WO2018116190A1 - Compositions pulvérisables à usage topique de kétorolac trométhamine - Google Patents

Compositions pulvérisables à usage topique de kétorolac trométhamine Download PDF

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Publication number
WO2018116190A1
WO2018116190A1 PCT/IB2017/058185 IB2017058185W WO2018116190A1 WO 2018116190 A1 WO2018116190 A1 WO 2018116190A1 IB 2017058185 W IB2017058185 W IB 2017058185W WO 2018116190 A1 WO2018116190 A1 WO 2018116190A1
Authority
WO
WIPO (PCT)
Prior art keywords
topical
composition
topical composition
solvents
ketorolac tromethamine
Prior art date
Application number
PCT/IB2017/058185
Other languages
English (en)
Inventor
Lalatendu Panigrahi
Alok Ranjan SAMAL
Jitesh Kumar BEHERA
Anumula MANASA
Abhijit Ashok TELI
Original Assignee
Dr. Reddy's Laboratories Limited
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Dr. Reddy's Laboratories Limited filed Critical Dr. Reddy's Laboratories Limited
Priority to EA201991537A priority Critical patent/EA201991537A1/ru
Publication of WO2018116190A1 publication Critical patent/WO2018116190A1/fr

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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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/12—Aerosols; Foams
    • 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]

Definitions

  • the present invention relates to topical sprayable compositions of ketorolac tromethamine.
  • the invention also provides the process for preparation of such compositions.
  • the invention relates to the use of said compositions for the treatment of acute pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.
  • Ketorolac is a non-steroidal anti-inflammatory agent. It exhibits analgesic, antiinflammatory and antipyretic activity. It is mainly indicated for short term management of acute pain.
  • Ketorolac refers to the compound having a chemical name ( ⁇ )-5-benzoyl-2,3-dihydro- lH-pyrrolizine-l-carboxylic acid and the following structural formula (1).
  • ketorolac encompasses the free acid, its pharmaceutically acceptable salts and esters thereof.
  • Pharmaceutically acceptable salt refers to those salts, which retain the biological effectiveness and properties of the free acid, and which are not biologically or otherwise undesirable.
  • a commercially used pharmaceutically acceptable salt is the "tromethamine" salt of ketorolac, i.e., ketorolac tromethamine (2), available in various dosage forms eg. tablets, injectables, topical gel, intranasal spray and ophthalmic solution.
  • a commercial product containing ketorolac tromethamine for the treatment of acute pain is available in the form of 2% topical gel.
  • This topical gel product is inconvenient to apply on large areas of the skin and has slower onset of action.
  • a quick onset of action and instant relief is a prerequisite in few conditions, specifically for acute pain due to tissue injury in sports or during exercise. Therefore, a topical composition, which is easy to apply and provides instant relief, is often preferred.
  • Ketorolac tromethamine For topical compositions of ketorolac tromethamine, the key challenge is its re- crystallization. Ketorolac tromethamine has a very good solubility in non-aqueous solvents, which rapidly evaporate after the application and leads to its re -crystallization. This affect the performance of the composition as the entire drug does not permeate through skin. Hence, a specific ratio of aqueous and non-aqueous solvents is required.
  • a composition comprising one or more solvents, a penetration enhancer and a buffering agent, delivered as a topical spray provides quick onset of action and instant relief, thereby improving the patient convenience and also exhibiting at least comparable efficacy to topical gel compositions currently available in the market.
  • Such compositions are effective in the treatment of pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.
  • the present specification relates to a topical sprayable composition of ketorolac tromethamine comprising one or more solvents, a penetration enhancer and a buffering agent.
  • a topical sprayable composition comprising:
  • the present specification relates to a topical sprayable composition
  • a topical sprayable composition comprising:
  • the present specification provides a stable and transparent topical sprayable composition of ketorolac tromethamine.
  • topical sprayable composition according to the present specification may be used for treating pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.
  • the present specification relates to a topical sprayable composition of ketorolac tromethamine comprising one or more solvents, a penetration enhancer and a buffering agent.
  • the present specification relates to a topical sprayable composition
  • a topical sprayable composition comprising:
  • the present specification relates to a topical sprayable composition
  • a topical sprayable composition comprising:
  • the present specification relates to a topical sprayable composition
  • a topical sprayable composition comprising:
  • ketorolac tromethamine The concentration of ketorolac tromethamine employed in the present specification is from 1-5% w/w, e.g. 2% w/w of the composition.
  • topical sprayable compositions refers to a ketorolac composition, which provides a convenient application in a form of topical spray on external body surface.
  • solvents refers to any pharmaceutically acceptable solvent e.g. aqueous or non-aqueous solvents or combinations thereof.
  • the aqueous solvent is purified water.
  • the ratio of aqueous to non-aqueous solvents employed in the present specification is 1 :1 to 1 :10, e.g. 1 :2, 1 :8.
  • the range of one or more solvents employed in the present specification is from 10-95% w/w of the composition.
  • Suitable “Solvents” may be selected from purified water or non-aqueous solvents.
  • the non-aqueous solvent may be selected from aliphatic alcohol, propylene glycol, polyethylene glycol 400, N-methyl pyrrolidone, acetone, ethyl acetate, ethyl formate, methyl acetate, methyl ethyl ketone or combinations thereof.
  • the aliphatic alcohol may be selected from methanol, ethanol, propanol, isopropyl alcohol, butanol or combinations thereof.
  • the range of purified water that may be employed in the present specification is from 5-40% w/w of the composition.
  • the range of one or more non-aqueous solvent that may be employed in the present specification is from 20-90% w/w, e.g. 40-80% w/w of the composition.
  • the range of isopropyl alcohol that may be employed in the present specification is from 30-70% w/w, e.g. 50% w/w of the composition.
  • the range of propylene glycol that may be employed in the present specification is from 10-30% w/w, e.g. 15% w/w of the composition.
  • the term "penetration enhancer” refers to a substance, which increases the penetration of composition in the skin.
  • the penetration enhancers used herein may be single or a combination of two or more, selected but not limited to lipophilic solvents, surfactants, fatty acid esters and polyhydric alcohols.
  • the penetration enhancers may be selected from dimethyl sulfoxide, diethylene Glycol Mono ethyl ether, glycerin, benzyl alcohol, cetyl alcohol, ispropyl isostearate, stearic acid, isobutyl palmitate, isocetyl stearate, oleyl alcohol or combinations thereof.
  • the penetration enhancer as described above may be employed in the present specification in concentration ranging from 1-15% w/w, e.g. 5-10% w/w of the composition.
  • buffering agent refers to a pharmaceutically acceptable agent that provides sufficient buffering capacity at the desired pH range.
  • buffers useful in the present specification include, but are not limited to, acetate, glutamate, citrate, tartrate, benzoate, lactate, gluconate, phosphate and glycine and conjugate acids thereof.
  • the buffering agent that may be employed in the present specification comprises sodium acetate trihydrate and glacial acetic acid in concentration ranging from 0.1-5% w/w, e.g. 0.1-2% w/w of the composition.
  • composition according to the present specification optionally comprises one or more pharmaceutically acceptable excipients used in the cosmetics or pharmaceutical field, such as surfactants, sequestering agents, antioxidants, preservatives, fillers, electrolytes, humectants, colorants, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingo lipids, self-tanning compounds such as DHA, and calmants and protective agents for the skin such as allantoin.
  • pharmaceutically acceptable excipients used in the cosmetics or pharmaceutical field, such as surfactants, sequestering agents, antioxidants, preservatives, fillers, electrolytes, humectants, colorants, common mineral or organic acids or bases, fragrances, essential oils, cosmetic active agents, moisturizers, vitamins, essential fatty acids, sphingo lipids, self-tanning compounds such as DHA, and calmants and protective agents for the skin such as allantoin.
  • excipients may be present in the composition in a range from 0 - 20% w/w of the composition.
  • fragrances include plant extracts and essential oils like eucalyptus, lemon, orange, cinnamon, mint, tangerine, grapefruit, spearmint, peppermint, clove, or rosemary oil, or synthetic fragrances such as vanilline and calm valley.
  • preservatives examples include benzalkonium chloride, phenoxy-ethanol, benzyl alcohol, diazolidinylurea and parabens, or combinations thereof.
  • the topical sprayable composition of ketorolac tromethamine is packed in a HDPE bottle fitted with spray pump or a kit comprising HDPE bottle and a spray pump assembly, which needs to be assembled with the bottle by removing screw cap before the first application.
  • the topical composition of ketorolac tromethamine may be delivered as a spray on external body surface.
  • the present specification provides a process for the preparation of the topical sprayable composition of ketorolac tromethamine.
  • the process for the preparation may be any conventional suitable process comprising the mixing of ketorolac tromethamine with other excipients of composition.
  • topical sprayable composition according to the present specification may be used for treating pain affecting joints and surrounding tissues such as tendons, muscles, and ligaments.
  • a buffer solution was prepared by mixing sodium acetate trihydrate and glacial acetic acid in purified water. Ketorolac was added to this buffer solution to prepare the drug solution.
  • a solvent mixture was prepared by mixing DMSO in ethanol followed by the addition of propylene glycol. 3.
  • drug solution was added into the solvent mixture followed by the addition of calm valley to form a clear solution and this solution was filled into HDPE bottles.
  • a buffer solution was prepared by mixing sodium acetate trihydrate and glacial acetic acid in purified water. Ketorolac was added to this buffer solution to prepare the drug solution.
  • a solvent mixture was prepared by mixing DMSO in isopropyl alcohol followed by the addition of propylene glycol.
  • the stability of the topical spray compositions of present specification were evaluated through accelerated stability studies.
  • the composition was prepared according to the formula and process of example 2, and was subjected to stability study at various temperature and humidity conditions. The composition was found to be stable at accelerated conditions.
  • Table 1 represents the study result data.
  • Table 1 Stability study
  • Staining property of the composition of the present specification was evaluated by spraying the composition prepared in accordance with example 2 on a white cotton cloth and was kept for few minutes and observed for staining. The study was conducted on initial sample (room temperature) and stability sample kept on 40°C/75 %RH 1 Month. No stain was observed in both the sample after spraying. The studies indicate that the non-staining property of the composition retained both in room temperature condition and accelerated condition (40°C/75 %RH).
  • Spray volume per actuation of the composition of the present specification was evaluated by using an analytical balance. Spray rate was performed by taking initial weights of spray bottles and weight taken each actuation. Quantity of liquid was delivered by difference between initial weight and final weight. The study repeated 10 times for each spray pump and five pumps were taken as different experiments. Table 2 represents the spray volume data. Table 2: Spray volume per actuation
  • Bioavailability of the topical spray composition according to the present specification was compared with a reference gel product, which is a 2% Ketorolac topical gel composition.
  • the reference product was prepared in accordance to composition disclosed in table 3 using conventional methods.
  • Carbomer 974 P (Carbopol 974P) 2
  • test spray product of the present specification and the reference gel product were subjected to a randomized, open-label, balanced, single -dose, two-treatment, 2-period, 2-sequence crossover bioavailability study in 24 normal healthy, adult, human subjects. Following an overnight fast of at least 10 hours, subjects were administered with either test or reference product in sitting position as per the randomization schedule as described in Table 4.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Dispersion Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des compositions pulvérisables à usage topique de kétorolac trométhamine, la composition comprenant un ou plusieurs solvants, un activateur de pénétration et un agent de tamponnage. L'invention concerne également des procédés de préparation desdites compositions. L'utilisation des compositions pulvérisables à usage topique selon l'invention pour le traitement des douleurs aiguës affectant les articulations et tissus environnants tels que tendons, muscles et ligaments est en outre décrite.
PCT/IB2017/058185 2016-12-21 2017-12-20 Compositions pulvérisables à usage topique de kétorolac trométhamine WO2018116190A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EA201991537A EA201991537A1 (ru) 2016-12-21 2017-12-20 Топические распыляемые композиции кеторолака трометамина

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201641043639 2016-12-21
IN201641043639 2016-12-21

Publications (1)

Publication Number Publication Date
WO2018116190A1 true WO2018116190A1 (fr) 2018-06-28

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Application Number Title Priority Date Filing Date
PCT/IB2017/058185 WO2018116190A1 (fr) 2016-12-21 2017-12-20 Compositions pulvérisables à usage topique de kétorolac trométhamine

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EA (1) EA201991537A1 (fr)
WO (1) WO2018116190A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040213744A1 (en) * 1999-05-20 2004-10-28 U & I Pharmaceuticals Ltd. Topical spray compositions
WO2016164158A1 (fr) * 2015-04-09 2016-10-13 Insys Development Company, Inc. Formulations de pulvérisation sublinguale de kétorolac

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040213744A1 (en) * 1999-05-20 2004-10-28 U & I Pharmaceuticals Ltd. Topical spray compositions
WO2016164158A1 (fr) * 2015-04-09 2016-10-13 Insys Development Company, Inc. Formulations de pulvérisation sublinguale de kétorolac

Also Published As

Publication number Publication date
EA201991537A1 (ru) 2020-03-12

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