WO2020136466A1 - Relaxant musculo-squelettique injectable et ains et son procédé de fabrication - Google Patents

Relaxant musculo-squelettique injectable et ains et son procédé de fabrication Download PDF

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Publication number
WO2020136466A1
WO2020136466A1 PCT/IB2019/059874 IB2019059874W WO2020136466A1 WO 2020136466 A1 WO2020136466 A1 WO 2020136466A1 IB 2019059874 W IB2019059874 W IB 2019059874W WO 2020136466 A1 WO2020136466 A1 WO 2020136466A1
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WO
WIPO (PCT)
Prior art keywords
formulation
solution
injection
injectable formulation
sodium
Prior art date
Application number
PCT/IB2019/059874
Other languages
English (en)
Inventor
Sanjeev Khandelwal
Original Assignee
Sanjeev Khandelwal
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 Sanjeev Khandelwal filed Critical Sanjeev Khandelwal
Publication of WO2020136466A1 publication Critical patent/WO2020136466A1/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
    • A61K9/0019—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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/196—Carboxylic acids, e.g. valproic acid having an amino group the amino group being directly attached to a ring, e.g. anthranilic acid, mefenamic acid, diclofenac, chlorambucil
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/27—Esters, e.g. nitroglycerine, selenocyanates of carbamic or thiocarbamic acids, meprobamate, carbachol, neostigmine
    • 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
    • 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
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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

Definitions

  • This invention relates to a synergistic formulation consisting of a muscle relaxant and at least one analgesic in an injectable pharmaceutical dosage form and to a method of making the same.
  • This invention envisages a synergistic formulation composition containing muscle relaxant methocarbamol and at least one analgesic selected from a group containing paracetamol and diclofenac sodium.
  • methocarbamol and the analgesic produces a synergistic response for the effective relief of pain.
  • this invention envisages an injectable formulation for parenteral administration of methocarbamol with diclofenac sodium and/or paracetamol.
  • the formulation is meant to be administrating into the human body either by slow intravenous infusion, or by intramuscular route.
  • Methocarbamol is centrally acting skeletal muscle relaxant useful in painful musculoskeletal conditions associated with spasm.
  • Paracetamol is one of the most widely used analgesics and is regarded to offer highest degree of safety and tolerability in the recommended dose. Although I ts mode of action is not fully understood, Paracetamol is believed to inhibit cyclo- oxygenase (COX) in the central nervous system, besides exerting action on the peripheral pain chemoreceptors (Bradykinin).
  • COX cyclo- oxygenase
  • Paracetamol is immediately acting, thus has a matching
  • Diclofenac is one of the most trusted NS AID, since the drug achieves excellent concentration in the synovial fluids.
  • Diclofenac Potassium alongwith Methocarbamol and Paracetamol, not only exhibits a matching pharmacokinetic profile/ but more importantly the synergistic effect in alleviating painful conditions of skeletal muscle spasm-
  • the major indications are- Dorstagia and to combat muscle spas with pain in inflammatory ulcerative conditions like arthritis, bursitis, tendonitis and also in chronic condition of pain.
  • the aspect of the invention comprises the incorporation of ingredients or excipients for making a stable pH adjusted formulation and preventing occurrence of any precipitation reaction during storage.
  • the formulation mainly comprise of at least one adjuvant co-solvent, optionally one preservative(s), one surfactant, and pH adjusting/ buffering agent and a carrier aqueous base (water for injection)
  • the formulation includes glycolic co-solvents along with the water for injection, which may be one or in combination that is selected from the glycols such as propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400, glycerin, esters of fatty acids, cremophor RS40 and other oil solvents suitable for the parenteral formulation. These co solvents can also prevent the microbial growth and act as a preservative when used in higher concentration.
  • glycols such as propylene glycol, polyethylene glycols - 300, polyethylene glycols - 400, glycerin, esters of fatty acids, cremophor RS40 and other oil solvents suitable for the parenteral formulation.
  • These co solvents can also prevent the microbial growth and act as a preservative when used in higher concentration.
  • the injectable formulation contains antioxidants that mainly prevent the oxidation of the active drug and to stabilize the formulation throughout the shelf life of the formulation.
  • the anti-oxidant used in the formulation is selected from the group consisting of sodium metabisulfide, sodium sulfide, and sodium disulfide.
  • the formulation contains chelating agent that forms a complex with the oxidizing agent and thus prevent oxidation of the active drug and thus potentiate the stabilizing action of the other antioxidants used thus stabilize the formulation throughout the shelf life of the formulation.
  • the chelating agent used in the formulation is preferably sodium salt of EDTA (ethylene diamino tetra acetic acid).
  • the formulation contains surfactant that mainly solubilizes the drug in the medium and thus prevents the precipitation of drug that may occur during the storage of the formulation.
  • the surfactant used in the formulation is selected from the group of polysorbates.
  • the formulation preferably contains polysorbate 80.
  • Another aspect of the invention comprises the incorporation of ingredients or excipients for adjusting the pH.
  • the pH of the injection is the single most crucial parameter for stability of the drug in the formulation.
  • the formulation of this invention comprises pH- adjusting agent in its dilute solution that may be preferably sodium hydroxide, hydrochloric acid, citric acid, ammonium acetate, glacial acetic acid, ammonium acetate, sodium acetate and phosphates.
  • the pH of the formulation is kept within the range of 4.5 to 7.5 throughout its shelf life.
  • the formulation contains preservatives that mainly prevent the deterioration of the formulation from the microbial contamination.
  • the preservative used in the formulation is a pharmaceutically acceptable material and is preferably selected from the group of benzyl alcohol, methyl paraben, propyl paraben and the like.
  • the preservative may be used optionally in the formulation where the quantity of the said adjuvant solvents is more than 40 % of the total volume.
  • the adjuvant solvent itself acting as a preservative.
  • a preferred content of added preservative is from 0.001 % to 5% of the total volume of the formulation.
  • a process of making a stable injectable antispasmodic and analgesic formulation comprising methocarbamol with paracetamol and/or diclofenac sodium which comprises the steps, carried out throughout in an inert atmosphere, of
  • the Injection solution was filtered through sterile membrane filter assembly (0.45 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).
  • Example - 2 The hopper of the filling machine was loaded with sterile ampoules.
  • Example - 2 The hopper of the filling machine was loaded with sterile ampoules.
  • the Injection solution was filtered through sterile membrane filter assembly (0.45 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).
  • the hopper of the filling machine was loaded with sterile vial/ampoule and filled aseptically with nitrogen gas.
  • the Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).
  • the hopper of the filling machine was loaded with sterile vial/ampoule and filled aseptically with nitrogen gas.
  • methocarbamol 7.5 kg is then transfer slowly with stirring to the diclofenac sodium solution.
  • polysorbate 80 3.50 kg was added slowly under constant stirring for about 10 minutes.
  • sufficient quantity of the fresh water for injection was added to make up the volume to about 90.00 lits and mixed by stirring for 30 minutes.
  • the pH value of solution was checked and found to be between 5.36, Add 5 % of sodium hydroxide solution under continuous stirring to adjust the pH Value of injection solution between 5.4 and 7.5.
  • Sufficient fresh water for injection was added to make up the final volume of the batch to 100.0 lits and Mixed by stirring for 30 minutes. Actual pH recorded was 6.21.
  • the Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).
  • the hopper of the filling machine was loaded with sterile ampoules.
  • Each ml of the formulation contain [Fill - 5 ml ampoules/vtal]
  • washing and sterilization After completion of the process of washing and sterilization of ampoules/vial, these were transferred to a filling area though a double door chamber.
  • methocarbamol 10.0 kg to this solution is then transfer slowly with stirring to the diclofenac sodium injection. Then sufficient quantity of the fresh water for injection was added to make up the volume to about 90.00 lits and mixed by stirring for 30 minutes. The pH value of solution was checked and found to be between 5.48. Add 5 % of sodium acetate solution under continuous stirring to adjust the pH Value of injection solution between 5.4 and 7.5. Sufficient fresh water for injection was added to make up the final volume of the batch to 100.0 lits and Mixed by stirring for 30 minutes. Actual pH recorded was 6.25.
  • the Injection solution was filtered through sterile membrane filter assembly (0.22 micron) using nitrogen pressure and collected in four sterilized 50 lits. s.s. pressure vessels with aspirators (vent).
  • the hopper of the filling machine was loaded with sterile ampoules.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • General Health & Medical Sciences (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Dermatology (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne des procédés et une composition pour le soulagement efficace de la douleur. La composition comprend une formulation synergique. L'invention concerne également des procédés de fabrication de ceux-ci. La composition contient du méthocarbamol et au moins un médicament anti-inflammatoire non stéroïdien dans une formulation pharmaceutique injectable fournie sous une forme posologique unique ou à dose multiple. Les médicaments anti-inflammatoires non stéroïdiens dans la formulation comprennent préférentiellement du diclofénac sodique et du paracétamol.
PCT/IB2019/059874 2018-12-27 2019-11-18 Relaxant musculo-squelettique injectable et ains et son procédé de fabrication WO2020136466A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IN201821049458 2018-12-27
IN201821049458 2018-12-27

Publications (1)

Publication Number Publication Date
WO2020136466A1 true WO2020136466A1 (fr) 2020-07-02

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ID=71126022

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IB2019/059874 WO2020136466A1 (fr) 2018-12-27 2019-11-18 Relaxant musculo-squelettique injectable et ains et son procédé de fabrication

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WO (1) WO2020136466A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL298129B1 (en) * 2020-08-28 2024-07-01 Cybin Uk Ltd An injectable formulation containing the fumarate salt of dimethyltryptamine or deuterium-containing dimethyltryptamine

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL298129B1 (en) * 2020-08-28 2024-07-01 Cybin Uk Ltd An injectable formulation containing the fumarate salt of dimethyltryptamine or deuterium-containing dimethyltryptamine

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