WO2009087658A2 - Composition appropriée pour une administration parentérale - Google Patents

Composition appropriée pour une administration parentérale Download PDF

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Publication number
WO2009087658A2
WO2009087658A2 PCT/IN2008/000755 IN2008000755W WO2009087658A2 WO 2009087658 A2 WO2009087658 A2 WO 2009087658A2 IN 2008000755 W IN2008000755 W IN 2008000755W WO 2009087658 A2 WO2009087658 A2 WO 2009087658A2
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WO
WIPO (PCT)
Prior art keywords
composition
volume
weight
present
ketorolac tromethamine
Prior art date
Application number
PCT/IN2008/000755
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English (en)
Other versions
WO2009087658A3 (fr
Inventor
Ajay Jaysingh Khopade
Arindam Halder
Subhas Balaram Bhowmick
Original Assignee
Sun Pharma Advanced Research Company Limited
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Filing date
Publication date
Application filed by Sun Pharma Advanced Research Company Limited filed Critical Sun Pharma Advanced Research Company Limited
Publication of WO2009087658A2 publication Critical patent/WO2009087658A2/fr
Publication of WO2009087658A3 publication Critical patent/WO2009087658A3/fr

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Classifications

    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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

Definitions

  • the present invention relates to a composition comprising ketorolac tromethamine in a pharmaceutically acceptable vehicle.
  • Ketorolac is a racemic, non steroidal anti-inflammatory drug (NSAID) that inhibits the cyclo-oxygenase (COX-I and COX-2) system and hence prostaglandin synthesis. It has potent analgesic and moderate anti- inflammatory activity. It is indicated for the short-term management of moderate to severe acute pain by administering as an intravenous (IV) or intramuscular (IM) injection.
  • IV intravenous
  • IM intramuscular
  • the injection is currently available in United States in two strengths, namely 1.5 % and 3 % weight by volume under the brand name of Toradol ® .
  • the injection contains ketorolac tromethamine, sodium chloride, ethanol and water and is available in one milliliter ampoules.
  • Ketorolac is indicated in the management of acute pain by parenteral administration. Our objective was to formulate ketorolac composition having higher concentration of ketorolac tromethamine than Toradol ® injection as such higher concentration would be more suitable for autoinjectors for self administration during acute pain. While attempting to formulate the concentrated ketorolac tromethamine injection, we found that ketorolac tromethamine having a concentration of 6 % weight by volume in a vehicle containing ethanol and sodium chloride crystallized out on storage. Further more we found that the ketorolac tromethamine is susceptible to significant degradation in aqueous compositions.
  • US 6,333,044 discloses an intranasal composition having about 50 mg per ml of ketorolac tromethamine.
  • the compositions of '044 patent comprises 5 % ketorolac tromethamine, chelating agent, preservatives and cellulose derivatives.
  • ketorolac compositions having more than 5 % weight by volume of ketorolac tromethamine. Surprisingly, we have found that the addition of one or more sugar alcohols in the composition resulted in a composition that was suitable for parenteral administration and was stable upon storage.
  • ketorolac tromethamine having a concentration of more than 5 % weight by volume of the composition. It is further object of the present invention to provide a composition of ketorolac tromethamine suitable for parenteral administration particularly, self administration.
  • the present invention provides a composition comprising ketorolac tromethamine having a concentration of more than 5 % weight by volume of the composition and an osmotic agent selected from a group comprising of one or more sugar alcohols in a pharmaceutically acceptable vehicle, wherein said composition is stable and suitable for parenteral administration.
  • a composition comprising ketorolac tromethamine having a concentration of more than 5 % weight by volume of the composition and an osmotic agent selected from a group comprising of one or more sugar alcohols in a pharmaceutically acceptable vehicle wherein the said composition is stable and suitable for parenteral administration.
  • composition as in I above wherein the sugar alcohol is selected from the group comprising of mannitol, sorbitol, inositol, xylitol, glycerol, glucitol, iditol, dulcitol, glycerol, adonitol, arabitol, erythritol, threitol and the like and mixtures thereof.
  • composition as in I wherein the viscosity of the composition is about 1 cps when measured at 20° C.
  • the present invention provides a composition
  • a composition comprising ketorolac tromethamine having a concentration of more than 5 % weight by volume of the composition and an osmotic agent selected from a group comprising of one or more sugar alcohols in a pharmaceutically acceptable vehicle wherein the said composition is stable and suitable for parenteral administration.
  • compositions of the present invention are stable and suitable for parenteral administration.
  • a composition that a) retains its chemical purity within desired limits and b) dose not exhibit any undesired changes in physical characteristics; during storage of the composition on the shelf until it is consumed by the patient.
  • the composition does not show turbidity, crystallization, precipitation, colour change or any other physical change making it unacceptable for parenteral administration.
  • the composition of the present invention is a transparent solution having a percent transmittance of more than 97% when measured at 650 runs and retains its transparency on storage.
  • Ketorolac tromethamine is known to undergo chemical degradation via oxidation, hydroxylation and other unknown routes.
  • the oxidative degradation product reported is 1-keto analogue; the hydroxylation degradation product reported is 1-hydroxy analogue.
  • These known degradation products may be separated by high performance liquid chromatography and measured by absoiption in the ultravoilet region. However, any other suitable method may also be used.
  • the ketorolac injection shows at least not more than 0.5 % of any single known impurity such as 1-keto analog, 1-hydroxy analog and the like or not more than 0.5 % of any single unknown impurity or the total of known and unknown impurities are not more than 2 % weight by volume of the composition.
  • the composition of the present invention comprises more than 5 % weight by volume of ketorolac tromethamine.
  • the amount of ketorolac tromethamine in the composition of the present invention may vary from about 6 % to about 9 % weight by volume, most preferably about 6 % to about 8 % weight by volume of the composition.
  • the sugar alcohols that may be used as osmotic agents according to the present invention may be in any stereoisomers or geometric isomers or/and optical isomers forms.
  • the sugar alcohol may be straight chain or cyclic in nature.
  • the straight chain sugar alcohols may be trihydric to hexahydric sugar alcohol.
  • straight chain sugar alcohols examples include, but are not limited to, hexitols such as sorbitol, mannitol, glycerol, allitol, talitol, glucitol, iditol and dulcitol; pentitols such as xylitol, adonitol (also called ribitol) and arabitol; tetritols such as erythritol and threitol; and triols such as glycerol.
  • cyclic sugar alcohol examples include, but are not limited to, inositol and the like.
  • the composition comprises mannitol as the osmotic agent.
  • concentration of mannitol used in the composition may range from about 0.1 % weight by volume to about 3.0 % weight by volume of the composition, preferably from about 0.5 % weight by volume to about 2.5 % weight by volume and most preferably it is used in concentration of about 1.5 % weight by volume of composition.
  • the osmolality of the composition may be determined by freezing point depression method, but any other suitable method may also be used. According to one embodiment, the osmolality of the composition of the present invention ranges from about 180 mOsmoles per litre to about 400 mOsmoles per litre, preferably from about 290 mOsmoles per litre to about 310 mOsmoles per litre. According to one preferred embodiment, the composition of the present invention is iso-osmolal.
  • the pharmaceutically acceptable vehicle of the present invention optionally comprises buffers, antioxidants, pH adjusting agents and the like and mixtures thereof.
  • buffers that may be used in the composition of the present invention, includes, but are not limited to phosphate, borate, citrate, acetate, carbonate, borate-polyol complexes and the like and mixtures thereof.
  • antioxidants examples include, but are not limited to, ascorbic acid, malic acid, citric acid, sodium citrate, burylated hydroxyanisole, butylated hydroxytoluene, propyl gallate, sodium ascorbate, sodium metabisulfite and the like and mixtures thereof.
  • the composition of the present invention may use pH adjusting agents.
  • the alkaline agents that may be used to increase pH value of the composition, include, but are not limited to, sodium hydroxide (NaOH), potassium hydroxide (KOH), tromethamine, monoethanolamine, sodium bicarbonate (NaH 2 CO 3 ) and other organic bases.
  • Examples of the acidic agents that may be used to decrease the pH value of the composition include, but are not limited to, hydrochloric acid, citric acid, tartaric acid, lactic acid and other organic acids and the like and mixtures thereof.
  • the pH of the solution may be measured by any conventionally known techniques for example, digital pH meter.
  • the pH of the composition of the present invention generally ranges from about 6.0 to about 8.0, preferably about 6.2 to about 7.6.
  • the viscosity of the composition of the present invention may range from about 1 cps to about 5 cps. In one embodiment, the viscosity of the composition is about 1 cps when measured at about 20 ° C.
  • composition of the present invention uses water as the pharmaceutically acceptable vehicle.
  • the aqueous vehicle comprises one or more polyhydric alcohols as the water miscible solvents.
  • the water miscible solvents include, but are not limited to, polyethylene glycol and propylene glycol and the like and mixture thereof.
  • the composition of the present invention comprises 6 % weight by volume of ketorolac tromethamine and about 1.33 % weight by volume of mannitol as the osmotic agent.
  • the pH of the composition is adjusted by sodium hydroxide and hydrochloric acid.
  • the composition does not contain ethanol.
  • the composition comprises 6 % weight by volume of ketorolac tromethamine, about 1.33 % weight by volume of mannitol as the osmotic agent, sodium hydroxide and hydrochloric acid to adjust the pH and about 10 % volume by volume of ethanol.
  • the amount of ethanol that may be used ranges from about 0.1 % to about 10 % volume by volume of the composition.
  • the suitable container used to dispense the composition of the present invention include, but are not limited to ampoules, vials, pref ⁇ lled syringes and the like.
  • the composition of the present invention is suitable for a single dose parenteral self administration wherein the composition is dispensed in a prefilled syringe.
  • the amount of ketorolac tromethamine per single administration may range from 50 mg to about 80 mg per ml of the composition.
  • the present invention allows a higher concentration of ketorolac tromethamine to be self administered via parenteral route to treat acute pain.
  • the composition is filled in prefilled syringe with an autoi ⁇ jector.
  • an autoinjector is spring powered and designed to administer the entire contents of the prefilled syringe in one single dose.
  • the components of autoinjector may be made up of plastic and steel.
  • the design and performance features of the autoinjector device may include a safety mechanism to prevent inadvertent activation, automatic sheathing of the used needle, cutout window on the front assembly, locking tabs to prevent disassembly of the autoinjector device once the two sub assemblies have been connected, and self disabling to prevent reuse.
  • the present invention provides a process of preparing the composition comprising steps of preparing the composition and sterilizing the composition.
  • One embodiment of the process for preparing the composition of the present invention includes steps of dissolving ketorolac tromethamine in pharmaceutically acceptable vehicle such as, for example, water for injection.
  • pharmaceutically acceptable vehicle such as, for example, water for injection.
  • Other ingredients like osmotic agents, buffers, antioxidants, and the like may be dissolved separately in water for injection and then the two solutions may be mixed under constant stirring. pH of the solution can be adjusted by pH adjusting agents like sodium hydroxide, potassium hydroxide, hydrochloric acid, citric acid and the like and mixtures thereof.
  • ketorolac tromethamine, osmotic agents, optionally buffers and antioxidants and the like may be dissolved together in pharmaceutically acceptable vehicle such as water for injection. Small amount of ethanol, for example, upto about 10 % volume by volume may be added in the composition.
  • pH of the resulting composition may be adjusted by pH adjusting agents like sodium hydroxide, potassium hydroxide hydrochloric acid citric acid and the like.
  • Sterilization methods that may be used in the present invention, include, but are not limited to, filtration sterilization, autoclaving, aseptically preparing and dispensing in the sterile containers or combination of one or more said methods.
  • a decision tree such as one recommended by the European agency for the evaluation of medicinal products under CPMP/QWP/054/98 (Decision tree for the selection of sterilization methods) may be followed.
  • the composition is sterilized by microbial retentive filter such as membrane filter having pore size of about 0.2 micron. The filtered composition may then be dispensed into final sterile container.
  • the composition filtered through 2 micron filter may be dispensed in final container and then the final filled container is subjected to autoclaving.
  • the autoclaving may be carried out at about 15 psi pressure and at temperature of about 121 0 C.
  • the autoclaving time may be from about 8 minutes to about 20 minutes, preferably about 15 minutes.
  • the composition is prepared by mixing ketorolac tromethamine and the osmotic agents in water for injection separately, mixing the two solutions and adjusting the pH. According to this embodiment of the present invention, where the composition is free of ethanol.
  • the solution is filtered through 2 micron filter.
  • This solution is filled in barrel portion of the prefiUed syringe, sealed at one end with the plunger stopper and having a covered needle at the other end.
  • the sealed filled, prefilled syringes are sterilized by autoclaving at pressure of about 15 psi at temperature of about 121 0 C for about 15 minutes.
  • the solution is first sterilized by filtering it through about 0.2 micron membrane filter. This sterile solution is then dispensed in previously sterilized prefilled syringe.
  • the composition is prepared by mixing ketorolac tromethamine and the osmotic agent in water for injection, mixing the two solutions and adjusting the pH. To the mixed solution about 10 % of ethanol is added. The final solution is filtered through 2 microns filters and then subjected filtration sterilization by using 0.2 micron membrane filers.
  • Example l The composition according to Example l was prepared as follows.
  • Ketorolac tromethamine was dissolved in water for injection under stirring at 80 rpm. Mannitol was dissolved separately in water for injection with continuous stirring. The two solutions were mixed and the pH was adjusted by sodium hydroxide solution at 6.90 to 7.90. The volume was made up and the solution was filtered through 2 micron glass fiber filter. The filtered solution was dispensed into prefilled syringes under nitrogen gas.
  • the pre-filled syringe consists of 1 ml long barrel made of USP type I glass (Borosilicate) with staked needle 26 G 5/8" or equivalent & the plunger stopper made up of Flurotech coated bromobutyl rubber. The needle is covered by a needle cover. These prefilled syringes were then sterilized by autoclaving at pressure and temperature of 15 psi and 121 0 C respectively for 15 minutes.
  • composition according to Example 2 was prepared as follows.
  • Ketorolac tromethamine was dissolved in water for injection under stirring at 80 rpm. Mannitol was dissolved separately in water for injection with continuous stirring. The two solutions were mixed and the pH was adjusted by sodium hydroxide solution at 6.90 to 7.90. 10 % ethanol is added in the solution and the volume was made up. The solution was filtered through 2 micron glass fiber filter and then was sterilized by filtration through 0.2 micron membrane filter. The sterilized solution was dispensed into sterile prefilled syringes as described in example 1 under nitrogen gas purging.
  • Example 1 and Example 2 were checked for stability in the accelerated conditions of 4O 0 C at 75% relative humidity (40°C/75% RH).
  • the prefilled syringes containing composition were kept in the stability chamber.
  • the composition was analyzed for the ketorolac tromethamine content by HPLC.
  • the degradation products for example, 1-keto analogue and 1-hydroxy analogue were separated by HPLC and quantified by measuring the absorption in the UV region.
  • the physical stability of the compositions was checked by measuring the % transmittance at 650 nm by UV. The details of the results are given in table 4.
  • ND mentioned in above table means not detected and — mentioned above means not determined.
  • Example 1 The composition according to Example 1 was tested in W ⁇ star rats for any occurrence of any skin irritation when administered via intramuscular route.
  • the irritation at the site of intramuscular injection was scored depending upon the severity of hemorrhage, inflammation and necrosis. It was found that the composition of example 1 showed scores comparable to the marketed ketorolac injection administered at the dose of 60 mg. Both the compositions were found to be non irritant at the site of intramuscular injection.
  • Ketorolac Tromethamine was dissolved in water for injection under stirring. Other ingredients were mixed with the Ketorolac tromethamine solution according to the formula given in table 5. pH of the solution was adjusted by sodium hydroxide solution at 6.90 to 7.90. The solution was then filtered through 2 micron glass fiber filter and 0.2 micron Nylon 66 membrane disc filter. The filtered solution was dispensed into sterile 10 ml colourless Type 1 glass vials. The vials were Stoppard with bromobutyl flange rubber stopper and sealed with aluminum flip.
  • compositions according to comparative example 1, 2, 3, were stored at room temperature. It was found that in Example 1 and 2 ketorolac tromethamine crystallized out within 6 days of storage and in Example 3 crystallization was observed in 2 days.

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

L'invention porte sur une composition contenant de la kétorolac trométhamine présentant une concentration supérieure à 5 pour cent en poids par volume de la composition et un agent osmotique choisi dans un groupe constitué par un ou plusieurs alcools de sucre dans un véhicule pharmaceutiquement acceptable, ladite composition étant stable et appropriée pour une administration parentérale.
PCT/IN2008/000755 2007-11-07 2008-11-05 Composition appropriée pour une administration parentérale WO2009087658A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN2225/MUM/2007 2007-11-07
IN2225MU2007 2007-11-07

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WO2009087658A2 true WO2009087658A2 (fr) 2009-07-16
WO2009087658A3 WO2009087658A3 (fr) 2009-11-19

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Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2616064A4 (fr) * 2010-10-21 2016-07-20 Rtu Pharmaceuticals Llc Formulations de kétorolac prêtes à l'emploi
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
EP3345598A1 (fr) * 2017-01-09 2018-07-11 Steadymed Ltd. Formulations de kétorolac à économie de dose 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
WO2019122982A1 (fr) 2017-12-21 2019-06-27 Grünenthal GmbH Association pharmaceutique sous forme de comprimé bicouche comprenant du kétorolac trométhamine et du chlorhydrate de tramadol et son utilisation en traitement de la douleur
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
CN114432240A (zh) * 2022-03-04 2022-05-06 郑州市中心医院 一种稳定不刺激的酮咯酸氨丁三醇注射液及其制备方法

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EP0612521A1 (fr) * 1991-11-11 1994-08-31 Hisamitsu Pharmaceutical Co., Inc. Fomentation contenant du cetorolac
WO1996028144A1 (fr) * 1995-03-13 1996-09-19 The Procter & Gamble Company Emploi de ketorolac pour le traitement d'epithelioma spinocellulaires de la cavite buccale ou de l'arriere gorge
US20030004142A1 (en) * 2001-04-18 2003-01-02 Prior Christopher P. Use of NSAIDs for prevention and treatment of cellular abnormalities of the lung or bronchial pathway

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
US4410534A (en) * 1979-12-26 1983-10-18 Syntex (U.S.A.) Inc. 3-Substituted-5,6,7,8-tetrahydropyrrolo[1,2-a]-pyridine-and 6,7,8,9-tetrahydro-5H-pyrrolo[1,2-a]-azepine carboxylic acid derivatives useful as blood platelet aggregation inhibitors
EP0612521A1 (fr) * 1991-11-11 1994-08-31 Hisamitsu Pharmaceutical Co., Inc. Fomentation contenant du cetorolac
WO1996028144A1 (fr) * 1995-03-13 1996-09-19 The Procter & Gamble Company Emploi de ketorolac pour le traitement d'epithelioma spinocellulaires de la cavite buccale ou de l'arriere gorge
US20030004142A1 (en) * 2001-04-18 2003-01-02 Prior Christopher P. Use of NSAIDs for prevention and treatment of cellular abnormalities of the lung or bronchial pathway

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11116750B2 (en) 2010-10-21 2021-09-14 Rtu Pharmaceuticals, Llc Ready to use ketorolac formulations
KR102307601B1 (ko) * 2010-10-21 2021-09-30 알티유 파머수티컬즈, 엘엘시 즉시 사용가능한 케토로락 제제
US10278959B2 (en) 2010-10-21 2019-05-07 Rtu Pharmaceuticals, Llc Ready to use ketorolac formulations
KR102114568B1 (ko) * 2010-10-21 2020-05-22 알티유 파머수티컬즈, 엘엘시 즉시 사용가능한 케토로락 제제
US9421191B2 (en) 2010-10-21 2016-08-23 Rtu Pharmaceuticals, Llc Ready to use ketorolac formulations
EP2616064A4 (fr) * 2010-10-21 2016-07-20 Rtu Pharmaceuticals Llc Formulations de kétorolac prêtes à l'emploi
KR20200078541A (ko) * 2010-10-21 2020-07-01 알티유 파머수티컬즈, 엘엘시 즉시 사용가능한 케토로락 제제
KR20180119610A (ko) * 2010-10-21 2018-11-02 알티유 파머수티컬즈, 엘엘시 즉시 사용가능한 케토로락 제제
EP4190327A1 (fr) * 2010-10-21 2023-06-07 Rtu Pharmaceuticals LLC Formulations de kétorolac prêt à l'emploi
US9962371B2 (en) 2010-10-21 2018-05-08 Rtu Pharmaceuticals, Llc Ready to use ketorolac formulations
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
US20180193460A1 (en) * 2017-01-09 2018-07-12 Steadymed, Ltd. Enhanced stability ketorolac formulations and methods and devices for use with same
EP3345598A1 (fr) * 2017-01-09 2018-07-11 Steadymed Ltd. Formulations de kétorolac à économie de dose 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
WO2019122982A1 (fr) 2017-12-21 2019-06-27 Grünenthal GmbH Association pharmaceutique sous forme de comprimé bicouche comprenant du kétorolac trométhamine et du chlorhydrate de tramadol et son utilisation en traitement de la douleur
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
CN114432240A (zh) * 2022-03-04 2022-05-06 郑州市中心医院 一种稳定不刺激的酮咯酸氨丁三醇注射液及其制备方法

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