CN101217939A - Injectable compositions and process of preparation thereof - Google Patents
Injectable compositions and process of preparation thereof Download PDFInfo
- Publication number
- CN101217939A CN101217939A CNA2006800250937A CN200680025093A CN101217939A CN 101217939 A CN101217939 A CN 101217939A CN A2006800250937 A CNA2006800250937 A CN A2006800250937A CN 200680025093 A CN200680025093 A CN 200680025093A CN 101217939 A CN101217939 A CN 101217939A
- Authority
- CN
- China
- Prior art keywords
- compositions
- mixture
- cox
- solution
- inhibitor
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Engineering & Computer Science (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pain & Pain Management (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Biomedical Technology (AREA)
- Dermatology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Novel and highly stable injectable pharmaceutical compositions comprising at least one cyclooxygenase-II enzyme (COX-II) inhibitor or non-steroidal anti-inflammatory drug (NSAID) or COX/LOX inhibitor, or its tautomeric forms, analogues, isomers, polymorphs, solvates, prodrugs or salts thereof as active ingredient suitable for parenteral administration preferably by intramuscular (IM) or intravenous (IV) route; process of preparing such compositions and therapeutic methods of using such compositions are provided. The analgesic and anti-inflammatory injectable compositions of the present invention are very useful in mammals particularly in humans for the treatment of acute painful conditions like one or more of post-operative trauma, pain associated with cancer, sports injuries, migraine headache, neurological pain and pain associated with sciatica and spondylitis, and the like, and/or chronic painful conditions, and/or a variety of painful and inflammatory conditions like postoperative pain, primary dysmenorrhea and painful osteoarthritis, and/or other associated disorders such as inflammation, fever, allergy, or the like.
Description
Invention field
The present invention relates to new and high stability Injectable composition, it comprises at least a cyclo-oxygenase-II enzyme (COX-II) inhibitor or NSAID (non-steroidal anti-inflammatory drug) (NSAID) or COX/LOX inhibitor as active component, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt, said composition is suitable for parenterai administration, preferably by intramuscular (IM) or intravenous (IV) approach; The Therapeutic Method for preparing the method and the use said composition of said composition.
Pain relieving of the present invention and antiinflammatory Injectable composition are very useful in the mankind mammal especially, be used for the treatment of the acute pain disease, as wound after surgery, the pain relevant with cancer, athletic injury, migraine, one or more in neuralgia and pain relevant etc., and/or chronic pain disorders with sciatica and spondylitis, and/or other relevant obstacles, as inflammation, heating, allergy etc.
Background of invention
NSAID (non-steroidal anti-inflammatory drug) (NSAID) and cyclo-oxygenase-II enzyme (COX-II) is even normally highly hydrophobic chemical compound of inhibitor and also precipitation easily in the presence of low amounts of water.Therefore, be very difficult to such chemical compound is mixed with the Injectable composition that is used for intramuscular or intravenous use.
Can play the NSAID of the non-intestinal form of therapeutical effect at once, as nimesulide, ketorolac, diclofenac, ibuprofen and naproxen, and the COX-II inhibitor is very ideal.In order to prepare the parenteral formulation of these compounds, it is suitable to need, safety and nontoxic carrier/medium, and these medicines are soluble therein.Because the physicochemical characteristic of these compounds, therefore NSAID or the poorly soluble of COX-II inhibitor in water present the difficulty that these medicines is mixed with non-intestinal form.Find to use all kinds of solvents such as alcohols, dimethyl sulfoxide, propylene glycol and glycerol provide the NSAID of non-intestinal form and the trial of COX-II suppressive drug or its analog to get nowhere, this is because the problem of dissolubility, or these medicine dissolutions are in solvent such as different glucic acid mixture, in the time of in dimethyl sulfoxide and the propylene glycol, not allowing to use above-mentioned solvent for the required concentration range of said medicine therapeutic administration (particularly by the intramuscular approach), is deleterious because find them.Owing to these problems, be very difficult to research and develop the stabilized injectable preparation of these medicines.
Past has carried out several trials and has prepared the Injectable composition that comprises NSAID such as nimesulide.The injectable formulation of nimesulide has been reported among the PCT patent No.WO95/34533, and it discloses the salt form that uses nimesulide and L-lysine, and it is further compound with the cyclodextrin that can be dissolved in the water again, obtains injectable formulation.The maxima solubility that obtains by this Injectable composition is reported as 2.4mg/ml, and this is not enough to be used for intramuscular administration, because this needs very large volume to come drug treatment dosage.In addition, the nimesulide of preparation salt form, combined with cyclodextrin then, the process that not only makes bothers but also has increased the cost of preparation.Another piece list of references (Daffonehio, L. etc., Inflammatory Research, 45,259-264,1995), wherein nimesulide is dissolved in the saline, the intravenous administration that is used for animal experiment study has also just been described very rare solution, and it can not transmit the nimesulide of therapeutic dose in the mankind.
Nimesulide is effective non-steroidal anti-inflammatory (NSAID) medicine, is used for the treatment of the pain inflammatory disease that causes owing to rheumatoid arthritis at present, and it also has antipyretic activity.Compare with other NSAID, nimesulide has better treatment ratio, low stomach toxicity and common good tolerability.Nimesulide is the strong-hydrophobicity material, almost insoluble in water (dissolubility under the room temperature in the water is 0.01mg/ml).Because nimesulide in water and a variety of non-toxic solvents (particularly those approvals be used for non-intestinal uses) be insoluble, be very difficult to it is mixed with the solution that is suitable for by intramuscular or intravenous route parenterai administration.Other NSAID, as diclofenac, ibuprofen, indomethacin and naproxen, the acceptable concentration that they are used for non-intestinal use in the excipient that uses approval and approval is prepared into them and has also produced a lot of difficulties aspect the Injectable composition.Because such medicine is easy to precipitation, the non-intestinal compositions that particularly comprises cyclo-oxygenase-II inhibitor such as rofecoxib or valdecoxib is highly unsettled when storage, and therefore becomes in the pot-life of this product and be difficult to obtain to be used for the homogeneous solution of parenterai administration.Known and be recognized that the parenterai administration of the medicine that is used for the treatment of the pain inflammatory disease is more effective than other administration route, because medicine directly enters circulation and presents its therapeutic effect apace.
Seedher, Neelam etc. (Indian Journal of PharmaceuticalScience, 65 (1), 58-61,2003) have described nimesulide at various solvents relevant with the parenteral formulation research and development and the dissolubility in solvent-cosolvent mixtures.Described publication demonstrates being dissolved among semi-polarity solvent such as Polyethylene Glycol (PEG) and non-ionic surface active agent such as tween 80 and the Brij 30 of nimesulide to be increased.Yet the PEG concentration that is used to obtain required dissolubility is too high, promptly 90%, and this uses for non-intestinal, particularly for the IV administration, does not recommend.US patent No.4,056,635 and 4,452,817 disclose the compositions that is suitable for parenterai administration that contains propofol, and to produce anesthesia in homoiothermic animal, said composition is as propofol in the aqueous medium and surfactant such as Cremophor RH40, the mixture of Cremophor EL and tween 80 can also contain ethanol or other drug and learn upward acceptable composition.US patent No.4; 794; 117 claimed methods of in water, dissolving indomethacin; in at least a Polyethylene Glycol with molecular weight 300 to 700 that consists essentially of that indomethacin with the antiinflammatory amount is dissolved in meltage and resulting solution is dissolved in the aqueous medium that is buffered in 4.5 to 8pH scopes of meltage, particularly be intended for use outside the use.US patent No.4,798,846 disclose aseptic propofol composition, and it contains 1% to 2% independent propofol or is dissolved in oil as the propofol in Oleum Arachidis hypogaeae semen or the ethyl oleate.Stablize these preparations with surfactant.US patent No.5,858,999 disclose the aseptic aqueous pharmaceutical composition that is used for parenterai administration, it comprise about 0.9 to about 90mg/ml Lazaroids (lazaroid) or its materia medica acceptable salt, about 0.002 to about 2.0M citrate, high to about 80% the propylene glycol that is selected from, Polyethylene Glycol, glycerol, ethanol, dimethyl sulfoxide, dimethyl acetylamide, dimethyl isosorbide, the cosolvent of N-N-methyl-2-2-pyrrolidone N-and water, pH about 2.4 to about 3.5.These compositionss are used the very cosolvent of high concentration.
Transfer the present patent application people's US patent No.5,688,829 disclose the therapeutic injectable analgesic composition that is used for intramuscular administration, are included in the nimesulide in the non-intestinal absorption enhancing base material basically, this base material comprises dimethyl acetylamide, benzyl benzoate and ethyl oleate.Described compositions uses the oiliness lipophilic solvent to dissolve nimesulide, and this does not allow the injection administration by intravenous route.Another transfers the US patent No.6 of same Applicant, and 451,302 have described injectable water miscibility compositions, and it comprises nimesulide; Benzyl alcohol; Be selected from dimethyl acetylamide, dimethyl formamide, the material of dimethyl sulfoxide and N-Methyl pyrrolidone; Be selected from Polyethylene Glycol (PEG 200 to 600), propylene glycol, hexanediol, the glycol of butanediol and Polyethylene Glycol 660 hydroxy stearic acid esters.Described patent need use alkylamide/alkyl sulfoxide or ketopyrrolidine to dissolve nimesulide.
US patent No.6,589,973 relate to the clarification of selective COX-2-II inhibitor of non-intestinal form and stable new pharmaceutical formulation is used for the treatment of because pain and the inflammatory disease that cyclo-oxygenase-the II activity causes.Especially, the pharmaceutical preparation of COX-II inhibitor comprises the selective COX-2-II inhibitor that is dissolved in the selectivity isosorbide type solvent, as celecoxib, and rofecoxib and analog thereof.EP patent No.1228757 relates to the stable drug solution that is suitable for the parenterai administration nimesulide, by 80% glycerol formal, and 15% ethanol and 5% water and/or 75% glycerol formal, 10% ethanol, 10% propylene glycol and 5% water are formed.Yet solvent and its employed concentration are not given the ratification and are used for parenterai administration.The open No.WO2000072884 of PCT has described new nimesulide and 2,5-two-O-methyl isophthalic acid, 4:3, the pharmaceutical composition of 6-two dehydration-D-glucitols, contain or not moisture, optionally contain the diluent that one or more can be used for IV/IM administration or oral or topical formulations.The open No.20030078266 of US is particularly related to pharmaceutical composition, at least a water-soluble therapeutic agents that is selected from selective COX-2-inhibitor 2 medicine and its prodrug and salt that comprises powder type, to constitute about 30% to the effective total amount of the treatment of about 90% composition weight, content is that the acceptable buffer agent of non-intestinal and the total amount of about 5% to 60% composition weight is the zero acceptable excipient composition of other non-intestinals to about 10% composition weight; Described compositions can be in non-intestinal acceptable solvent liquid reprovision to form Injectable solution.
The solvent that is used to prepare the compositions that is intended to non-intestinal use should be nontoxic and should preferably exist with low concentration.Most of existing patent and list of references have been described non-intestinal compositions, and it comprises that very the script of high concentration not have approval to be used for the solvent of non-intestinal use and is unsettled at storing process yet.
Therefore, comprise for research and development that the effective nontoxic non-intestinal compositions (latter be substantive soluble) therein of COX-II inhibitor or NSAID and those do not have the problems referred to above and in the whole storage period of product the maintenance stable compositions still have the needs of failing to satisfy.
Inventor of the present invention has used different innoxious solvents to carry out extensive studies and has carried out some experiments, and find that they cause producing the high dissolution system that is suitable for parenterai administration with various concentration combination together with suitable reducing and basifier, wherein COX-II inhibitor and/or NSAID are soluble, and also be stable in the product storing process, therefore proved the marked improvement that is better than prior art.
Summary of the invention
The purpose of this invention is to provide new Injectable composition, it comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient.
The purpose of this invention is to provide new Injectable composition, it comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt; The solvent system that comprises diol mixture; At least a basifier; The optional other drug that contains is learned upward acceptable excipient.
The purpose of this invention is to provide new Injectable composition, it comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt; The solvent system that comprises diol mixture; At least a basifier; At least a buffer agent; The optional other drug that contains is learned upward acceptable excipient.
Still another object of the invention provides new Injectable composition, and it comprises the NSAID as active component, preferred nimesulide, the solvent system that comprises diol mixture, at least a basifier, at least a buffer agent, the optional other drug that contains is learned upward acceptable excipient.
Another object of the present invention provides new Injectable composition, it comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient, comprises upward acceptable activity composition of one or more other drugs in addition.
Another object of the present invention provides the high stability Injectable composition that is suitable for intramuscular (IM) or intravenous (IV) administration.
A further object of the present invention provides the method for this new Injectable composition of preparation.
A further object of the present invention provides the method for the new Injectable composition of preparation, said composition comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient, and this method may further comprise the steps:
I) active component is added in the diol mixture, then mixes,
Ii) optional adding other drug is learned to go up acceptable excipient and mix and is produced Injectable composition.
A further object of the present invention provides the method for the new Injectable composition of preparation, said composition comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient, comprises one or more buffer agents and/or basifier in addition, and this method may further comprise the steps:
I) one or more buffer agents are added in the mixture of glycol and mix and obtain uniform mixture,
Ii) active component is added in the mixture, then mixes,
Iii) add basifier, then mix,
Iv) add buffer agent and obtain uniform mixture while mixing,
V) optionally produce Injectable composition to alkaline pH by adding pH that basifier regulates mixture.
A further object of the present invention provides the method for using said composition, and it comprises that the compositions with effective dose delivers medicine to the patient of some needs.
Compositions of the present invention is used in particular for treating one or more acute pain diseases, as wound after surgery, the pain relevant with cancer, athletic injury, migraine, neuralgia (neurological pain) and the pain relevant, or chronic pain disorders, and/or other relevant obstacles with sciatica and spondylitis.
Detailed Description Of The Invention
The invention describes new Injectable composition, it comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.Preferred active component is NSAID, is more preferably nimesulide.Compositions of the present invention comprises solvent system in addition, and it comprises the mixture of glycol, and the optional other drug that contains is learned upward acceptable excipient.
In one embodiment, the new Injectable composition of the present invention comprises at least a basifier and/or at least a buffer agent in addition.
In one embodiment, new Injectable composition comprises about 0.1% at least a COX-II inhibitor or NSAID or COX/LOX inhibitor as active component to about 80%w/v compositions, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and about 1% the solvent system that contains diol mixture to about 80%v/v compositions; The optional other drug that contains is learned upward acceptable excipient.In another embodiment, compositions of the present invention comprises about 0.2% at least a basifier and/or the about 2% at least a buffer agent to about 80%v/v compositions to about 60%v/v compositions in addition.
In one embodiment, the invention provides new Injectable composition, it comprises the nimesulide as active component, the solvent system that comprises diol mixture, at least a basifier, at least a buffer agent, the optional other drug that contains is learned upward acceptable excipient.
According to embodiment of the present invention, can use the mixture of the different innoxious solvents of various concentration to prepare the Injectable composition that contains COX-II inhibitor or NSAID or COX/LOX inhibitor with suitable reducing and basifier.These compositionss are limpid, and are tasteless, high stability, nontoxic and uniformly, and therefore are suitable for parenterai administration.In embodiments of the invention, Injectable composition is particularly suitable for by intravenous (IV) or intramuscular (IM) administration.
In the present invention, be used for that the solubilising technology of the deliquescent COX-II inhibitor of poor dissolution or NSAID or COX/LOX inhibitor is based on cosolubilization (cosolvation) and/or pH modifies (modification) technology.Especially, compositions of the present invention is high stability, preferably in about 7.5 to 11.5 pH scope, more preferably in about 9.0 to about 11.0 pH scope.
Useful active component NSAID preferably among the present invention is selected from but is not limited to nimesulide, nabumetone, tapoxalin, diclofenac, flosulide, ibuprofen, indomethacin, naproxen etc., its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt, or the COX-II inhibitor, be selected from but be not limited to celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib, itacoxib, deracoxib etc., or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.In one embodiment, active component of the present invention belongs to COX/LOX (cyclo-oxygenase/lipoxygenase) inhibitor class, as licofelone.In one embodiment of the invention, active component exists with the micronization form.
In embodiments of the invention, comprise at least a COX-II inhibitor or NSAID or COX/LOX inhibitor as active component, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional new Injectable composition that can accept excipient in other drug that contains comprises upward acceptable activity composition of one or more other drugs in addition.The last acceptable activity composition of other drug that is used for the present invention is any activating agent known in the art, it can unite COX-II inhibitor or NSAID or COX/LOX inhibitor, as acetaminophen, Serratieae peptidase (serratiopeptidase), antibacterial agent, the CNS medicament, CVS medicament etc.
In embodiments of the invention, the diol mixture that is used to prepare solvent system is to be selected from but to be not limited to PEG 200, and PEG 300, and PEG 400, Polyethylene Glycol (PEG) or its mixture of PEG 600 and PEG 700; And propylene glycol.In preferred embodiments, solvent system comprises the mixture of PEG 400 and propylene glycol.
In embodiments of the invention, used basifier is inorganic base or organic base or both combinations.In embodiments of the invention, used basifier is selected from but is not limited to, inorganic base, and as sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate, magnesium oxide etc., or its mixture; And/or organic base, as meglumine, triethanolamine, diethanolamine etc., or its mixture.In preferred embodiments, basifier is an inorganic base, as sodium hydroxide or potassium hydroxide.Preferably use basifier, by described agent dissolves is prepared in water with moisture (water) solution.The amount of the described reagent that uses and wherein the volume of the water of solubilising reagent make the reagent concentration that acquisition is required.
Used buffer agent ealkaline buffer preferably among the present invention is selected from but is not limited to, glycine buffer, and the lysine buffer agent, phosphate buffer, acetate buffers etc., or its mixture preferably have about 7.2 to about 12.5 pH scope.In preferred embodiments, with glycine buffer as the buffer agent in the present composition.In preferred embodiments, will have about 8.3 to about 11.3 pH glycine buffer as buffer agent.Preferably use buffer agent, prepare by required compound is dissolved in the water with moisture (water) solution.The amount of the required compound that uses and the volume that wherein dissolves the water of required compound make reagent concentration and the pH that acquisition is required.
In the present composition on the used materia medica acceptable excipient be selected from but be not limited to well known to a person skilled in the art excipient, for example, carrier, filler, stabilizing agent, antiseptic, surfactant, hydrophilic polymer, solubility enhancing agent such as glycerol, various other poly(ethylene oxide) of level, beta-schardinger dextrin-such as sulfo group butyl ether-beta-schardinger dextrin-, transcutol and glycofurol, tension regulator, local anesthetic, pH regulator agent, antioxidant, penetrating agent, chelating agen, viscosifier, wetting agent, emulsifying agent, acid, sugar alcohol, reducing sugar, non-reducing sugar etc., or its mixture.In one embodiment, with about 0.1% to about 70%w/v or the amount of v/v compositions use acceptable excipient on the materia medica.
Useful carrier can be selected from but is not limited to dimethyl acetylamide among the present invention, dimethyl formamide, dimethyl sulfoxide, N-Methyl pyrrolidone, benzyl benzoate, benzyl alcohol, ethyl oleate, polyoxyethylene glycol Oleum Ricini (polyoxyethylene glycolated castoroils) (Cremophor BL), Polyethylene Glycol is as having those of about 200 to 6000 molecular weight, propylene glycol, hexanediol, butanediol and diol, derivatives such as Polyethylene Glycol 660 hydroxy stearic acid esters (Solutrol HS15) etc., or its mixture.
In another embodiment of the invention, compositions comprises anti-microbial preservative in addition, and as benzyl alcohol, preferred concentration is about 0.001% to 5.0%w/w compositions.
In another embodiment of the invention, compositions comprises conventional known antioxidant in addition, is selected from but is not limited to ascorbyl palmitate, Butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, alpha-tocopherol etc., or its mixture.
Compositions of the present invention is high stability.In one embodiment, before administration, can use suitable diluted fluid known in the art to dilute new compositions of the present invention and prepare solution or dispersion or transfusion.New compositions of the present invention is high stability and compatible with different diluted fluids, as softening (DM) water, glucose 5%w/v, sodium chloride 0.9%w/v or its mixture.These fluids can use in the preparation of compositions process and maybe can be used in the diluted before administration compositions.For example, described compositions is used DM water, stablizes 5 hours at the dilution factor up to 1: 150, stablizes 48 hours at the dilution factor up to 1: 5; Use 5.0% glucose solution, stablized 2 hours, stablized 4 hours at dilution factor up to 1: 3 at dilution factor up to 1: 150; Use 0.9%NaCl solution, stablized 24 hours, stablized 48 hours at dilution factor, particularly in room temperature up to 1: 100 at dilution factor up to 1: 150.
Preferably compositions of the present invention is packed in the ampoule bottle.Nimesulide injection (inclusions of an ampoule bottle) and different infusion solutions are carried out Study on Compatibility study injection with the physical stability (in the intravenous infusion process) after the infusion solution dilution.Most of infusion solution has pH (for example, normal saline, about 6.2 of acid range; Ringer lactate solution, about 6.5; With glucose 5%w/v, about 5.5).Mix with the infusion solution of the known injection liquid that is used to comprise COX-II inhibitor or NSAID or COX/LOX inhibitor and to cause saturated and therefore crystallization.If dilution after this manner, this is unfavorable for solution, because such solution is intended for use parenterai administration.Therefore, particularly in the situation of nimesulide as active component, the pH that need keep final solution is in alkaline side, to stablize the nimesulide in the infusion solution.Therefore, the nimesulide in the infusion solution is carried out Study on Compatibility, this infusion solution has been used sodium bicarbonate buffer, so that therefore last solution also prevent recrystallization for alkalescence.This studies show that described Injectable composition is high stability and compatible with different infusion solutions.
In further embodiment, can also ethanol and/or dimethyl acetylamide (DMA) add the dissolubility that further improve active component in the compositions of the present invention.
Compositions described in the embodiment 1 is herein carried out stability study.Product is carried out for a long time (in controlled room temperature, promptly 25 ℃), and medium (at 30 ℃ and 70%RH) quickens (at 40 ℃ and 75%RH), and adverse circumstance (at 60 ℃) stability study, and analytic sample, comprises the control sample that remains on refrigerated condition (2-8 ℃).Find that product is stable above six months under above-mentioned every kind of condition, and change that as particulate matter, crystallization and color change, or chemical modification as the change of effect or the existence of any catabolite, do not demonstrate any stability problem for physics.In addition, in order to estimate product stability, also carried out " freeze-thaw circulation " research, and it is find product at physics with chemically be stable, even (that is, that product is freezing at four freeze-thaw cycle, then product is remained on 40 ℃ and 75%RH, each continues one day) after.
In the present invention, preferably Nimesulide injection is mixed with the contain water injection of preparation, particularly in the situation of IV administration with the infusion solution dilution.Nimesulide has the pH dependent solubility, and promptly nimesulide is soluble at alkaline pH, and is almost insoluble at acid pH.Therefore, the preferred solvent system that comprises solvent (particularly glycol) mixture and the optional pH regulator system that adopts of adopting prepares stabilization formulations among the present invention.
Pharmaceutical research
In the female Swiss mice of heavy 20-25g, carried out the studies on acute toxicity (only every group of n=6) of nimesulide IV injection.The sample that is used to study is nimesulide IV injection (label for labelling: every 3ml contains the 100mg nimesulide) and placebo injection liquid.Equal 41.6,50 by the IV administration, 54.17,58.3 and the 0.1ml injection of the every kg body weight of 83.3mg nimesulide dosage, continue 14 days.Injection equals 50.0mg/kg, and the mice of the 0.1ml injection of 54.17mg/kg and 83.3mg/kg dosage demonstrates spontaneous activity and reduces, the numb and poisoning symptom of trembling.The mice of injection 41.6mg/kg dosage level and 5ml/kg placebo does not demonstrate any poisoning symptom.At 54.17mg/kg, the dosage level of 58.3mg/kg and 83.8mg/kg is observed 16.6%, 50% and 100% mortality rate separately.Find the LD of Nimesulide injection (IV)
50Be 57.54mg/kg.
In the female Swiss mice of heavy 20-25g, carried out the studies on acute toxicity (only every group of n=5) of nimesulide IM injection.The sample that is used to study is nimesulide IM injection (label for labelling: every 3ml contains the 100mg nimesulide) and placebo injection liquid.The dosage that gives by the IM approach is respectively and equals 41.6,83.3, and 166.67,208.33 and 1.25,2.5,5,6.25 and 7.5ml/kg nimesulide IM injection of 250mg nimesulide per kilogram of body weight, continue 14 days.Dosage level and 2.5ml/kg placebo injection liquid at the 41.6mg/kg Nimesulide injection are not observed poisoning symptom in mice.The mice of injection 83.3,166.67,208.33 or 250mg/kg dosage demonstrates poisoning symptom.At 166.67mg/kg, the dosage level of 208.33mg/kg and 250mg/kg is observed 40%, 80% and 100% mortality rate separately.The LD of Nimesulide injection when finding intramuscular administration
50Be 173.78mg/kg.
The IV/IM injection of studying 100mg/ml nimesulide IV injection more of the present invention and can buying is to the haemolysis potential of rat whole blood (the citric acid salinization) and rat Red Blood Cells Concentrate (the citric acid salinization).The buied IV/IM injection that is used to study is diazepam (Diazepam) injection 5mg/ml (CALMPOSE ), diclofenac sodium injection 25mg/ml (VOVERAN ), furosemide inj 10mg/ml (LASIX ), Nimesulide injection 10%w/v (NIMOVET ) and Liticon (Lagap) injection 30mg/ml (FORTWIN ).This studies show that nimesulide IV injection of the present invention is when testing rat Red Blood Cells Concentrate (the citric acid salinization) (blood and specimen ratio 1: 10), demonstrate with CALMPOSE, FORTWIN , the healthy cell mark that NIMOVET and VOVERAN compare suitable.Nimesulide IV injection demonstrates the with CALMPOSE, the healthy cell mark that FORTWIN and LASIX compare suitable when rat whole blood (the citric acid salinization) (blood and specimen ratio 13: 1) is tested.
Research is with respect to the toleration around the placebo Composition single intravenous administration nimesulide IV of the present invention injection 100mg/3ml posterior vein in rabbit.This animal that studies show that intravenous injection nimesulide IV of the present invention injection or placebo does not demonstrate any local irritant sign in the injection site of auris dextra.
In rabbit, carry out the pharmacokinetics research of nimesulide IV injection of the present invention.Select the white rabbit (1.9-2.1kg) (n=4 rabbit) of any sex to be used for research.Use nimesulide IV injection, every 2ml ampoule bottle contains the 75mg nimesulide.Equal the dosage of the 3.75mg/kg rabbit body weight of 75mg/60kg people's dosage by the IV approach via the edge ear vein administration of rabbit, and 0,0.25,0.5,1,1.5,2,2.5,3,4,6,8,10, blood-sample withdrawal is carried out at 12 and 24 hours interval, and by the nimesulide in the LC-MS/MS analysed for plasma sample.Below presented the pharmacokinetics feature of Nimesulide injection in the rabbit:
Table-1: the pharmacokinetics feature of Nimesulide injection in the rabbit
| S.No. | Time (hour) | The mean plasma concentration of nimesulide (microgram/ml) |
| 1 2 3 4 5 6 7 8 9 10 11 12 13 14 | 0 0.25 0.5 1 1.5 2 2.5 3 4 6 8 10 12 24 | 0.00 17.00 15.90 13.35 10.73 8.57 8.18 7.83 6.26 3.10 1.41 0.62 0.24 0.00 |
In an embodiment more of the present invention, provide the method for preparing so new Injectable composition.
In one embodiment, preparation comprises at least a COX-II inhibitor or NSAID or the COX/LOX inhibitor as active component, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional method that contains the new Injectable composition of the last acceptable excipient of other drug may further comprise the steps:
I) active component is added in the diol mixture, then mixes,
Ii) optional adding other drug is learned to go up acceptable excipient and mix and is produced Injectable composition.
In another embodiment, preparation comprises at least a COX-II inhibitor and/or NSAID or the COX/LOX inhibitor as active component, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient, comprises that in addition the method for the new Injectable composition of one or more buffer agents and/or basifier may further comprise the steps:
I) one or more buffer agents are added in the mixture of glycol and mix and obtain uniform mixture,
Ii) active component is added in the mixture, then mixes,
Iii) add basifier, then mix,
Iv) add buffer agent and obtain uniform mixture while mixing,
V) optionally produce Injectable composition to alkaline pH by adding pH that basifier regulates mixture.
In another embodiment, described herein method comprises and is selected from least a COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, the active component of prodrug or its salt, optional contain one or more can with the other active component of COX-II inhibitor known in the art or NSAID associating.Preferred NSAID is nimesulide or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
In another embodiment of the invention, provide the Therapeutic Method that uses said composition.Pain relieving of the present invention and antiinflammatory Injectable composition are used for the treatment of mammal, particularly humans and animals, more especially people's acute pain disease, as wound after surgery, the pain relevant, athletic injury with cancer, migraine, neuralgia and pain relevant etc. with sciatica and spondylitis.
In further embodiment, the invention provides the method for using described new Injectable composition, it comprises that the compositions with effective dose delivers medicine to the patient of these needs.
In further embodiment, the invention provides the method for using described Injectable composition, be preferred for treating mammal, particularly mammiferous acute and/or chronic pain disorders, comprise multiple pain and inflammatory disease, as postoperative pain, primary dysmenorrhea and painful osteoarthritis and/or other relevant obstacle such as inflammation, heating, allergy etc.
In further embodiment, the invention provides the method for using described Injectable composition, especially for the management of acute pain disease, wherein such disease is a wound after surgery, the pain relevant with cancer, athletic injury, migraine, one or more in neuralgia and the pain relevant with sciatica and spondylitis.
In further embodiment, provide the present composition to be used to prepare the purposes of medicine, described medicine is used for the treatment of the acute pain disease, wherein such disease is a wound after surgery, the pain relevant with cancer, athletic injury, migraine, in neuralgia and the pain relevant one or more, and/or chronic pain disorders, and/or pain and inflammatory disease with sciatica and spondylitis, as postoperative pain, primary dysmenorrhea and painful osteoarthritis and/or other associated disorders such as inflammation, heating, allergy etc.
Some exemplary embodiments of explanation embodiment of the present invention are provided.Yet, it should also be understood that explanation particular composition of the present invention, process and method are exemplary, and not will be understood that it is limitation of the present invention.
Embodiment
Embodiment-1: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 20.00ml
3. glycine buffer pH 11.3 36.00ml
4. nimesulide 3.34gm
5. sodium hydroxide (NaOH) solution 4.0%w/v 11.20ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i), use the mechanical agitator continuous stirring.
Iii) about 30.0ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
The nimesulide that passes through the #60 screen cloth (3.34gm) that iv) will weigh add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (11.20ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH 11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-2: diclofenac injection (75mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-300) 30.00ml
2. propylene glycol 20.00ml
3. glycine buffer pH 12.0 30.00ml
4. diclofenac 2.50gm
5. sodium hydroxide (NaOH) solution 4.0%w/v 10.00ml
Method:
I) get the PEG-300 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 25.0ml glycine buffer pH12.0 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the diclofenac that weighs by the #60 screen cloth add step (iii) in.
V) NaOH 4.0% solution of specified amount (10.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
Vii) the glycine buffer with surplus adds step (vi).
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 7.5.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-3: indomethacin for injection (25mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 20.00ml
3. lysine buffer agent pH 10 42.00ml
4. indomethacin 0.84gm
5. sodium hydroxide (NaOH) solution 4.0%w/v 11.20ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 36.0ml lysine buffer agent is added step (ii) in, continuous stirring.
Iv) will the indomethacin that weighs by the #60 screen cloth add step (iii) in.
V) NaOH 4.0% solution of specified amount (11.20ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
Vii) the lysine buffer agent with surplus adds step (vi).
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 11.5.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-4: rofecoxib injection (25mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 20.00ml
2. propylene glycol 20.00ml
3. dimethyl acetylamide 10.00ml
4. glycine buffer pH 11.3 36.00ml
5. rofecoxib 0.84gm
6. sodium hydroxide (NaOH) solution 4.0%w/v 12.00ml
Method:
I) get the PEG-400 of specified amount (20.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i), use the mechanical agitator continuous stirring.Add 10.00ml dimethyl acetylamide and mixing.
Iii) about 30.0ml glycine buffer pH11.3 is added step (ii) in.
Iv) will the rofecoxib that weighs by the #60 screen cloth add step (iii) in.
V) NaOH 4.0% solution of specified amount (12.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 11.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-5:Licofelone injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 20.00ml
3. glycine buffer pH 11.3 36.00ml
4.Licofelone 3.34gm
5. sodium hydroxide (NaOH) solution 3.0%w/v 14.40ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 30.0ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the licofelone that weighs by the #60 screen cloth add step (iii) in.
V) NaOH 3.0% solution of specified amount (14.40ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 3.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-6: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 20.00ml
3. glycine buffer pH 11.3 36.00ml
4. micronized nimesulide 3.34gm
5. sodium hydroxide (NaOH) solution 5.0%w/v 11.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 30.0ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the micronization nimesulide that weighs by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 5.0% solution of specified amount (11.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 5.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-7: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 20.00ml
3. glycine buffer pH 11.3 36.00ml
4. nimesulide 3.34gm
5. potassium hydroxide (KOH) solution 5.6%w/v 11.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 30.0ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the nimesulide that weighs (3.34gm) by the #60 screen cloth add step (iii) in, continuous stirring.
V) KOH 5.6% solution of specified amount (11.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding KOH 5.6%w/v solution final pH is adjusted to 11.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-8: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-400) 30.00ml
2. propylene glycol 10.00ml
3. glycine buffer pH 11.3 46.00ml
4. nimesulide 3.34gm
5. potassium hydroxide (KOH) solution 4.0%w/v 13.80ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (10.00ml) is added in the step (i) continuous stirring.
Iii) about 40.0ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will be added to by the nimesulide that weighs (3.34gm) of #60 screen cloth step (iii) in, continuous stirring.
V) KOH 4.0% solution of specified amount (13.80ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding KOH 4.0%w/v solution final pH is adjusted to 11.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-9: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-600) 20.00ml
2. propylene glycol 10.00ml
3. phosphate buffer pH 7.2 56.00ml
4. nimesulide 3.34gm
5. potassium hydroxide (KOH) solution 5.6%w/v 11.20ml
Method:
I) get the PEG-600 of specified amount (20.00ml) in container.
Ii) propylene glycol (10.00ml) is added in the step (i) continuous stirring.
Iii) about 50.0ml phosphate buffer pH7.2 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the nimesulide that weighs (3.34gm) by the #60 screen cloth add step (iii) in, continuous stirring.
V) KOH 4.0% solution of specified amount (11.20ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The phosphate buffer pH7.2 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding KOH 5.6%w/v solution final pH is adjusted to 11.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-10: Nimesulide injection (100mg/3ml)
S.No. become component/100ml
1. Polyethylene Glycol (PEG-300) 30.00ml
2. glycine buffer pH 11.3 56.00ml
3. micronization nimesulide 3.34gm
4. potassium hydroxide (KOH) solution 6.5%w/v 9.50ml
Method:
I) get the PEG-300 of specified amount (30.00ml) in container.
Ii) about 40.0ml glycine buffer pH11.3 is added in the step (i), continuous stirring forms uniform mixture.
Iii) will the micronization nimesulide that weighs by the #60 screen cloth add step (ii) in, continuous stirring.
Iv) KOH 6.5% solution of specified amount (9.50ml) is added step (iii) in, continuous stirring forms uniform solution.
V) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vi) adds surplus supplies volume to 100ml.
Vii) solution was mixed about 10 minutes by continuous stirring.
Viii) final pH is adjusted to 9.5 by adding KOH 6.5%w/v solution.
Ix) by continuous stirring solution was mixed about 10 minutes.
Embodiment-11: Nimesulide injection (75mg/2ml):
S.No. become component/100ml
1. micronization nimesulide 3.77gm
2. Polyethylene Glycol (PEG 400) 30.00ml
3. propylene glycol 20.00ml
4. glycine buffer pH 11.3 35.00ml
5.NaOH solution 4.0% 13.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 30.00ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the nimesulide that weighs (3.75g) by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (13.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-12:Licofelone injection (100mg/3ml):
S.No. become component/100ml
1.Licofelone 3.34g
2. Polyethylene Glycol (PEG-400) 30.00ml
3. propylene glycol 20.00ml
4. glycine buffer pH 11.3 30.00ml
5.NaOH solution 4.0% 15.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i), use the mechanical agitator continuous stirring.
Iii) about 28.00ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the Licofelone that weighs (3.34g) by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (15.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-13: parecoxib injection (50mg/2ml):
S.No. become component/100ml
1. parecoxib 2.50g
2. Polyethylene Glycol (PEG-400) 30.00ml
3. propylene glycol 20.00ml
4. glycine buffer pH 11.3 34.00ml
5.NaOH solution 4.0% 14.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i), use the mechanical agitator continuous stirring.
Iii) about 30.00ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the parecoxib that weighs (2.50g) by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (14.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-14: diclofenac sodium injection (75mg/2ml):
S.No. become component/100ml
1. diclofenac sodium 3.77g
2. Polyethylene Glycol (PEG-400) 30.00ml
3. propylene glycol 20.00ml
4. glycine buffer pH 11.3 35.00ml
5.NaOH solution 4.0% 13.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i), use the mechanical agitator continuous stirring.
Iii) about 30.00ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the diclofenac sodium that weighs (3.77g) by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (13.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Embodiment-15: ibuprofen injection (200mg/2ml)
S.No. become component/100ml
1. ibuprofen 10g
2. Polyethylene Glycol (PEG-400) 30.00ml
3. propylene glycol 20.00ml
4. glycine buffer pH 11.3 25.00ml
5.NaOH solution 4.0% 18.00ml
Method:
I) get the PEG-400 of specified amount (30.00ml) in container.
Ii) propylene glycol (20.00ml) is added in the step (i) continuous stirring.
Iii) about 22.00ml glycine buffer pH11.3 is added step (ii) in, continuous stirring forms uniform mixture.
Iv) will the ibuprofen that weighs (10.00g) by the #60 screen cloth add step (iii) in, continuous stirring.
V) NaOH 4.0% solution of specified amount (18.00ml) is added step (iv) in, continuous stirring forms uniform solution.
Vi) solution was mixed about 30 minutes by continuous stirring.
The glycine buffer pH11.3 that vii) adds surplus supplies volume to 100ml.
Viii) solution was mixed about 10 minutes by continuous stirring.
Ix) by adding NaOH 4.0%w/v solution final pH is adjusted to 10.0.
X) by continuous stirring solution was mixed about 10 minutes.
Claims (34)
1. new Injectable composition, comprise 0.1% to 80%w/v at least a COX-II inhibitor or NSAID or COX/LOX inhibitor as active component, or its tautomeric form, or its analog, isomer, polymorph, solvate, prodrug or its salt and 1% to 80%v/v the solvent system that comprises diol mixture; The optional other medicines that contain are learned upward acceptable excipient.
2. according to the compositions of claim 1, wherein said compositions comprises 0.2% to 60%v/v at least a basifier in addition.
3. according to the compositions of claim 1, wherein said compositions comprises 2% to 80%v/v at least a buffer agent.
4. according to the compositions of claim 1 to 3, wherein the COX-II inhibitor is selected from celecoxib, rofecoxib, valdecoxib, etoricoxib, parecoxib, itacoxib, deracoxib, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
5. according to the compositions of claim 1 to 3, wherein NSAID is selected from nimesulide, nabumetone, tapoxalin, diclofenac, flosulide, ibuprofen, indomethacin, naproxen, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
6. according to the compositions of claim 5, wherein NSAID is nimesulide or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
7. according to the compositions of claim 1, wherein the COX/LOX inhibitor is licofelone.
8. according to the compositions of claim 1 to 7, wherein active component is the micronization form.
9. according to the compositions of claim 1, wherein solvent system comprises the mixture of Polyethylene Glycol and propylene glycol.
10. according to the compositions of claim 9, wherein Polyethylene Glycol (PEG) is selected from PEG 200, and PEG 300, and PEG 400, PEG 600 and PEG 700, or its mixture.
11. according to the compositions of claim 10, wherein solvent system comprises the mixture of PEG 400 and propylene glycol.
12. according to the compositions of claim 2, wherein basifier is selected from inorganic base and/or organic base.
13. according to the compositions of claim 12, wherein inorganic base is selected from sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, calcium carbonate, magnesium carbonate and magnesium oxide, or its mixture.
14. according to the compositions of claim 12, wherein organic base is selected from meglumine, triethanolamine and diethanolamine or its mixture.
15. according to the compositions of claim 3, wherein buffer agent is an ealkaline buffer.
16. according to the compositions of claim 15, wherein ealkaline buffer is selected from glycine buffer, the lysine buffer agent, and phosphate buffer and acetate buffer or its mixture have about 7.2 to about 12.5 pH.
17. according to the compositions of claim 16, wherein buffer agent is to have about glycine buffer of 8.3 to about 11.3pH.
18. according to the compositions of claim 1, wherein drug excipient is selected from carrier, filler, stabilizing agent, antiseptic, surfactant, hydrophilic polymer, solubility enhancing agent, tension regulator, local anesthetic, pH regulator agent, antioxidant, penetrating agent, chelating agen, viscosifier, wetting agent, emulsifying agent, acid, sugar alcohol, reducing sugar and non-reducing sugar, separately or with its combination, use amount be compositions about 0.1% to about 70%w/v or v/v.
19. according to the compositions of claim 18, wherein solubility enhancing agent is selected from glycerol, various other polyethylene glycol oxides of level, beta-schardinger dextrin-, transcutol and glycofurol, or its mixture.
20. according to the compositions of claim 18, wherein carrier is selected from dimethyl acetylamide, dimethyl formamide, dimethyl sulfoxide, N-Methyl pyrrolidone, benzyl benzoate, benzyl alcohol, ethyl oleate, polyoxyethylene glycol Oleum Ricini, Polyethylene Glycol, propylene glycol, hexanediol, butanediol and diol, derivatives, or its mixture.
21. according to the compositions of claim 1 to 20, it comprises anti-microbial preservative in addition.
22. according to the compositions of claim 1 to 21, it comprises antioxidant in addition.
23. according to the compositions of claim 22, wherein antioxidant is selected from ascorbyl palmitate, Butylated hydroxyanisole, butylated hydroxytoluene, propyl gallate and alpha-tocopherol or its mixture.
24., wherein add the dissolubility that ethanol and/or dimethyl acetylamide further improve active component according to the compositions of claim 1 to 23.
25. according to the compositions of claim 1 to 24, wherein Injectable composition is suitable for the parenterai administration by intravenous or intramuscular approach.
26. prepare the method for new Injectable composition, said composition comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other medicines that contain are learned upward acceptable excipient, and this method may further comprise the steps:
I) active component is added in the diol mixture, then mixes,
Ii) optional adding other drug is gone up acceptable excipient and is mixed and produce Injectable composition.
27. prepare the method for new Injectable composition, said composition comprises as at least a COX-II inhibitor of active component or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt and comprise the solvent system of diol mixture; The optional other drug that contains is learned upward acceptable excipient, comprises one or more buffer agents and/or basifier in addition, and this method may further comprise the steps:
I) one or more buffer agents are added in the mixture of glycol and mix and obtain uniform mixture,
Ii) active component is added in the mixture, then mixes,
Iii) add basifier, then mix,
Iv) add buffer agent and obtain uniform mixture while mixing,
V) choose wantonly by adding basifier pH regulator to the alkaline pH of mixture is produced Injectable composition.
28. according to the method for claim 26 or 27, wherein active component is selected from least a COX-II inhibitor or NSAID or COX/LOX inhibitor, or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
29. according to the method for claim 28, wherein NSAID is nimesulide or its tautomeric form, analog, isomer, polymorph, solvate, prodrug or its salt.
30. the using method according to the Injectable composition of claim 1 comprises that the compositions with effective dose delivers medicine to the patient of these needs.
31. using method according to the Injectable composition of claim 30, be used for the treatment of the acute pain disease, wherein such disease is a wound after surgery, the pain relevant with cancer, athletic injury, migraine, one or more in neuralgia and the pain relevant with sciatica and spondylitis; Postoperative pain, primary dysmenorrhea, painful osteoarthritis and/or other relevant obstacle such as inflammation, heating or allergy.
32. be used to prepare the purposes of medicine according to the compositions of claim 1, described medicine is used for the treatment of the acute pain disease, wherein this disease is a wound after surgery, the pain relevant with cancer, athletic injury, in the migraine, neuralgia and the pain relevant one or more with sciatica and spondylitis; Postoperative pain, primary dysmenorrhea, painful osteoarthritis and/or other relevant obstacle such as inflammation, heating or allergy.
33. in fact as described in this article and the pharmaceutical composition by embodiment explanation.
34. in fact as described in this article and the preparation of drug combination method by embodiment explanation.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN1357DE2005 | 2005-05-27 | ||
| IN1357/DEL/2005 | 2005-05-27 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101217939A true CN101217939A (en) | 2008-07-09 |
Family
ID=36917368
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2006800250937A Pending CN101217939A (en) | 2005-05-27 | 2006-05-25 | Injectable compositions and process of preparation thereof |
Country Status (15)
| Country | Link |
|---|---|
| EP (1) | EP1895983A2 (en) |
| JP (1) | JP2008542260A (en) |
| KR (1) | KR20080016689A (en) |
| CN (1) | CN101217939A (en) |
| AU (1) | AU2006250765A1 (en) |
| BR (1) | BRPI0611170A2 (en) |
| CA (1) | CA2609242A1 (en) |
| CR (1) | CR9616A (en) |
| EA (1) | EA200702646A1 (en) |
| MX (1) | MX2007014862A (en) |
| NO (1) | NO20076468L (en) |
| RS (1) | RS20070461A (en) |
| TN (1) | TNSN07482A1 (en) |
| WO (1) | WO2006126214A2 (en) |
| ZA (1) | ZA200711068B (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102335114A (en) * | 2010-07-23 | 2012-02-01 | 重庆医药工业研究院有限责任公司 | Stable ibuprofen arginine injection and preparation method thereof |
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102413687A (en) * | 2009-03-12 | 2012-04-11 | 坎伯兰医药品股份有限公司 | Administration of intravenous ibuprofen |
| CN103263385A (en) * | 2013-05-17 | 2013-08-28 | 江苏正大清江制药有限公司 | Celecoxib long-acting nano injection and preparation method thereof |
| CN103372216A (en) * | 2012-04-26 | 2013-10-30 | 北京京卫燕康药物研究所有限公司 | Solid medical composition containing celecoxib |
| US9295639B2 (en) | 2009-07-15 | 2016-03-29 | Cumberland Pharmaceuticals Inc. | Treating critically ill patients with intravenous ibuprofen |
| CN107303266A (en) * | 2016-04-18 | 2017-10-31 | 重庆润泽医药有限公司 | Levo-oxiracetam parenteral solution and preparation method thereof |
| CN107303264A (en) * | 2016-04-18 | 2017-10-31 | 重庆润泽医药有限公司 | Non-foam levo-oxiracetam parenteral solution and preparation method thereof |
| CN109498852A (en) * | 2018-12-29 | 2019-03-22 | 广州噢斯荣医药技术有限公司 | Biodegradation material and its application for treating orthopaedic disease |
| US11806400B2 (en) | 2012-03-16 | 2023-11-07 | Cumberland Pharmaceuticals Inc. | Injectable ibuprofen formulation |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| ES2728785T3 (en) | 2007-09-07 | 2019-10-28 | United Therapeutics Corp | Buffer solutions with selective bactericidal activity against gram-negative bacteria and methods to use them |
| ES2859676T3 (en) | 2011-10-18 | 2021-10-04 | Askat Inc | Medicinal composition |
| CN102512383A (en) * | 2011-12-25 | 2012-06-27 | 天津市嵩锐医药科技有限公司 | Parecoxib sodium pharmaceutical composition for injection |
| TWI646091B (en) | 2012-12-28 | 2019-01-01 | 日商衛斯克慧特股份有限公司 | Salt and crystal form |
| US20140187635A1 (en) * | 2012-12-28 | 2014-07-03 | Themis Medicare Limited | Diclofenac compositions |
| US20140275261A1 (en) | 2013-03-15 | 2014-09-18 | Dr. Reddy's Laboratories, Inc. | Diclofenac parenteral compositions |
| JP2017538762A (en) * | 2014-12-20 | 2017-12-28 | トロイカ ファーマスーティカルズ リミテッド | Paracetamol injection formulation |
| WO2016170401A1 (en) * | 2015-04-20 | 2016-10-27 | Umedica Laboratories Pvt. Ltd | Novel injectable composition of diclofenac sodium |
| FR3077984B1 (en) * | 2018-02-16 | 2020-02-21 | Vetoquinol Sa | MULTI-PURPOSE COMPOSITION OF TORASEMIDE |
| CN111103381A (en) * | 2019-12-25 | 2020-05-05 | 南京希麦迪医药科技有限公司 | Method for determining nimesulide concentration in human plasma by liquid chromatography-mass spectrometry |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5389681A (en) * | 1992-10-22 | 1995-02-14 | Ciba-Geigy Corporation | Parenteral solutions for diclofenac salts |
| IT1283252B1 (en) * | 1996-03-15 | 1998-04-16 | Pulitzer Italiana | SOLUTIONS OF PIROXICAM INJECTABLE BY PARENTERAL WAY |
| IN187306B (en) * | 1998-01-12 | 2002-03-23 | Panacea Biotec Ltd | |
| MY137736A (en) * | 2001-04-03 | 2009-03-31 | Pharmacia Corp | Reconstitutable parenteral composition |
| AU2003249510A1 (en) * | 2002-08-12 | 2004-02-25 | Ranbaxy Laboratories Limited | A parenteral dosage form of selective cox-2 inhibitors |
-
2006
- 2006-05-25 JP JP2008513009A patent/JP2008542260A/en not_active Withdrawn
- 2006-05-25 MX MX2007014862A patent/MX2007014862A/en not_active Application Discontinuation
- 2006-05-25 BR BRPI0611170-0A patent/BRPI0611170A2/en not_active IP Right Cessation
- 2006-05-25 CN CNA2006800250937A patent/CN101217939A/en active Pending
- 2006-05-25 RS RSP-2007/0461A patent/RS20070461A/en unknown
- 2006-05-25 EP EP06756263A patent/EP1895983A2/en not_active Withdrawn
- 2006-05-25 KR KR1020077030585A patent/KR20080016689A/en not_active Application Discontinuation
- 2006-05-25 CA CA002609242A patent/CA2609242A1/en not_active Abandoned
- 2006-05-25 ZA ZA200711068A patent/ZA200711068B/en unknown
- 2006-05-25 AU AU2006250765A patent/AU2006250765A1/en not_active Abandoned
- 2006-05-25 WO PCT/IN2006/000177 patent/WO2006126214A2/en active Application Filing
- 2006-05-25 EA EA200702646A patent/EA200702646A1/en unknown
-
2007
- 2007-12-14 NO NO20076468A patent/NO20076468L/en not_active Application Discontinuation
- 2007-12-19 CR CR9616A patent/CR9616A/en not_active Application Discontinuation
- 2007-12-21 TN TNP2007000482A patent/TNSN07482A1/en unknown
Cited By (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102413687A (en) * | 2009-03-12 | 2012-04-11 | 坎伯兰医药品股份有限公司 | Administration of intravenous ibuprofen |
| US9012508B2 (en) | 2009-03-12 | 2015-04-21 | Cumberland Pharmaceuticals | Administration of intravenous ibuprofen |
| US9931311B2 (en) | 2009-07-15 | 2018-04-03 | Cumberland Pharmaceuticals Inc. | Treating critically ill patients with intravenous ibuprofen |
| US9649284B2 (en) | 2009-07-15 | 2017-05-16 | Cumberland Pharmaceuticals, Inc. | Treating critically ill patients with intravenous ibuprofen |
| US9295639B2 (en) | 2009-07-15 | 2016-03-29 | Cumberland Pharmaceuticals Inc. | Treating critically ill patients with intravenous ibuprofen |
| CN102335114B (en) * | 2010-07-23 | 2015-07-15 | 重庆医药工业研究院有限责任公司 | Stable ibuprofen arginine injection and preparation method thereof |
| CN102335114A (en) * | 2010-07-23 | 2012-02-01 | 重庆医药工业研究院有限责任公司 | Stable ibuprofen arginine injection and preparation method thereof |
| CN102370615B (en) * | 2010-08-19 | 2013-09-04 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| CN102370615A (en) * | 2010-08-19 | 2012-03-14 | 四川科伦药物研究有限公司 | Ibuprofen injection preparation and preparation method thereof |
| US11806400B2 (en) | 2012-03-16 | 2023-11-07 | Cumberland Pharmaceuticals Inc. | Injectable ibuprofen formulation |
| CN103372216B (en) * | 2012-04-26 | 2015-05-06 | 北京京卫燕康药物研究所有限公司 | Solid medical composition containing celecoxib |
| CN103372216A (en) * | 2012-04-26 | 2013-10-30 | 北京京卫燕康药物研究所有限公司 | Solid medical composition containing celecoxib |
| CN103263385A (en) * | 2013-05-17 | 2013-08-28 | 江苏正大清江制药有限公司 | Celecoxib long-acting nano injection and preparation method thereof |
| CN107303266A (en) * | 2016-04-18 | 2017-10-31 | 重庆润泽医药有限公司 | Levo-oxiracetam parenteral solution and preparation method thereof |
| CN107303264A (en) * | 2016-04-18 | 2017-10-31 | 重庆润泽医药有限公司 | Non-foam levo-oxiracetam parenteral solution and preparation method thereof |
| CN107303266B (en) * | 2016-04-18 | 2020-09-08 | 重庆润泽医药有限公司 | Levo-oxiracetam injection and preparation method thereof |
| CN109498852A (en) * | 2018-12-29 | 2019-03-22 | 广州噢斯荣医药技术有限公司 | Biodegradation material and its application for treating orthopaedic disease |
| CN109498852B (en) * | 2018-12-29 | 2022-06-24 | 广州噢斯荣医药技术有限公司 | Biodegradable material for treating orthopedic diseases and application thereof |
Also Published As
| Publication number | Publication date |
|---|---|
| BRPI0611170A2 (en) | 2010-08-17 |
| JP2008542260A (en) | 2008-11-27 |
| EP1895983A2 (en) | 2008-03-12 |
| EA200702646A1 (en) | 2008-06-30 |
| CR9616A (en) | 2008-10-30 |
| MX2007014862A (en) | 2008-02-21 |
| TNSN07482A1 (en) | 2009-03-17 |
| WO2006126214A3 (en) | 2007-06-07 |
| KR20080016689A (en) | 2008-02-21 |
| NO20076468L (en) | 2008-02-27 |
| AU2006250765A1 (en) | 2006-11-30 |
| ZA200711068B (en) | 2009-03-25 |
| WO2006126214A2 (en) | 2006-11-30 |
| RS20070461A (en) | 2008-11-28 |
| CA2609242A1 (en) | 2006-11-30 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101217939A (en) | Injectable compositions and process of preparation thereof | |
| CN100366244C (en) | Local used composition containing antifungal agent | |
| ES2263182T3 (en) | SUITABLE COMPOSITION FOR THE TREATMENT OF EQUINE LAMINITIS. | |
| TW442295B (en) | Stable freeze-dried pharmaceutical composition | |
| KR100303095B1 (en) | Topical pharmaceutical compositions containing allyl amine compounds | |
| JP3925900B2 (en) | Long-acting injection containing hydrogenated castor oil | |
| KR20090090387A (en) | Effervescent formulations of florfenicol for addition in drinking water systems | |
| US20080027011A1 (en) | Homogeneous paste and gel formulations | |
| JP2023154054A (en) | Antiparasitic pour-on compositions | |
| US8859603B2 (en) | Method for solubilizing metronidazole | |
| US7879899B2 (en) | Injectable veterinary composition for small animals | |
| CN111825548A (en) | Pharmaceutical composition containing aryl propionic acid compounds | |
| CA2673193C (en) | Homogeneous paste and gel formulations | |
| PT1646425E (en) | Parasiticidal composition | |
| JP2018021027A (en) | Pharmaceutical preparation containing loxoprofen | |
| US20060014834A1 (en) | Retinoid solutions and formulations made therefrom | |
| AU2017317523B2 (en) | Pharmaceutical solution of Asenapine for sublingual or buccal use | |
| US20130089575A1 (en) | Pharmaceutical methods and topical compositions containing acitretin | |
| CN102202651A (en) | Topical formulation of 3-(2,2,2-trimethylhydrazinium) propionate dihydrate | |
| RU2649809C2 (en) | Liquid homogeneous phase for transdermal pharmaceutical compositions | |
| CN117715623A (en) | Novel oral liquid composition of enzalutamide and preparation method thereof | |
| TW200418516A (en) | Droplet dispersed ointment | |
| ES2316308B1 (en) | METRONIDAZOL BASED DRUG AND AZELAIC ACID FOR THE TOPICAL TREATMENT OF THE ROSACEA DISEASE OF BETTER ASSIMILATION, AND PREPARATION PROCEDURE. | |
| EP2145618A1 (en) | Retinoid solutions and formulations made thereform | |
| WO2004014431A1 (en) | A parenteral dosage form of selective cox-2 inhibitors |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1119574 Country of ref document: HK |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20080709 |
|
| REG | Reference to a national code |
Ref country code: HK Ref legal event code: WD Ref document number: 1119574 Country of ref document: HK |