2). The examples given below serve to illustrate the embodiments of the present invention. However, they are not intended to limit the scope of the present invention.
EXAMPLES
EXAMPLE 1 (Capsule)
Ingredient mg / capsule Chondroitin Sulfate 200.0 Indomethacin 100.0 Microcrystalline Cellulose 200.8 Mannitol 72.0 Talc 3.2 Sodium Starch Glycolate 12.0 Colloidal Silicon Dioxide 12.0
Procedure: 1) Chondroitin sulfate, indomethacin, microcrystalline cellulose and mannitol were selected and mixed together. 2) The talc, the sodium starch glycollate and the colloidal silicon dioxide were passed through fine molecular sieves individually and then mixed together.
3) The materials of step 1 and step 2 were mixed and filled into empty hard gelatin capsules.
EXAMPLE 2 (Tablet not covered)
Ingredient mg / tablet Chondroitin sulfate 200.0 Diclofenac-free acid 50.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0
Procedure: 1) Chondroitin sulfate, diclofenac free acid, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were selected and mixed together. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a molecular sieve and mixed. 4) The talc, the colloidal silicon dioxide and the croscarmellose sodium were passed through a fine molecular sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed into tablets.
EXAMPLE 3 (Tablet not covered)
Ingredient mg / tablet Chondroitin sulfate 400.0 Nimesulide 100.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0
Procedure: 1) Chondroitin sulfate, nimesulide, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were selected and mixed together.
2) The material from step 1 was compacted. 3) The step compacts passed through a molecular sieve and mixed. 4) The talc, the colloidal silicon dioxide and the croscarmellose sodium were passed through a fine molecular sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed into tablets.
EXAMPLE 4 (Tablet not covered)
Ingredient mg / tablet Dermatan sulfate 100.0 Diclofenac sodium 75.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0 Procedure: 1) Dermatan sulfate, diclofenac sodium, was classified and mixed together microcrystalline cellulose, mannitol, croscarmellose sodium and lactose. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a molecular sieve and mixed. 4) The talc, the colloidal silicon dioxide and the croscarmellose sodium were passed through a fine molecular sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed into tablets.
EXAMPLE 5 (Tablet not covered)
Ingredients mg / tablet Chondroitin sulfate 200.0 Nimesulide 100.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0
Procedure: 1) Chondroitin sulfate, nimesulide, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were classified and mixed together. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a molecular sieve and mixed. 4) Talc, colloidal silicon dioxide and croscarmellose sodium passed through a fine molecular sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed into tablets.
EXAMPLE 6 (Table with film layer)
Ingredient mg / tablet
Composition of the central tablet Chondroitin sulfate 200.0 Diclofenac sodium 75.0 Microcrystalline cellulose 120.0 Mannitol 80.0 Croscarmellose sodium 10.0 Lactose 66.0 Talcum 4.0 Colloidal silicon dioxide 10.0 Croscarmellose sodium 10.0
Film layer composition Hydroxypropylmethyl cellulose (E-15) 12.0 Polyethylene glycol 400 (PEG 400) 2.4 Red iron oxide 0.75 Yellow iron oxide 0.50 Titanium dioxide 0.25 Isopropyl alcohol q.s. (lost in processing) Dichloromethane q.s. (lost in processing) Procedure: 1) Chondroitin sulfate, diclofenac sodium, microcrystalline cellulose, mannitol, croscarmellose sodium and lactose were classified and mixed together. 2) The material from step 1 was compacted. 3) The compacts from step 2 were passed through a molecular sieve and mixed. 4) The talc, the colloidal silicon dioxide and the croscarmellose sodium were passed through a fine molecular sieve and mixed together. 5) The material from step 3 was mixed with the material from step 4. 6) The material from step 5 was compressed into tablets. 7) Hydroxypropylmethyl cellulose was dispersed in a mixture of isopropyl alcohol and dichloromethane with continuous mixing in a homogenizer. 8) The polyethylene glycol 400 was added to the previous solution of step 7 and mixed. 9) The red iron oxide, the yellow iron oxide and the titanium dioxide were passed through a fine molecular sieve and mixed. 10) The material from step 9 was added to the material from step 8 and mixed for 30 minutes.
11) The core tablets were loaded onto a coating tray and covered with the coating solution from step 10 until an average tablet weight gain of -2-3% was achieved.
Claims (10)
1. - A novel pharmaceutical composition comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients, wherein said composition provides a gastroprotective effect and minimizes gastric toxicity induced by the administration of a non-steroidal anti-inflammatory drug.
2. The composition according to claim 1, further characterized in that the glycosaminoglycan is chondroitin sulfate.
3. The composition according to any of claims 1 and 2, further characterized in that the non-steroidal anti-inflammatory drug is selected from a group comprising flurbiprofen, naproxen, diclofenac, ketorolac, mefenamic acid, ibuprofen, ketoprofen, meloxicam, piroxicam, nimesulide, celecoxib, rofecoxib, etoricoxib, parecoxib, valdecoxib, lumiracoxib, licofelone, and the like, or salts thereof.
4. The composition according to any of claims 1 to 3, further characterized in that the ratio of glycosaminoglycan or salts thereof and the non-steroidal anti-inflammatory drug or salts thereof is from 100: 1 to 1: 100.
5. - The composition according to any of claims 1 to 4, further characterized in that the pharmaceutically acceptable excipients are selected from a group comprising diluents, disintegrators, fillers, bulking agents, vehicles, pH adjusting agents, stabilizers, anti- oxidizers, binders, pH regulators, lubricants, antiadherents, coating agents, preservatives, emulsifiers, suspending agents, control agents. release, polymers, colorants, flavoring agents, plasticizers, solvents, preservatives, glidants, chelating agents; used either alone or in combination thereof.
6. The composition according to claims 1 to 5, further characterized in that it is formulated as an oral dosage form such as tablets, pills, capsules, gels, finely divided powders, dispersions, suspensions, solutions, emulsions, etc .; the pulmonary and nasal dosage form such as sprays, aerosols, etc .; topical dosage forms such as gels, ointments, creams, etc .; parenteral dosage forms; controlled release formulations; fast fusion formulations, lyophilized formulations, delayed release formulations, sustained release formulations, extended release formulations, pulsatile release formulations, and mixed and controlled immediate release formulations.
7. A process for preparing a pharmaceutical composition according to claim 1, comprising the mixture of glycosaminoglycan or salts thereof and at least one non-steroidal antiinflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients and formulated in a form of suitable dosage.
8. The method according to claim 7, further characterized in that the ratio of glycosaminoglycan or salts thereof and the non-steroidal anti-inflammatory drug or salts thereof is from 100: 1 to 1: 100.
9. The use of a combination comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof optionally with pharmaceutically acceptable excipients, to prepare a composition for a gastroprotective effect and to minimize gastric toxicity induced by the administration of the non-steroidal anti-inflammatory drug.
10. A composition comprising glycosaminoglycan or salts thereof and at least one non-steroidal anti-inflammatory drug or salts thereof, as described herein and illustrated through the examples.
Applications Claiming Priority (1)
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DE102/DEL/2004 | 2004-01-20 |
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