WO2012127497A1 - Compositions pharmaceutiques stables de kétorolac ou des sels de celui-ci - Google Patents

Compositions pharmaceutiques stables de kétorolac ou des sels de celui-ci Download PDF

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Publication number
WO2012127497A1
WO2012127497A1 PCT/IN2012/000152 IN2012000152W WO2012127497A1 WO 2012127497 A1 WO2012127497 A1 WO 2012127497A1 IN 2012000152 W IN2012000152 W IN 2012000152W WO 2012127497 A1 WO2012127497 A1 WO 2012127497A1
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Prior art keywords
ketorolac
pharmaceutical composition
stable pharmaceutical
composition
salts
Prior art date
Application number
PCT/IN2012/000152
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English (en)
Inventor
Sunilendu Bhushan Roy
Ravindra Nandlal PUROHIT
Shailesh Arvindbhai Patel
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Cadila Healthcare Limited
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Publication date
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Publication of WO2012127497A1 publication Critical patent/WO2012127497A1/fr

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    • 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
    • A61K9/0043—Nose
    • 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
    • A61K31/407—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 other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin

Definitions

  • the present invention relates to stable pharmaceutical compositions of ketorolac or salts thereof.
  • the present invention relates to storage stable pharmaceutical compositions of ketorolac or salts thereof and processes Ojf manufacturing such compositions.
  • the composition is particularly suitable for topical administration into the nose for the treatment of pain or inflammation.
  • Ketorolac is a nonsteroidal agent with potent analgesic and moderate antiinflammatory activity. Chemically it is 5-benzoyl-2, 3-dihydro- l H-pyrrolizine- 1 - carboxylic acid and the formula of which is:
  • Ketorolac has been known for several years, for example in U.S. Patent No. 4,089,969, and is used in human therapy as an analgesic and an anti-inflammatory.
  • ketorolac for example "Ketorolac - A review of its pharmacodynamic and pharmacokinetic properties and its therapeutic
  • ketorolac Due to its bioactivity, a commercially available ketorolac contained pharmaceutical preparation for topicjal (mucosal) or systemic diseases is preferred. Suitable formulations of ketorolac that can be formulated as a nasally administrate composition are disclosed for example in U.S. Patent No. 6,333,044.
  • U.S. Patent Publication noisy 2009/0042968 discloses a composition that is a combination of ketorolac and a local anesthetic for nasal administration to reduce the stinging sensation.
  • WO 2009/152369 discloses a unit dose formulation for nasal administration to one or two nostrils comprising:
  • ketorolac per nostril at a concentration of greater than 22.5 % w/v; and (b) a pharmaceutically acceptable carrier; wherein said unit dose has a volume of 100 microliters or less per nostril.
  • U.S. Patent No. 6,090,368 discloses a pharmaceutical nasal spray consisting of an effective amount of ketorolac based analgesic admixed with a phospholipid or a bioadhesive polymer selected from the group consisting of polyacrylics, cellulosics, gums,, cyclodextrins. chitosans. hyaluronates and albumins said spray when administered intranasally haVing a therapeutic blood level compared to that of the same spray when injected.
  • U.S. Patent Publication No. US 201 10021 595 discloses a topical aqueous ophthalmic solution comprising ketorolac, a combination of medium and high molecular weight carboxymethyl cellulose and containing no preservative, wherein the carboxymethyl cellulose is present in the amount of about 0.5 percent by weight and ketorolac is present in a concentration of about 0.40 to about 0.45 percent by w/v.
  • nasal spray product of ketorolac is marketed in the US in the form of a nasal spray under the trade name Sprix® by Roxro Pharmaceuticals Inc.
  • ketorolac or salts thereof are susceptible to degradation when subjected to long term storage under room temperature (without subjecting to cold chain storage)
  • the recommended storage condition for commercially available product requires cold chain storage, an uninterrupted series of storage and distribution activities so as to maintain a temperature range, particularly within 36°F and 46°F (2°C and 8°C) and also ought to be protected from light.
  • This specialty storage requirement thus leads to increase in the final product cost when it reaches to the end consumer.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof with one or more pharmaceutically acceptable excipients, wherein the composition retains at least 80% of the potency of ketorolac or salts thereof in the pharmaceutical composition, after storage for at least four months at room temperature.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one stabilizing agent and one or more pharmaceutically acceptable excipients.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one stabilizing agent and one or more pharmaceutically acceptable excipients, wherein when said composition is stored to 25°C in closed vials for four months, the total amount of related substances does not increase more than 0.4%.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one stabilizing agent and one or more pharmaceutically acceptable excipients, wherein when said composition is stored to 25°C in closed vials for four months, the total amount of ketorolac- 1 -keto impurity does not increase more than 0.2%.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one stabilizing agent, " wherein the ratio of the amount of ketorolac or salt thereof to the amount of stabilizing agent is in the range of from about 1 :0. 1 to about 1 :0.5. !
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof and at least one stabilizing agent, wherein the amount of stabilizing agent is from about 10% to about 50% by weight of the ketorolac or salts thereof.
  • a storage stable aqueous nasal spray composition comprising ketorolac or salts thereof, at least one stabilizing agent and one or more pharmaceutically acceptable excipients.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one polyhydroxy alcohol and one or more pharmaceutically acceptable excipients.
  • a storage stable pharmaceutical composition comprising ketorolac or salts thereof, at least one stabilizing agent, at least one buffer, at least one preservative, at least one taste masking agent, at least one antioxidant, at least one pH adjusting agent, and optionally one or more pharmaceutical ly acceptable excipients.
  • the. pharmaceutical composition may include one or more pharmaceutically acceptable excipients selected from surfactant, preservatives, chelating agents, tonicity adj usting agent, absorption promoters, viscosifier, pH adjusting agents, sweetener/taste masking agents and the like.
  • a process of preparing a storage stable pharmaceutical composition comprising ketorolac or salts thereof comprises steps of:
  • step (b) adding ketorolac or a salt thereof to the solution of step (a) and adjusting the pH of the solution using one or more pH adjusting agents;
  • step (d) fi lling the solution of step (c) into suitable containers.
  • Embodiments of the storage stable pharmaceutical composition may include one or more of the following features.
  • the pharmaceutical composition may include one or more pharmaceutically acceptable excipients selected from surfactant, preservatives, chelating agents, absorption promoters, viscosifier, pH adjusting agents, one or more tonicity adjusting agent, sweetener/taste masking agents and the like.
  • a stabilizing agent for preparing a storage stable pharmaceutical composition comprising ketorolac or salts thereof with one or more pharmaceutically acceptable excipients for use in preparation of medicament for treatment of pain or inflammation comprising administering the said composition to the patient in need thereof.
  • a method of treating moderate to moderately severe pain that requires analgesia at the opioid level in a subject in need thereof comprising nasally administering to the subject a storage stable pharmaceutical composition comprising ketorolac or salt thereof with one or more pharmaceutically acceptable excipients.
  • the inventors of the present invention have surprisingly found that it is possible to develop a storage stable pharmaceutical composition of ketorolac using judicial combination of pharmaceutically acceptable excipients.
  • ketorolac a stable pharmaceutical composition of ketorolac may be obtained by using pharmaceutically acceptable
  • i excipients comprising one or more stabilizing agents.
  • the inventors of the present invention have found that that the resulting pharmaceutical composition of ketorolac may remain stable when subjected to the stability condition.
  • the composition can be stored at room temperature over the storage period and does not require cold chain storage and/or protection from light.
  • ketorolac for the purpose of the present invention, the term 'ketorolac' shall encompass individually or collectively the racemic mixture or either optically active compound and shall encompass the free acid as well as the tromethamine salt or any other pharmaceutically acceptable salt of any one of the foregoing.
  • stable or “storage stable” indicates that when the composition is stored at room temperature (25°C) for extended period of time such as four months, there is no significant change in dissolution profile and/or therapeutically effective amount and/or total impurities percentages do not exceed 5% by weight to the ketorolac or salt thereof.
  • the invention relates to a stable pharmaceutical composition comprising ketorolac or salts thereof, wherein when said composition is stored to 25°C in closed vials for four month ' s, the total amount of related substances does not increase more than 0.4%. Additionally, the invention relates to a stable pharmaceutical composition comprising ketorolac or salts thereof, wherein when said composition is stored to 25°C in closed vials for four months, the total amount of ketorolac- 1 -keto impurity does not increase more than 0.2%.
  • stabilizing agent refers to a pharmaceutically acceptable excipient that enhances the chemical or physical stability of the active ingredient in the formulation.
  • the inventors of the present invention believe that use of judicial combination of pharmaceutical excipients including one or more stabilizing agents, for example polymer/s may contribute in improving the stability of liquid compositions of ketorolac.
  • the present invention relates to a stable pharmaceutical composition for nasal administration comprising, ketorolac or salt thereof, together with J a stabi lizing agent.
  • the composition further may comprise one or more physiologically compatible bliffer in a suitable amount for the pH of the composition to remain in the range of from 3.5 to 8.0.
  • composition is able to guarantee long stability and may provide good absorption of the active ingredient, thereby may restrain the use of irritant absorption enhancing agents/promoters or complicated preparation and delivery techniques.
  • the stabilizing agent present in the pharmaceutica ⁇ l composition of ketorolac or a salt thereof comprises at least one polymer.
  • the polymer can be selected from water soluble polymers and water insoluble polymers or mixtures thereof.
  • suitable polymers which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not imited to polyihydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, l ,2,6fhexanetriol and thioglycol, alginic acid, polyoxyethylene polyoxypropylene glycol, low methoxyl pectin, cellulose derivatives such as- methyl cellulose, carboxymethyl cellulose sodium, xanthan gum, hydroxypropyl cellulose, hydroxypropyl methyl cellulose or mixtures thereof.
  • polyihydroxy alcohols such as glycerin, polyethylene glycol, propylene glycol, diethylene glycol, triethylene glycol, tetraethylene glycol, 2-methyl-2,4-pentanediol, l ,2,6fhexanetriol and thiog
  • the amount of stabil izing agent in the composition may range from about 10% to about 50% by weight of the ketorolac or salts thereof.
  • the ratio of the amount of ketorolac or salt thereof to the amount of stabilizing agent in the composition is in the range of from about 1 :0.1 to about 1 :0.5.
  • the present invention further provides a stable pharmaceutical composition comprising ketorolac or salts thereof which retains at least therapeutic effective concentration of ketorolac after subjecting to the stability condition.
  • the stable pharmaceutical composition comprising ketorolac or salts thereof retains at least 80% of the potency of ketorolac or salts thereof in the pharmaceutical composition after storage for three months at room temperature.
  • the stable pharmaceutical composition comprising ketorolac or salts thereof retains at least therapeutic effective concentration of ketorolac after subjecting to the stressed stability conditions. for at least 1 month.
  • the stable pharmaceutical composition comprising ketorolac or salts thereof retains at least therapeutic effective concentration of ketorolac after subjecting to the storage at room temperature for at least 1 year.
  • the invention provides use of a stabilizing agent for preparing a storage stable pharmaceutical composition comprising ketorolac or salts thereof.
  • the invention further provides a process of preparing the stable pharmaceutical composition of ketorolac or salt thereof.
  • the process of preparing the stable pharmaceutical composition of ketorolac or salt thereof comprises preparing the solution of ketorolac or its salts thereof with one or more pharmaceutically acceptable excipients.
  • the process of preparing the stable pharmaceutica l composition of ketorolac or salt thereof comprises steps of-
  • step (b) adding ketorolac or salt thereof,, to the solution of step (a); (b) adjusting the pH of solution of step (b) using one or more pH adjusting agents;
  • step (d) filling the solution of step (c) into suitable containers.
  • the composition can be filled in to commercially available bottles and fit with metered dose pumps for nasal delivery of the drug products.
  • the composition of the present invention is manufactured under an inert gas (e.g. nitrogen) atmosphere.
  • the composition is packed in the container by purging inert gas in the headspace of the container.
  • composition can, for nasal administration, be applied in all medicament forms which are suitable for nasal administration, such as, for example, nasal drops or nasal sprays, by means of dispensing devices suitable for this purpose, such as bottles with drop device or nasal spray pumps.
  • the stable pharmaceutical composition of ketorolac or salt thereof comprise one or more pharmaceutically acceptable excipients selected from vehicles, surfactants, chelating agents, preservative, pH adjusting agents, absorption promoters, viscosifiers, sweetener/taste masking agents.
  • Suitable vehicles for the composition according to the invention include aqueous based vehicles suitable for topical administration.
  • aqueous based vehicles suitable for topical administration.
  • other vehicles which may be used in the compositions according to the invention comprise solvent systems containing ethyl alcohol, isopropyl alcohol, propylene glycol, polyethylene glycol, mixtures thereof or mixtures of one or more of the foregoing with water.
  • the purified water used to prepare the storage stable composition of the invention is, preferably, has oxygen content of less than 8%.
  • Suitable surfactants which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to polysorbates, their ether ethoxylates, produced by reaction of sorbitan esters with ethylene oxide, polyoxyethylene alkyl phenol, polyoxyethylene cetyl ether, polyoxyethylene alkyl-aryl ether, polyoxyethylene monolaurate, polyoxyethylene vegetable oil, polyoxyethylene sorbitan monolaurate, polyoxyethylene esters or mixed fatty and resin acids, polyoxyethylene sorbitol lanolin derivative, polyoxyethylene tridecylether, polyoxyethylene sorbitan esters of mixed fatty and resin acids, polyoxyethylene sorbitan monostearate, polyoxyethylene sorbitan monooleate, polyoxyethylene monostearate, polyoxyethylene stearyl ether, polyoxyethylene oleyl ether, polyoxyethylene tridecyl ether, polyoxyethylene fatty alcohol, polyoxyethylene alkyl amine, polyoxyethylene glycol monopalmitate
  • the osmolality can be set by variation of the amounts of the dissolved substances present in the composition besides ketorolac and any further substances present, and/or by addition of an isotonicity agent, preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.
  • an isotonicity agent preferably a physiologically tolerated salt, such as, for example, sodium chloride or potassium chloride, or a physiologically tolerated polyol, such as, for example, a sugar alcohol, in particular sorbitol or glycerol, in the concentration necessary for rendering isotonic.
  • Examples suitable of the preservatives which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to benzyl alcohol, quaternary ammonium halides, phenylcarbinol, thimerosal, disodium edetate. Quaternary ammonium halide preservatives are preferred. Suitable quaternary ammonium halide preservatives include polyquaternium- 1 and benzalkonium halides. The amount of the preservative present in the pharmaceutical composition may range from about 0.005 to about 0.5% w/w relative to the total weight of the composition.
  • the amount of the antioxidant present in the pharmaceutical composition may ranges from about 0.0002 to about 0.5% w/w relative to the total weight of the composition. .
  • Suitable chelating agents which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to edetate disodium (EDTA); edetate trisodium; edetate tetrasodium; and diethyleneamine pentaacetate, preferably EDTA.
  • the amount of the chelating agent present in the aqueous pharmaceutical composition may range from about 0.0001 - 1 %) w/w relative to the total weight of the composition.
  • viscosifiers which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to water insoluble polymers, acrylic polymers, polyoxyethylene-polyoxypropylene block copolymers, xanthan gum, tragacanth gum, alginates, agar-agar.
  • suitable pH adjusting agents which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to sodium hydroxide, hydrochloric acid, citric acid, acetic acid, fumaric acid, hydrochloric acid, malic acid, nitric acid, phosphoric acid, propionic acid, sulfuric acid, tartaric acid, or combinations thereof.
  • composition of the present invention comprises an amount of a pH adjusting agent sufficient to adjust the pH of the composition to from about 3.5 to about 8.0.
  • suitable buffers may include one or more of borate buffers, tartarate buffers, lactate buffers, citrate buffers, phosphate buffers (e.g. potassium phosphate monobasic), citric acid/phosphate buffers, carbonate/carbonic acid buffers, succinate/succinic acid bu ffers, and tris(hydroxymethyl)am inomethane /hydrochloric acid buffers and the l ike.
  • the amount of aqueous solvent and co-solvent may range from about 0.005% w/vv to about 1 % w/w of the composition.
  • sweetener/taste masking agents which can be employed in the stable pharmaceutical composition of ketorolac may be selected from, but not limited to sucralose, thaumatin (e.g., Talin ® ) sucrose, saccharin (including the salt forms: sodium, calcium, etc.), fructose, glucose, dextrose, corn syrup, aspartame, acesulfame- , xylitol, sorbitol, erythritol, ammonium glycyrrhizinate, thaumatin, neotame, mannitol, eucalyptus oil, camphor, and natural or artificial flavors or flavoring agents (for example menthol, mints, vanilla, orange, etc.), or combinations of two or more of such agents.
  • thaumatin e.g., Talin ®
  • saccharin including the salt forms: sodium, calcium, etc.
  • fructose glucose, dextrose, corn syrup
  • the stable pharmaceutical composition of ketorolac may comprise one or more additional pharmaceutical active agent/s selected from the therapeutic category of, but not limited to, corticosteroids, non- steroidal anti-inflammatory agents, antihistaminic agents, decongestants, antiallergic agents and the like.
  • the pharmaceutical composition of the present invention can be administered as a nasal spray, drop, suspension or solution.
  • the composition may also be administered using a nasal tampon or a nasal sponge.
  • the aqueous pharmaceutical composition is provided in the form of nasal spray.
  • Other means for delivering the nasal spray such as inhalation via a metered dose inhaler (MDl), may also be used.
  • MDIs are regularly used for administration by inhalation. These types of devices can include breath-actuated MDI, spacer/holding chambers in combination with MDI, and nebulizers.
  • MDI refers to an inhalation delivery system comprising, for example, a canister containing mixture of active agent and a propellant optionally with one or more excipients, a metered dose valve, an actuator, and a mouthpiece.
  • the canister is usually filled with a solution of an active agent, such as the nasal spray composition, and a propellant.
  • an active agent such as the nasal spray composition
  • a propellant such as one or more hydrofluoroalkanes [e.g. 1 , 1 , 1 ,2-tetrafluoroethane (HFA- 1 34a) and 1 , 1 , 1 ,2,3,3,3-heptaflUoropropane (HFA-227)]; chlorofluorocarbons; and alcohols such as ethanol. isopropanol, butanol, propanol or mixtures thereof.
  • a metered dose of the solution is aerosolized for inhalation. Particles comprising the active agent are propelled toward the mouthpiece where they may then be inhaled by a subject.
  • a method of treating moderate to moderately severe pain that requires analgesia at the opioid level in a subject in need thereof comprising: nasally administering to the subject a storage stable pharmaceutical composition comprising ketorolac or salt thereof with one or more pharmaceutically acceptable excipients.
  • ketorolac tromethamine prepared in accordance with the present invention and marketed product was carried out.
  • the composition of the present invention in closed vials was stored at room temperature over four months.
  • Marketed product was stored in labeled storage condition (at 2-8°C).
  • the amount (potency) of ketorolac tomethamine, relative substances and impurities were determined in both the formulation.
  • composition of the present invention remains stable and retains at least 80% potency of ketorolac tromethamine over the storage period.
  • composition of the present invention possesses excellent storage stability over marketed composition, and also does not require cold chain storage (2-8°C).

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Otolaryngology (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des compositions pharmaceutiques de kétorolac ou des sels de celui-ci, qui présentent une stabilité au stockage améliorée par rapport aux compositions connues. Elle concerne également un procédé de préparation de telles compositions qui sont particulièrement appropriées pour une administration topique dans le nez lors du traitement d'une douleur ou d'une inflammation.
PCT/IN2012/000152 2011-03-04 2012-03-05 Compositions pharmaceutiques stables de kétorolac ou des sels de celui-ci WO2012127497A1 (fr)

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IN605MU2011 2011-03-04

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2014120293A1 (fr) * 2013-01-31 2014-08-07 Sentiss Pharma Pvt.Ltd. Formulations ophthalmiques
WO2016164158A1 (fr) * 2015-04-09 2016-10-13 Insys Development Company, Inc. Formulations de pulvérisation sublinguale de kétorolac
EP3345592A1 (fr) * 2017-01-09 2018-07-11 Michael Laird Hurrey Formulations de kétorolac à stabilité améliorée et procédés et dispositifs à utiliser avec celles-ci
WO2018197932A1 (fr) 2017-04-27 2018-11-01 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques de kétorolac
CN113384524A (zh) * 2021-07-05 2021-09-14 四川尚锐生物医药有限公司 一种稳定的酮咯酸氨丁三醇注射液的制备方法
CN114159384A (zh) * 2021-02-07 2022-03-11 南京锐志生物医药有限公司 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液

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WO2009152369A1 (fr) 2008-06-13 2009-12-17 Roxro Pharma, Inc. Formulation pharmaceutique du kétorolac pour une administration intranasale
US20110021595A1 (en) 2009-07-23 2011-01-27 Allergan, Inc. Ketorolac tromethamine compositions for treating or preventing ocular pain

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WO2014120293A1 (fr) * 2013-01-31 2014-08-07 Sentiss Pharma Pvt.Ltd. Formulations ophthalmiques
WO2016164158A1 (fr) * 2015-04-09 2016-10-13 Insys Development Company, Inc. Formulations de pulvérisation sublinguale de kétorolac
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WO2018197932A1 (fr) 2017-04-27 2018-11-01 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques de kétorolac
CN114159384A (zh) * 2021-02-07 2022-03-11 南京锐志生物医药有限公司 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液
CN114159384B (zh) * 2021-02-07 2023-04-07 南京锐志生物医药有限公司 一种化学性质稳定的低刺激性酮咯酸氨丁三醇注射液
CN113384524A (zh) * 2021-07-05 2021-09-14 四川尚锐生物医药有限公司 一种稳定的酮咯酸氨丁三醇注射液的制备方法

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