WO2020017578A1 - Agent d'injection contenant un médicament à base d'oxycam - Google Patents

Agent d'injection contenant un médicament à base d'oxycam Download PDF

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Publication number
WO2020017578A1
WO2020017578A1 PCT/JP2019/028206 JP2019028206W WO2020017578A1 WO 2020017578 A1 WO2020017578 A1 WO 2020017578A1 JP 2019028206 W JP2019028206 W JP 2019028206W WO 2020017578 A1 WO2020017578 A1 WO 2020017578A1
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Prior art keywords
oxicam
drug
containing injection
meloxicam
minutes
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PCT/JP2019/028206
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English (en)
Japanese (ja)
Inventor
喜一郎 鍋田
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テクノガード株式会社
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Priority to JP2020531356A priority Critical patent/JP7385881B2/ja
Publication of WO2020017578A1 publication Critical patent/WO2020017578A1/fr

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    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/5415—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with carbocyclic ring systems, e.g. phenothiazine, chlorpromazine, piroxicam
    • 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
    • A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
    • A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • 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
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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 an oxicam drug-containing injection having transparency and excellent stability and safety.
  • Oxicam drugs such as meloxicam, piroxicam, and lornoxicam are one of non-steroidal anti-inflammatory drugs (NSAIDs: Non-Steroidal Anti-Inflammatory Drugs) and have excellent anti-inflammatory effects, but are poorly water-soluble. Due to the fact that (the solubility in water specified by the Japanese Pharmacopoeia / general rule is "almost insoluble" (the amount of solvent required to dissolve 1 g or 1 mL of solute is 10,000 mL or more: the solute corresponds to the drug and the solvent corresponds to water) )))
  • the form of the preparation is limited to oral preparations, external preparations, suppositories and the like.
  • a method of administering an oxicam-based drug as an injection has been desired in recent years.
  • a method of administering a poorly water-soluble drug such as an oxicam drug as an injection a method of making the drug into a fat emulsion is well known.
  • a drug-containing fat emulsion is generally used in a large amount compared to the drug content. It is a milky-white preparation using fats and oils (the content of which is, for example, 100 mg / mL or more even if estimated at a low level). Is difficult.
  • the present inventor has proposed a drug-containing fat emulsion which is less transmissive and has excellent transparency and stability.
  • the drug-containing fat emulsion proposed by the present inventors in Patent Document 1 can be produced by adjusting the content of fats and oils to a maximum of 2 mg / mL, and has high transparency and excellent stability. It is evaluated as an emulsion. However, since this drug-containing fat emulsion has a low fat content of 2 mg / mL at the maximum, the amount of the drug that can be carried by the fat emulsion is limited. There is a need for drug-containing fat emulsions that are more transparent and have better stability while still using larger amounts of fats and oils to be supported.
  • lecithin has a weak emulsifying power and is not always easy to handle because of its high viscosity at high concentrations.
  • the present inventor has attempted to develop it to meet such demands, but has not yet found any effective solution.
  • an object of the present invention is to provide an oxicam drug-containing injection having transparency and excellent stability and safety.
  • the present inventor has conducted intensive studies in view of the above points, and as a result, it has been found that the oxicam drug, lecithin, metal salt of a fatty acid, macrogol, N, N-dimethylacetamide, and an aqueous medium are used as at least the constituents, and thus the transparent medium is obtained. It has been found that an oxicam drug-containing injection having excellent stability and safety can be produced.
  • the oxicam-based drug-containing injection of the present invention based on the above findings, as described in claim 1, (1) Oxicams (2) Lecithin (up to 50% by weight of the lecithin used may be replaced by polysorbate) (3) a pharmaceutically acceptable salt of a fatty acid (4) macrogol and / or N, N-dimethylacetamide (5) an aqueous medium at least as a constituent, and a turbidity of 0.5 or less. I do.
  • the oxicam drug-containing injection according to claim 2 is the oxicam drug-containing injection according to claim 1, wherein the oxicam drug content is 0.1 to 50 mg / mL and the lecithin content is 50 to 200 mg / mL.
  • the oxicam-based drug-containing injection according to a third aspect is characterized in that the oxicam-based drug-containing injection according to the first aspect further comprises a fat and / or a tocopherol compound.
  • the oxicam drug-containing injection according to the fourth aspect is the oxicam drug-containing injection according to the third aspect, wherein the content of the fat and / or the tocopherol compound is 5 to 100 mg / mL, and the content of the fat and / or the tocopherol compound.
  • the weight ratio of the oxicam drug (oxicam drug / oil / fat and / or tocopherol compound) is 0.01 to 2 (provided that the total content of the oxicam drug and the fat / oil and / or tocopherol compound is 125 mg / mL at the maximum).
  • An oxicam-based drug-containing injection according to a fifth aspect is characterized in that, in the oxicam-based drug-containing injection according to the first aspect, the oxycam-based drug-carrying particles have an average particle diameter of 1 to 200 nm.
  • the oxicam-based drug-containing injection according to the sixth aspect is characterized in that the oxicam-based drug-containing injection according to the first aspect further comprises a saccharide.
  • an oxicam drug-containing injection having transparency and excellent stability and safety.
  • Oxycam drug-containing injection of the present invention (1) Oxicams (2) Lecithin (up to 50% by weight of the lecithin used may be replaced by polysorbate) (3) a pharmaceutically acceptable salt of a fatty acid (4) macrogol and / or N, N-dimethylacetamide (5) an aqueous medium at least as a constituent, and a turbidity of 0.5 or less. Is what you do.
  • examples of the oxicam-based drug include meloxicam represented by the following chemical structural formula, piroxicam, lornoxicam, ampiroxicam, droxicam, tenoxicam, isoxicam, sudoxicam, and tesicam. These are all poorly water-soluble.
  • examples of lecithin that plays a role as a solubilizing agent or an emulsifier include egg yolk lecithin, soybean lecithin, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, and the like.
  • polysorbate polyoxyethylene sorbitan fatty acid ester
  • polysorbate 20 40, 60, 65, 80 (in order to make the replaced polysorbate sufficiently effective, 10% by weight or more of lecithin used is used). Should be replaced).
  • pharmaceutically acceptable salts of fatty acids include medium-chain fatty acids having 8 to 12 carbon atoms (caprylic acid, capric acid, lauric acid and the like) and long-chain fatty acids having 14 to 18 carbon atoms ( Pharmaceutically acceptable salts of myristic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, etc., for example, alkali metal salts such as sodium salt and potassium salt, calcium salt and magnesium And alkaline earth metal salts such as salts.
  • the fatty acids may be saturated or unsaturated fatty acids.
  • macrogol polyethylene glycol
  • examples of the aqueous medium include water (pure water, purified water, water for injection, etc.), acetic acid-sodium acetate, boric acid-sodium carbonate, boric acid-sodium tetraborate, hydrochloric acid-sodium tetraborate, Phosphoric acid-sodium phosphate, sodium dihydrogen phosphate-disodium hydrogen phosphate, citric acid-sodium hydroxide, hydrochloric acid-potassium hydrogen phthalate, sodium hydroxide-potassium hydrogen phthalate, citric acid-disodium hydrogen phosphate , Succinic acid-sodium tetraborate, ammonia-ammonium chloride, potassium dihydrogen phosphate-disodium hydrogen phosphate-phosphoric acid, potassium dihydrogen phosphate-disodium hydrogen phosphate-sodium hydroxide, potassium dihydrogen phosphate -Disodium hydrogen phosphate, potassium di
  • the content of the oxicam drug may be, for example, 0.1 to 50 mg / mL.
  • the content of lecithin is preferably 50-200 mg / mL, more preferably 60-180 mg / mL, and even more preferably 70-160 mg / mL.
  • the solubilizing effect on the oxicam-based drug may not be sufficiently exerted.
  • the amount is more than 200 mg / mL, the viscosity may be increased, so that the oxicam-based drug may be difficult to be solubilized. .
  • 50% by weight or less of the lecithin used may be replaced with polysorbate.
  • the total content of lecithin and polysorbate is 50 to 200 mg / mL, and is composed of 50% by weight or more of lecithin and 50% by weight or less of polysorbate.
  • the content of the pharmaceutically acceptable salt of the fatty acid is preferably 0.1 to 50 mg / mL, more preferably 1 to 30 mg / mL, and still more preferably 5 to 25 mg / mL. If the amount is less than 0.1 mg / mL, the oxicam-based drug may be easily aggregated or precipitated, while if it is more than 50 mg / mL, the oxicam-based drug may be deteriorated.
  • the content of macrogol and / or N, N-dimethylacetamide is preferably from 0.2 to 300 mg / mL, more preferably from 1 to 250 mg / mL, even more preferably from 2 to 200 mg / mL.
  • the amount is less than 0.2 mg / mL, the effect of improving solubility and stability with respect to the oxicam-based drug may be difficult to be exhibited. May be difficult to solubilize or make into a formulation as an injection.
  • the oxicam drug-containing injection of the present invention may be a fat emulsion by further containing a fat and / or a tocopherol compound.
  • fats and oils besides vegetable oils such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, cottonseed oil, animal oils such as lanolin, mineral oils such as egg yolk oil, fish oil, liquid paraffin, medium
  • Known fats and oils that can be used as fats and oils such as chain fatty acid triglycerides, chemically synthesized triglycerides, and gelled hydrocarbons, are exemplified.
  • the tocopherol compound include tocopherol (vitamin E) and tocopherol acetate.
  • the oxicam drug-containing injection of the present invention is a fat emulsion by further containing a fat and / or a tocopherol compound
  • the content of the fat and / or the tocopherol compound is desirably 5 to 100 mg / mL, 10-75 mg / mL is more desirable, and 15-50 mg / mL is even more desirable. If the amount is less than 5 mg / mL, the amount of the oxicam-based drug that can be carried by the fat emulsion will decrease, while if it is more than 100 mg / mL, the emulsification may be difficult due to an excessive amount of the fat and / or the tocopherol compound. There is.
  • the weight ratio of the oxicam-based drug to the fat and / or tocopherol compound is preferably 0.01 to 2, more preferably 0.05 to 1, and more preferably 0.1 to 0. 5 is more desirable. If it is smaller than 0.01, the fat and / or tocopherol compound becomes excessive with respect to the oxicam-based drug, and unnecessary fats and / or tocopherol compounds are administered to the patient.
  • the oxicam-based drug may be excessive in the fat and / or the tocopherol compound, the stability of the oxicam-based drug may be impaired, and the oxicam-based drug may be easily aggregated or precipitated.
  • the total content of the oxicam drug, the fat and / or the tocopherol compound is preferably at most 125 mg / mL, more preferably 3 to 100 mg / mL, and even more preferably 5 to 75 mg / mL. If it is more than 125 mg / mL, it may be difficult to emulsify to obtain a transparent fat emulsion.
  • the weight ratio of lecithin to the fat and / or tocopherol compound is 1 to 100, preferably 1.5 to 50, and more preferably 2 to 25, transparency is obtained.
  • the content of the oxicam-based drug may be, for example, 0.1 to 50 mg / mL.
  • the amount of the fat or oil and / or the tocopherol compound exceeds 2 mg / mL
  • the fat-soluble Is dissolved in fats and oils and / or tocopherol compounds, and oxicam drugs that cannot be completely dissolved in fats and oils and / or tocopherol compounds are combined with lecithin at the interface between water and fats and / or tocopherol compounds.
  • lecithin at the interface between water and fats and / or tocopherol compounds.
  • a larger amount is carried on the fat emulsion.
  • the oxicam drug-containing injection of the present invention is prepared by setting the contents of the oxicam drug, lecithin, a pharmaceutically acceptable salt of a fatty acid, macrogol and / or N, N-dimethylacetamide to the above-mentioned numerical ranges. , An oxicam drug was dissolved in macrogol and / or N, N-dimethylacetamide, lecithin was added, and a solution of a pharmaceutically acceptable salt of a fatty acid in an aqueous medium was added.
  • the oxicam drug-containing injection of the present invention is a fat emulsion by further containing a fat and / or a tocopherol compound
  • a fat and / or a tocopherol compound for example, the content of the fat and / or tocopherol compound, the fat and / or
  • the weight ratio of the oxicam drug to the tocopherol compound, the total content of the oxicam drug and the fat and / or the tocopherol compound are set in the above numerical ranges, and the oxicam drug is dissolved in macrogol and / or N, N-dimethylacetamide.
  • lecithin and oil and fat and / or tocopherol compound is added to the oil phase, further, a solution of a pharmaceutically acceptable salt of a fatty acid dissolved in an aqueous medium, and emulsified using an ultrasonic emulsifier,
  • the mixture is vigorously stirred to prepare a coarse emulsion (for example, when the rotation speed is 000 by stirring for 5 to 30 minutes at ⁇ 15000 rpm), and then the crude emulsion can be prepared by or emulsified using a high pressure emulsifying machine such as a Manton Gaulin homogenizer.
  • the particle size distribution of the fat particles can be narrowed. Further, emulsification may be performed a plurality of times (for example, 3 to 50 times) in order to narrow the particle size distribution of fat particles.
  • the solubilizate or emulsification is performed by using an ultrasonic emulsifier.
  • the average particle diameter of the oxicam-based drug-carrying particles is 200 nm or less, preferably 180 nm or less, more preferably 120 nm or less, and still more preferably. Is 100 nm or less (the lower limit is, for example, 1 m), an oxicam drug having a transparency and excellent stability, having a turbidity of 0.5 or less, preferably 0.4 or less, more preferably 0.3 or less, and still more preferably 0.2 or less. The point is that the containing injection becomes easy to obtain.
  • propylene glycol, glycerin, lactic acid, polyvinyl alcohol, polyvinylpyrrolidone, methylcellulose, chondroitin sulfate or a salt thereof (such as a sodium salt), hyaluronic acid or a salt thereof (a sodium salt) may be used as a component of the oxicam drug-containing injection of the present invention.
  • Glycyrrhizic acid or a salt thereof (sodium salt, ammonium salt, etc.) to further improve the solubility of oxicam drugs, improve the stability of fat emulsions and oxicam drugs, and make the fat emulsion isotonic. For example, you may plan.
  • These contents are similar to the contents of macrogol and / or N, N-dimethylacetamide.
  • Suitable saccharides include monosaccharides such as inositol, glucose, sorbitol, fructose and mannitol, disaccharides such as trehalose, lactose, sucrose and maltose, as well as dextrin, cyclodextrin, dextran and xylitol.
  • the saccharide content is desirably from 10 to 600 mg / mL.
  • a pH adjuster or an osmotic pressure adjuster known per se is further used to adjust the pH (for example, 3.5 to 9.0) or to adjust the osmotic pressure.
  • the formulation may be stabilized.
  • a substance for example, a metal salt of ethylenediaminetetraacetic acid
  • the oxicam-based drug-containing injection of the present invention does not prevent the use of another drug in addition to the oxicam-based drug as a component.
  • the oxicam-based drug-containing injection of the present invention can be easily sterilized by filtration, for example, by setting the average particle size to 200 nm or less, and can also be subjected to high-pressure steam sterilization.
  • the high-pressure steam sterilization may be performed under a general condition (for example, 120 to 122 ° C. ⁇ 10 to 15 minutes) after filling the oxicam-based drug-containing injection of the present invention into a glass ampule or a synthetic resin container.
  • the oxicam drug-containing injection of the present invention is excellent in stability and can be stored at room temperature (for example, 5 to 30 ° C.).
  • having transparency facilitates the visual confirmation of the presence or absence of alteration or contamination of foreign matter, and the change in the composition, and also gives a patient a sense of security.
  • Example 1 Meloxicam-containing injection (Part 1) 20 mg of meloxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner (manufactured by AS ONE Corporation, the same applies hereinafter), and then commercially available dl- ⁇ -tocopherol 80 mg and 400 mg of purified egg yolk lecithin (PC-98: manufactured by Kewpie Co., Ltd., same hereafter) were added and uniformly mixed at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 3 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Part 1 20 mg of meloxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner (manufactured by AS ONE Corporation, the same applies hereinafter), and then commercially
  • Example 2 Meloxicam-containing injection (Part 2) Twenty mg of meloxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner, and then, commercially available dl- ⁇ -tocopherol 80 mg, purified egg yolk lecithin 400 mg, polysorbate 80 (GS: manufactured by NOF CORPORATION, the same applies hereinafter) was added, and the mixture was uniformly mixed at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 2.7 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 3 Meloxicam-containing injection (Part 3) 275 mg of meloxicam and 2.2 g of N, N-dimethylacetamide were weighed and uniformly dissolved at 50 ° C. using a hot stirrer, and then 5.5 g of purified egg yolk lecithin was added, followed by gentle stirring and uniform mixing. . On the other hand, 550 mg of sodium oleate and 40 mL of pure water were weighed and uniformly dissolved at 60 ° C. using a hot stirrer. The obtained solution was solubilized for 60 minutes using an ultrasonic emulsifier while being added to the meloxicam solution, 5.5 g of glucose was added, and the mixture was stirred and dissolved using a stirrer.
  • the pH of the solubilized solution thus obtained was adjusted to 7.3 by adding a 1N aqueous hydrochloric acid solution, and then pure water was added to adjust the total volume to 55 mL.
  • the solution was sterilized by filtration through a CA membrane of 0.22 ⁇ m ⁇ . Meloxicam-containing injection was obtained.
  • the compositions and physical properties are shown in Tables 1 and 2, respectively.
  • Example 4 Meloxicam-containing injection (Part 4) After weighing 275 mg of meloxicam and 2.2 g of N, N-dimethylacetamide and uniformly dissolving it at 50 ° C. using a hot stirrer, 1.1 g of commercially available dl- ⁇ -tocopherol, 2.75 g of purified egg yolk lecithin, 2.75 g of polysorbate 80 was added, and the mixture was uniformly mixed by slowly stirring to obtain an oil phase. On the other hand, 550 mg of sodium oleate and 39 mL of pure water were weighed and uniformly dissolved at 60 ° C. using a hot stirrer to form an aqueous phase.
  • Example 5 Meloxicam-containing injection (Part 5) 20 mg of meloxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner, and then 80 mg of commercially available medium-chain fatty acid triglyceride and 400 mg of purified egg yolk lecithin are added. At 50 ° C. for 15 minutes to form an oil phase. On the other hand, 40 mg of sodium oleate and 2.8 mL of pure water were weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase.
  • Example 6 Meloxicam-containing injection (Part 6) After weighing 20 mg of meloxicam and 160 mg of N, N-dimethylacetamide and uniformly dissolving them at 50 ° C. for 15 minutes using a small ultrasonic cleaner, commercially available purified soybean oil 200 mg, purified egg yolk lecithin 200 mg, polysorbate 80 200 mg was added and mixed uniformly at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 2.6 mL of pure water were weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner to obtain an aqueous phase.
  • Example 7 Meloxicam-containing injection (Part 7) 1 g of meloxicam and 8 g of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. using a hot stirrer. Then, 4 g of a commercially available medium-chain fatty acid triglyceride and 20 g of purified egg yolk lecithin are added, and a general-purpose mixer is used. And uniformly mixed at 50 ° C. to obtain an oil phase. On the other hand, 2 g of sodium oleate and 160 mL of pure water were weighed and uniformly dissolved at 50 ° C. using a general-purpose mixer to obtain an aqueous phase.
  • the aqueous phase was added to the oil phase with stirring using a Hyflex Disperser (manufactured by SMT), and after completion of the addition, the mixture was coarsely emulsified at 10,000 rpm for 10 minutes. Pure water was further added to adjust the total volume to 200 mL, followed by precision emulsification using a high-pressure homogenizer (manufactured by APV). The emulsification pressure was 1000 bar and the number of emulsifications was 15 (circulation emulsification).
  • Example 8 Meloxicam-containing injection (No. 8) After weighing 275 mg of meloxicam and 3.3 g of N, N-dimethylacetamide and uniformly dissolving it at 50 ° C. using a hot stirrer, 2.75 g of commercially available medium-chain fatty acid triglyceride, 2.75 g of purified egg yolk lecithin, and polysorbate 80. 1.375 g was added, and the mixture was uniformly mixed by stirring slowly to obtain an oil phase. On the other hand, 550 mg of sodium oleate and 38 mL of pure water were weighed and uniformly dissolved at 60 ° C. using a hot stirrer to obtain an aqueous phase.
  • Example 9 Meloxicam-containing injection (No. 9) After weighing 80 mg of meloxicam and 240 mg of N, N-dimethylacetamide and dissolving as much as possible at 50 ° C. for 15 minutes using a small ultrasonic cleaner, 200 mg of commercially available medium-chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added, and the mixture was uniformly mixed using an ultrasonic emulsifier for 10 minutes to obtain an oil phase. On the other hand, 80 mg of sodium oleate, 160 mg of fructose, and 2.8 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 10 Meloxicam-containing injection (Part 10) After weighing out 40 mg of meloxicam and 120 mg of N, N-dimethylacetamide and dissolving it as much as possible at 50 ° C. for 15 minutes using a small ultrasonic cleaner, furthermore, 100 mg of commercially available medium-chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added, and the mixture was uniformly mixed using an ultrasonic emulsifier for 10 minutes to obtain an oil phase. On the other hand, 60 mg of sodium caprylate, 120 mg of fructose, and 3 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 11 Meloxicam-containing injection (No. 11) After weighing 20 mg of meloxicam and 40 mg of N, N-dimethylacetamide and dissolving as much as possible at 50 ° C. for 15 minutes using a small ultrasonic cleaner, 60 mg of a commercially available medium-chain fatty acid triglyceride, 160 mg of purified egg yolk lecithin, 160 mg of polysorbate 80 was added, and the mixture was uniformly mixed at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium caprylate and 3.2 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 12 Meloxicam-containing injection (Part 12) After weighing out 20 mg of meloxicam and 200 mg of Macrogol 400 and dissolving as much as possible at 50 ° C. for 15 minutes using a small ultrasonic cleaner, 120 mg of commercially available medium-chain fatty acid triglyceride, 200 mg of purified yolk lecithin, 200 mg of polysorbate 80 was added and mixed uniformly at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium caprylate and 3 mL of pure water were weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner, and then 100 mg of fructose was dissolved to form an aqueous phase.
  • Example 13 Meloxicam-containing injection (Part 13) After weighing out 100 mg of meloxicam and 1 g of Macrogol 400 and dissolving as much as possible at 50 ° C. for 10 minutes using a hot stirrer, 600 mg of a commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin, and 1 g of polysorbate 80 are added. At 50 ° C. for 30 minutes to obtain an oil phase.
  • Example 14 Injection containing piroxicam (Part 1) Twenty milligrams of piroxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. for 15 minutes using a small ultrasonic cleaner, and then commercially available medium-chain fatty acid triglyceride 80 mg, purified egg yolk lecithin 200 mg, polysorbate 80 200 mg was added, and the mixture was uniformly mixed at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 2.8 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 15 Injection containing lornoxicam (part 1) After weighing 20 mg of lornoxicam and 480 mg of N, N-dimethylacetamide and dissolving as much as possible at 50 ° C. for 15 minutes using a small ultrasonic cleaner, furthermore, 80 mg of commercially available medium-chain fatty acid triglyceride, 200 mg of purified egg yolk lecithin, 200 mg of polysorbate 80 was added, and the mixture was uniformly mixed at 50 ° C. for 15 minutes to obtain an oil phase. On the other hand, 40 mg of sodium oleate and 2.5 mL of pure water were weighed and uniformly dissolved at 50 ° C.
  • Example 16 Meloxicam-containing injection (No. 14) Meloxicam 100 mg, Macrogol 400 1 g, commercially available medium-chain fatty acid triglyceride 600 mg, and polysorbate 80 1 g were weighed and dissolved as much as possible at 40 ° C. for 40 minutes using a hot stirrer. Further, 1 g of purified egg yolk lecithin was added, and the mixture was uniformly mixed at 60 ° C. for 20 minutes to obtain an oil phase. On the other hand, 200 mg of sodium caprylate and 15 mL of a potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution (0.05 mol / L, pH 6.9, the same applies hereinafter) are weighed and uniformly dissolved at 40 ° C.
  • a potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution 0.05 mol / L, pH 6.9, the same applies hereinafter
  • Example 17 Meloxicam-containing injection (No. 15) 100 mg of meloxicam and 1 g of Macrogol 400 were weighed and dissolved as much as possible at 50 ° C. for 40 minutes using a hot stirrer. Furthermore, 600 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin, and 1 g of polysorbate 80 were added, and uniformly mixed at 50 ° C. for 20 minutes to obtain an oil phase. On the other hand, 200 mg of sodium oleate, 500 mg of trehalose and 13 mL of pure water were weighed and uniformly dissolved at 50 ° C. using a hot stirrer to obtain an aqueous phase.
  • Example 18 Meloxicam-containing injection (Part 16) A desired pale yellow transparent meloxicam-containing injection (emulsion) was obtained in the same manner as in Example 17, except that the pure water was changed to a potassium dihydrogen phosphate-disodium hydrogen phosphate buffer solution. The compositions and physical properties are shown in Tables 1 and 2, respectively.
  • Example 19 Meloxicam-containing injection (Part 17) 100 mg of meloxicam and 1 g of Macrogol 400 were weighed and dissolved as much as possible at 50 ° C. for 40 minutes using a hot stirrer. Further, 600 mg of commercially available medium-chain fatty acid triglyceride, 1 g of purified egg yolk lecithin and 1 g of polysorbate 80 were added, and the mixture was uniformly mixed at 60 ° C. for 20 minutes to obtain an oil phase. On the other hand, 100 mg of sodium oleate, 100 mg of sodium caprylate, and 15 mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer were weighed and uniformly dissolved at 50 ° C.
  • Example 20 Meloxicam-containing injection (No. 18) 100 mg of meloxicam and 1 g of Macrogol 400 were weighed and dissolved as much as possible at 50 ° C. for 40 minutes using a hot stirrer. Furthermore, 400 mg of commercially available medium-chain fatty acid triglyceride, 800 mg of purified egg yolk lecithin, and 700 mg of polysorbate 80 were added and uniformly mixed at 60 ° C. for 40 minutes to obtain an oil phase. Separately, 200 mg of sodium oleate and 15 mL of potassium dihydrogen phosphate-disodium hydrogen phosphate buffer were weighed and uniformly dissolved at 50 ° C.
  • Comparative Example 1 20 mg of meloxicam and 200 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. using a hot stirrer, and then 40 mg of commercially available purified soybean oil and 320 mg of polysorbate 80 are added, and the mixture is mixed homogeneously. And The emulsion was emulsified for 10 minutes using an ultrasonic emulsifier while adding 3.4 mL of pure water to the oil phase. When pure water was added to the thus obtained emulsion to make the total amount 4 mL, the emulsion was a yellow liquid having a precipitate existing from the beginning of the pure water addition. The compositions and physical properties are shown in Tables 1 and 2, respectively.
  • Comparative Example 2 Twenty mg of meloxicam and 160 mg of N, N-dimethylacetamide are weighed and uniformly dissolved at 50 ° C. using a hot stirrer. Further, 400 mg of purified egg yolk lecithin is added, and after uniform mixing, 3.4 mL of pure water is added. The mixture was solubilized for 10 minutes using an ultrasonic emulsifier. Pure water was added to the solubilized solution thus obtained to make the total amount 4 mL. At the beginning of the pure water addition, a precipitate was generated and precipitated with the passage of time in the yellow liquid. The compositions and physical properties are shown in Tables 1 and 2, respectively.
  • Comparative Example 3 20 mg of meloxicam and 160 mg of N, N-dimethylacetamide were weighed and uniformly dissolved at 50 ° C. using a hot stirrer, and then dl- ⁇ -tocopherol 80 mg, purified egg yolk lecithin 400 mg, and polysorbate 80 400 mg were added. Mix to form an oil phase. The emulsion was emulsified for 10 minutes using an ultrasonic emulsifier while adding 2.8 mL of pure water to the oil phase. Pure water was added to the emulsion thus obtained to make the total amount 4 mL. At the beginning of the addition of pure water, a precipitate was generated and precipitated with the lapse of time in the yellow liquid (a smaller amount than Comparative Example 2). The compositions and physical properties are shown in Tables 1 and 2, respectively.
  • the measurement of the average particle diameter was performed using a particle diameter measuring apparatus (Zetasizer @ Nano ZS: manufactured by Malvern Co.) using a photon correlation method.
  • Example 21 Meloxicam-containing injection (No. 19) A meloxicam-containing injection having physical properties equivalent to that of the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16 except that the amount of macrogol 400 used was changed to 500 mg.
  • Example 22 Meloxicam-containing injection (Part 20) A meloxicam-containing injection having physical properties equivalent to the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16 except that the amount of macrogol 400 used was changed to 2 g.
  • Example 23 Ampiroxicam-containing injection (Part 1) An ampiroxicam-containing injection having physical properties equivalent to that of the meloxicam-containing injection obtained in Example 16 was obtained in the same manner as in Example 16 except that meloxicam was changed to ampiroxicam.
  • the present invention has industrial applicability in that it can provide an oxicam-based drug-containing injection having transparency and excellent stability and safety.

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Abstract

La présente invention aborde le problème de la fourniture d'un agent d'injection contenant un médicament à base d'oxycam ayant une transparence et ayant également une excellente stabilité et une excellente sécurité. En tant que solution associée, une émulsion de graisse contenant un médicament à base d'oxycam selon la présente invention est caractérisée en ce qu'elle contient, en tant que composants constitutifs, au moins (1) un médicament à base d'oxycam, (2) la lécithine (au plus 50 % en poids de la lécithine à utiliser peut être substituée par le polysorbate), (3) un sel pharmaceutiquement acceptable d'un acide gras, (4) macrogol et/ou N,N-diméthylacetamide, et (5) un milieu aqueux, et en ayant une turbidité de 0,5 ou moins.
PCT/JP2019/028206 2018-07-18 2019-07-18 Agent d'injection contenant un médicament à base d'oxycam WO2020017578A1 (fr)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007505154A (ja) * 2003-03-03 2007-03-08 エラン ファーマ インターナショナル リミテッド ナノ粒子のメロキシカム製剤
WO2009063962A1 (fr) * 2007-11-16 2009-05-22 Techno Guard Co. Ltd. Emulsion grasse contenant un agent médicinal, et procédé de production de celle-ci
WO2011145660A1 (fr) * 2010-05-21 2011-11-24 富士フイルム株式会社 Composition d'émulsion d'huile dans l'eau contenant du propofol
JP2013536805A (ja) * 2010-09-01 2013-09-26 北京大学 難溶性薬物の液体組成物及びその調製方法
WO2018131620A1 (fr) * 2017-01-12 2018-07-19 テクノガード株式会社 Émulsion grasse contenant un médicament et son procédé de production

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015198350A1 (fr) * 2014-06-25 2015-12-30 Synergia Bio Sciences Private Limited Nano émulsion pharmaceutique huile-dans-eau

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2007505154A (ja) * 2003-03-03 2007-03-08 エラン ファーマ インターナショナル リミテッド ナノ粒子のメロキシカム製剤
WO2009063962A1 (fr) * 2007-11-16 2009-05-22 Techno Guard Co. Ltd. Emulsion grasse contenant un agent médicinal, et procédé de production de celle-ci
WO2011145660A1 (fr) * 2010-05-21 2011-11-24 富士フイルム株式会社 Composition d'émulsion d'huile dans l'eau contenant du propofol
JP2013536805A (ja) * 2010-09-01 2013-09-26 北京大学 難溶性薬物の液体組成物及びその調製方法
WO2018131620A1 (fr) * 2017-01-12 2018-07-19 テクノガード株式会社 Émulsion grasse contenant un médicament et son procédé de production

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