CN117298048A - Emulsion and method for producing same - Google Patents

Emulsion and method for producing same Download PDF

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CN117298048A
CN117298048A CN202311398063.2A CN202311398063A CN117298048A CN 117298048 A CN117298048 A CN 117298048A CN 202311398063 A CN202311398063 A CN 202311398063A CN 117298048 A CN117298048 A CN 117298048A
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emulsion
nimodipine
mass
phospholipid
tris
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天野阳平
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Kewpie Corp
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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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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    • 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
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    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

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Abstract

The present invention relates to an emulsion and a method for producing the same. [ problem ] to provide a novel emulsion containing nimodipine. [ solution ] an emulsion comprising nimodipine, a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and salts thereof, a tocopherol, and water.

Description

Emulsion and method for producing same
Technical Field
The present invention relates to an emulsion and a method for producing the same. More specifically, the present invention relates to emulsions comprising lipid nanoparticles comprising nimodipine and methods of making the same.
Background
Nimodipine is known as a calcium channel blocker. In addition, nimodipine is also known to readily penetrate the blood brain barrier, improving cerebral blood supply. Thus, nimodipine is widely used clinically to improve blood circulation in recovery periods such as acute cerebrovascular injury, cerebral vasospasm after subarachnoid hemorrhage, ischemic nerve injury caused thereby, hypertension, migraine and the like.
As a commercially available nimodipine preparation, for example, nimodipine (bayer corporation) is known. Further, as an emulsion composition of nimodipine, for example, patent document 1 discloses a nimodipine injection composition characterized by comprising nimodipine 0.02 to 0.23 mass%, oil for injection 2 to 30 mass%, emulsifier 0.8 to 3 mass%, complexing agent 0 to 0.1 mass%, stabilizer 0 to 0.3 mass% and osmotic pressure regulator 1 to 3 mass%. Further, for example, patent document 2 discloses an amino acid-containing nimodipine submicron emulsion injection.
Prior art literature
Patent literature
Patent document 1: japanese patent application laid-open No. 2021-535932
Patent document 2: chinese patent application publication No. 105796494 specification
Disclosure of Invention
Problems to be solved by the invention
Nimodipine uses an organic solvent (PEG 400) other than ethanol in addition to 25% ethanol at a high concentration for dissolving nimodipine. In addition, nimodipine is required to be mixed with other diluents at the time of use, but in order to suppress precipitation of nimodipine, nimodipine crystals are required to be slowly precipitated when mixed with diluents such as physiological saline before administration and diluted with ethanol to dissolve nimodipine, so that a complicated infusion set comprising a three-way cock and a syringe pump is required to be used, the infusion rate is very slow, and the burden on the medical field is great. Furthermore, patients must endure vascular pain caused by ethanol used in nimodipine injections during administration of nimodipine injections (generally, more than 5 hours), and the pain is aggravated.
As a pharmaceutical carrier of nimodipine, use of micelles or emulsions is expected to greatly improve the stability of nimodipine and compliance of patients in administration. Several emulsion compositions of nimodipine are known, for example, as disclosed in patent documents 1 and 2, but it cannot be said that sufficient options have been provided.
It is therefore an object of the present invention to provide novel emulsions containing nimodipine. The present invention also provides a method for producing the emulsion.
Solution for solving the problem
The present invention relates to the following embodiments, for example.
[1]
An emulsion comprising nimodipine, a phospholipid, a neutral lipid, a tocopherol, and water, and at least 1 selected from the group consisting of tris and salts thereof.
[2]
The emulsion according to [1], wherein the phospholipid is at least 1 selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin.
[3]
The emulsion according to [1] or [2], wherein the neutral lipid is at least 1 selected from the group consisting of soybean oil, sesame oil, olive oil, rapeseed oil, corn oil and medium chain fatty acid triglyceride.
[4]
The emulsion according to any one of [1] to [3], wherein the pH is 5 to 9.
[5]
The emulsion according to any one of [1] to [4], wherein,
the content of nimodipine is 0.02 wt% to 0.2 wt% based on the total amount of the emulsion,
the content of the phospholipid is 1 to 3 wt% based on the total amount of the emulsion,
the content of the neutral fat is 5 to 10% by weight based on the total amount of the emulsion,
the content of at least 1 selected from the group consisting of tris (hydroxymethyl) aminomethane and salts thereof is 0.01 to 0.2 wt% based on the total amount of the emulsion,
the content of the tocopherol is 0.01 to 0.2 wt% based on the total amount of the emulsion.
[6]
The emulsion according to any one of [1] to [5], which is an injection.
[7]
The emulsion according to any one of [1] to [6], which is used in such a manner that it is administered without dilution.
[8]
A method of manufacturing an emulsion comprising:
a) Heating and dissolving nimodipine in an organic solvent;
b) A step of adding phospholipids, neutral lipids, tocopherols and at least 1 selected from the group consisting of tris and salts thereof to an aqueous solvent followed by a crude emulsification; and
c) And (c) a step of adding the solution obtained in step a) dropwise to the crude emulsion obtained in step b) and dispersing the solution, and further subjecting the dispersed liquid to high-pressure emulsification treatment.
[9]
A method of manufacturing an emulsion comprising:
a) Heating and dissolving nimodipine in an organic solvent;
b) A step of adding at least 1 selected from the group consisting of a phospholipid and tris (hydroxymethyl) aminomethane and a salt thereof to an aqueous solvent to disperse the phospholipid;
c) A step of mixing the solution obtained in the step A) with neutral fat and tocopherol; and
d) And (C) a step of adding the solution obtained in step C) dropwise to the dispersion obtained in step B) and performing coarse emulsification, and further performing high-pressure emulsification treatment on the coarse emulsified liquid.
ADVANTAGEOUS EFFECTS OF INVENTION
According to the present invention, a novel emulsion containing nimodipine can be provided. According to the present invention, a method for producing the emulsion can also be provided.
Detailed Description
The mode for carrying out the present invention will be described in detail below. However, the present invention is not limited to the following embodiments.
< feature of the invention >
(emulsion)
The present invention is characterized by providing an emulsion comprising nimodipine, a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and salts thereof, a tocopherol, and water.
(method for producing emulsion)
The present invention provides a method for producing an emulsion (production method 1), comprising: a) Heating and dissolving nimodipine in an organic solvent; b) A step of adding a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and a salt thereof, and a tocopherol to an aqueous solvent, followed by a crude emulsification; and c) a step of adding the solution obtained in step a) dropwise to the crude emulsion obtained in step b) and dispersing the solution, and further subjecting the dispersed liquid to high-pressure emulsification treatment.
The present invention also provides a method for producing an emulsion (production method 2), comprising: a) Heating and dissolving nimodipine in an organic solvent; b) A step of adding at least 1 selected from the group consisting of a phospholipid and tris (hydroxymethyl) aminomethane and a salt thereof to an aqueous solvent to disperse the phospholipid; c) A step of mixing the solution obtained in the step A) with neutral fat and tocopherol; and D) a step of adding the solution obtained in step C) dropwise to the dispersion obtained in step B) and performing coarse emulsification, and further performing high-pressure emulsification treatment on the coarse emulsified liquid.
< emulsion >
The emulsion of the present embodiment comprises nimodipine, a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and salts thereof, tocopherol, and water.
The emulsion of the present embodiment is an oil-in-water (O/W type) emulsion in which lipid nanoparticles containing nimodipine are dispersed in an aqueous phase. In the lipid nanoparticle, nimodipine is encapsulated in a shell composed of at least phospholipids.
(nimodipine)
Nimodipine is a compound also known as 3- (2-methoxyethyl) 5-propan-2-yl 2, 6-dimethyl-4- (3-nitrophenyl) -1, 4-dihydropyridine-3, 5-dicarboxylic acid ester. Nimodipine used in the emulsion of the present embodiment may be the R-form, the S-form, or a mixture of the R-form and the S-form (for example, a racemic mixture of the R-form and the S-form is included in 1:1).
The content of nimodipine in the emulsion of the present embodiment may be, for example, 0.001% by mass or more and 1% by mass or less, 0.005% by mass or more and 0.8% by mass or less, 0.01% by mass or more and 0.5% by mass or less, 0.015% by mass or more and 0.3% by mass or less, or 0.02% by mass or more and 0.2% by mass or less, based on the total amount of the emulsion.
The content of nimodipine in the emulsion of the present embodiment may be 70 mass% or more, 75 mass% or more, 80 mass% or more, 85 mass% or more, 90 mass% or more, or 95 mass% or more, based on the content before storage, for example, after storage at 40 ℃ for 1 month.
(phospholipid)
The emulsion of the present embodiment contains a phospholipid as a constituent of the lipid nanoparticle. Examples of the phospholipid include glycerophospholipids such as phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol and phosphatidylinositol, and sphingomyelins such as sphingomyelin. The phospholipid may be used alone or in combination of at least 2 kinds.
As the phospholipid, for example, phospholipids derived from animal and plant materials such as egg yolk, soybean, and rapeseed can be used without particular limitation.
The content of the phospholipid in the emulsion of the present embodiment may be, for example, 0.5 to 10 mass%, 0.6 to 8 mass%, 0.7 to 6 mass%, 0.8 to 5 mass%, 0.9 to 4 mass%, or 1 to 3 mass% based on the total amount of the emulsion, as long as the amount is sufficient to form the lipid film layer.
(neutral fat)
The emulsion of this embodiment contains neutral lipids. Neutral lipids are used, for example, to aid in dissolution of nimodipine. Examples of the neutral lipid include vegetable oils such as soybean oil, sesame oil, rapeseed oil, safflower oil, olive oil, castor oil, corn oil, cottonseed oil, rice oil, sunflower seed oil, grape seed oil, and wheat germ oil, medium chain fatty acid triglycerides (MCT), and long chain fatty acid triglycerides (LCT). The neutral fat may be used alone or in combination of 1 or more than 2 kinds.
The content of the neutral fat in the emulsion according to the present embodiment may be, for example, 1% by mass or more and 20% by mass or less, 1.2% by mass or more and 18% by mass or less, 1.4% by mass or more and 16% by mass or less, 1.6% by mass or more and 14% by mass or less, 1.8% by mass or more and 12% by mass or less, or 2% by mass or more and 10% by mass or less, based on the total amount of the emulsion.
(at least 1 selected from the group consisting of tris and salts thereof)
The emulsion of the present embodiment contains at least 1 selected from the group consisting of tris and salts thereof. By containing at least 1 selected from the group consisting of tris and salts thereof, decomposition of nimodipine can be suppressed, storage stability can be improved, and emulsion stability can also be improved.
Examples of the salt of tris (hydroxymethyl) aminomethane include hydrochloride, acetate, maleate, borate and the like. Preferably, at least 1 selected from the group consisting of tris (hydroxymethyl) aminomethane and salts thereof is used so that the pH in an aqueous solvent is in the range of 7 to 9. In addition, after the tris (hydroxymethyl) aminomethane is dissolved in water, a buffer solution having a pH adjusted to a range of 7 to 9 may be prepared using an acid such as hydrochloric acid, acetic acid, maleic acid, boric acid, or the like, and then the buffer solution may be used as a raw material for an emulsion.
The content of at least 1 selected from the group consisting of tris (hydroxymethyl) aminomethane and salts thereof in the emulsion of the present embodiment may be, for example, 0.002 to 1 mass%, 0.004 to 0.8 mass%, 0.006 to 0.6 mass%, 0.008 to 0.4 mass%, or 0.01 to 0.2 mass% based on the total amount of the emulsion, as long as the content is sufficient to improve the stability of nimodipine.
(tocopherols)
The emulsion of this embodiment comprises tocopherol. Tocopherols are used to inhibit nimodipine decomposition and improve storage stability. Examples of tocopherols include alpha-tocopherol, beta-tocopherol, gamma-tocopherol, and delta-tocopherol. The tocopherol may be any optical isomer, and is preferably a racemate (e.g., dl- α -tocopherol). In the emulsion of the present embodiment, 1 kind of tocopherol may be used alone, or 2 or more kinds may be used in combination.
The content of tocopherol in the emulsion of the present embodiment may be, for example, 0.002 mass% to 1 mass%, 0.004 mass% to 0.8 mass%, 0.006 mass% to 0.6 mass%, 0.008 mass% to 0.4 mass%, or 0.01 mass% to 0.2 mass%, based on the total amount of the emulsion, as long as the content is sufficient to improve the stability of nimodipine.
(Water)
The emulsion of this embodiment includes water. Examples of the water include distilled water, regular water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like defined in the eighteenth modified japanese pharmacopoeia. The water constitutes the outer phase (aqueous phase) of lipid nanoparticles containing nimodipine. The external phase includes, for example, an aqueous solvent (e.g., water, buffer) used when forming the aqueous phase, an organic solvent used when forming the oil phase, and the like.
The water content in the emulsion of the present embodiment may be the remainder of the above-described components, specifically, for example, may be more than 0% by mass and less than 100% by mass based on the total amount of the emulsion.
< other ingredients >
The emulsion of the present embodiment may contain other components acceptable as a pharmaceutical within a range that does not hinder the effects of the present invention. Examples of the other components include solvents, solubilizers, emulsification aids, osmotic pressure regulators, and pH regulators.
(solvent or solubilizer)
Solvents or solubilisers are used, for example, to aid solubilisation of nimodipine. As the solvent or solubilizing agent, for example, an organic solvent or a surfactant can be used.
Examples of the organic solvent include ethanol, dimethylformamide (DMF), propylene glycol, acetone, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and tetrahydrofuran.
Examples of the surfactant include polyoxyethylene hydrogenated castor oil, polysorbate, glycerin fatty acid ester, and sorbitan fatty acid ester.
(emulsification aid)
The emulsifying aid is used for improving the emulsion stability of the emulsion. Examples of the emulsifying aid include surfactants such as polyoxyethylene hydrogenated castor oil, polysorbates, glycerin fatty acid esters, and sorbitan fatty acid esters, higher alcohols such as behenyl alcohol and stearyl alcohol, higher fatty acids such as oleic acid and sodium oleate, and hyaluronic acid derivatives such as hydrophobized hyaluronic acid and salts thereof (for example, "hyaloepray", manufactured by Kewpie Corporation).
(osmotic pressure regulator)
The osmotic pressure regulator is used to adjust the osmotic pressure ratio of the emulsion to a desired value. Examples of the osmotic pressure regulator include saccharides such as sorbitol, xylitol, mannitol, glucose, trehalose, maltose, sucrose, raffinose, lactose, dextran, and salts such as sodium chloride and potassium chloride, and concentrated glycerin.
(pH adjustor)
Examples of the pH adjuster include strong acids such as hydrochloric acid and strong bases such as sodium hydroxide.
The emulsion of the present embodiment uses nimodipine, a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and salts thereof, tocopherol, and water in combination, and thus, nimodipine is excellent in storage stability and emulsion stability. Therefore, the emulsion of the present embodiment may be substantially free of an organic solvent (e.g., ethanol), a synthetic surfactant, an amino acid, or the like, or may have a lower content than the conventional emulsion.
The content of the organic solvent in the emulsion of the present embodiment may be, for example, 5 mass% or less, 4 mass% or less, 3 mass% or less, or 2.5 mass% or less based on the total amount of the emulsion. The content of ethanol in the emulsion of the present embodiment may be, for example, 5 mass% or less, 4 mass% or less, 3 mass% or less, or 2.5 mass% or less based on the total amount of the emulsion. The content of the synthetic surfactant in the emulsion of the present embodiment may be, for example, 5 mass% or less, 4 mass% or less, 3 mass% or less, 2 mass% or less, 1 mass% or less, or 0 mass% or less based on the total amount of the emulsion. The content of the amino acid in the emulsion of the present embodiment may be, for example, 5% by mass or less, 4% by mass or less, 3% by mass or less, 2% by mass or less, 1% by mass or less, or 0% by mass based on the total amount of the emulsion.
The particle diameter of the lipid nanoparticle contained in the emulsion of the present embodiment is preferably more than 0nm and 400nm or less. Thus, the emulsion is suitable for use as an injection. In the present specification, the term "particle size" means an average particle size measured by a dynamic light scattering method. The particle size can be measured by a particle size measuring apparatus (for example, manufactured by Zetasizer Nano, malvern Panalytical corporation) using a dynamic light scattering method. The lipid nanoparticles contained in the emulsion of the present embodiment may have a particle diameter of more than 0nm and not more than 350nm, more than 10nm and not more than 300nm, 15nm to 250nm and 20nm to 200nm, from the viewpoint of excellent emulsifying power and suitability for use as an injection. The average particle diameter of the lipid nanoparticles included in the emulsion of the present embodiment immediately after preparation and the average particle diameter after 1 month of storage at 40 ℃ may vary within 80nm, or within 70nm, or further within 60nm, within 50nm, within 40nm, or within 35 nm. The average particle diameter of the lipid nanoparticles contained in the emulsion of the present embodiment after storage falls within the above range.
The emulsion of the present embodiment is excellent in storage stability, and the ratio of the content of nimodipine immediately after preparation to the content of nimodipine after 1 month of storage at 40 ℃ (after 1 month of storage at 40 ℃/immediately after preparation) may be in the range of 95% to 105%.
The pH of the emulsion of the present embodiment is not particularly limited, and may be, for example, 3 to 11. The pH of the emulsion of the present embodiment is preferably 4 to 10, more preferably 5 to 9, still more preferably 6 to 9, still more preferably 7 to 9, from the viewpoint of suppressing decomposition of nimodipine and improving storage stability.
The emulsion of the present embodiment can be suitably used as a pharmaceutical composition, for example. Further, since nimodipine is contained in the emulsion of the present embodiment, it can improve cerebral vasospasm after acute cerebral vascular injury and subarachnoid hemorrhage, and blood circulation in recovery periods such as ischemic nerve injury, hypertension, and migraine caused by this, and thus can be suitably used as a therapeutic composition for cerebral hemorrhagic diseases such as hypertension, stroke, migraine, and subarachnoid hemorrhage.
The emulsion of the present embodiment can be used, for example, as an injection, a fat emulsion, or the like.
The subject to which the emulsion of the present embodiment is administered may be, for example, a mammal such as a human.
The amount of the emulsion, timing of administration, and period of administration of the emulsion of the present embodiment can be appropriately set according to the disease to be administered, the attribute (sex, age, etc.) of the administration subject, and the like.
The emulsion of the present embodiment may be administered without dilution.
< method for producing emulsion >
The emulsion of the present embodiment can be obtained by a production method (1 st production method) including the steps of: a) Heating and dissolving nimodipine in an organic solvent; b) A step of adding a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and a salt thereof, and a tocopherol to an aqueous solvent, followed by a crude emulsification; and c) a step of adding the solution obtained in step a) dropwise to the crude emulsion obtained in step b) and dispersing the solution, and further subjecting the dispersed liquid to high-pressure emulsification treatment.
The emulsion of the present embodiment can also be obtained by a production method (production method 2) including the steps of: a) Heating and dissolving nimodipine in an organic solvent; b) A step of adding at least 1 selected from the group consisting of a phospholipid and tris (hydroxymethyl) aminomethane and a salt thereof to an aqueous solvent to disperse the phospholipid; c) A step of mixing the solution obtained in the step A) with neutral fat and tocopherol; and D) a step of adding the solution obtained in step C) dropwise to the dispersion obtained in step B) and performing coarse emulsification, and further performing high-pressure emulsification treatment on the coarse emulsified liquid.
(method for producing 1 st)
(step a)
In step a), nimodipine is dissolved by heating in an organic solvent. The organic solvent used may be any solvent capable of dissolving nimodipine, and examples thereof include ethanol, dimethylformamide (DMF), propylene glycol, acetone, dimethylformamide, dimethyl sulfoxide, N-methyl-2-pyrrolidone, and tetrahydrofuran.
The temperature at the time of heating and dissolving in step a) may be set in the range of 40 to 80 ℃. The temperature at the time of heating and dissolution is preferably in the range of 50 to 70℃and 55 to 65 ℃.
In step a), if necessary, components other than nimodipine may be dissolved together in the organic solvent, but from the viewpoint of suppressing decomposition of nimodipine, the phospholipid and the neutral lipid are preferably not dissolved together in the organic solvent. In other words, the solution obtained in step a) preferably does not comprise phospholipids and neutral lipids. In the case of using an emulsifying aid as the other component, it is preferable that the emulsifying aid is not dissolved together in the organic solvent, and the solution obtained in step a) preferably does not contain the emulsifying aid.
In step b), a phospholipid, a neutral lipid, at least 1 selected from the group consisting of tris and salts thereof, and a tocopherol are added to an aqueous solvent, followed by crude emulsification. Examples of the aqueous solvent include distilled water, regular water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like defined in the eighteenth modified japanese pharmacopoeia. The buffer added in step b) may be added in the form of a buffer.
In step b), after adding the phospholipid, the neutral lipid, at least 1 selected from the group consisting of tris (hydroxymethyl) aminomethane and salts thereof, and the tocopherol to the aqueous solvent, it may be dissolved, for example, by stirring or the like. If necessary, the mixture may be heated to 40 to 80℃to dissolve the mixture.
In the 1 st production method, the steps a) and b) are performed in any order, and for example, the step a) may be performed first, the step b) may be performed first, or the steps a) and b) may be performed simultaneously.
(step c)
In step c), the solution obtained in step a) is added dropwise to the crude emulsion obtained in step b) and dispersed, and the dispersed liquid is further subjected to high-pressure emulsification treatment. By carrying out step c), an emulsion of the present embodiment is obtained. The dispersion before the high-pressure emulsification treatment can be carried out, for example, by slowly dropping the solution obtained in step a) into the crude emulsion obtained in step b) at a constant rate, followed by heating and stirring at 5,000 to 15,000rpm at 50 to 70℃for 1 to 30 minutes. The particle size of the lipid nanoparticles contained in the emulsion obtained in the dispersion before the high-pressure emulsification treatment is usually in the range of 1nm to 500 nm.
The high-pressure emulsification treatment can be performed using, for example, a high-pressure emulsifying machine. The high-pressure emulsification treatment can be performed by, for example, 3 to 30 passes under a pressure of 50 to 200MPa at a temperature of 50 to 70 ℃. Examples of the high-pressure emulsifying machine include a box-type high-pressure homogenizer such as a microfluidizer (manufactured by Microfluidics corporation), a Nanomizer (manufactured by YOSHIDA KIKAI co., ltd.), a STAR BURST (manufactured by SUGINO MACHINE LIMITED co., ltd.), a ganlin-type homogenizer (manufactured by APV corporation), a Rannie-type homogenizer (manufactured by Rannie corporation), a high-pressure homogenizer (manufactured by Niro Soavi corporation), a homogenizer (manufactured by three and machinery corporation), a high-pressure homogenizer (manufactured by IZUMI FOOD MACHINERY corporation), an ultra-high-pressure homogenizer (manufactured by ICA corporation), and other homogenizing valve-type high-pressure homogenizers. The particle size of the lipid nanoparticles contained in the emulsion obtained by the high-pressure emulsification treatment is usually in the range of 1nm to 250 nm.
(other steps)
The 1 st production method may include a step of sterilizing the emulsion in addition to the above steps, if necessary.
In the step of sterilizing, the emulsion obtained in step c) is sterilized. The sterilization of the emulsion may be carried out according to conventional methods. Specifically, for example, the emulsion can be sterilized by passing it through a membrane filter (e.g., a nylon syringe filter) having a pore size of 0.2 to 0.5 μm. Further, for example, the emulsion may be sterilized by heat and pressure treatment (for example, 121 ℃ C. For 20 minutes) with a wet heat sterilizer.
(method for producing 2)
(step A)
In step a), nimodipine is dissolved by heating in an organic solvent. Step a) may be performed in the same manner as step a) of the 1 st production method.
(step B)
In step B), a phospholipid and at least 1 selected from the group consisting of tris and salts thereof are added to an aqueous solvent to be dispersed. Examples of the aqueous solvent include distilled water, regular water, purified water, sterilized purified water, water for injection, distilled water for injection, and the like defined in the eighteenth modified japanese pharmacopoeia. At least 1 selected from the group consisting of tris and salts thereof added in step B) may be added in the form of a buffer.
In step B), the phospholipid and at least 1 selected from the group consisting of tris and salts thereof may be dispersed, for example, by stirring or the like, after being added to the aqueous solvent.
In step C), the solution obtained in step A) is mixed with neutral lipids and tocopherols. In step C), neutral fat and tocopherol may be mixed, for example, by stirring or the like, after being added to the solution obtained in step a).
In the 2 nd production method, the order of performing the steps a) and B) is arbitrary, and for example, the step a) may be performed first, the step B) may be performed first, or the step a) and the step B) may be performed simultaneously. When step C) is reached for a long period of time, it is possible to promote the decomposition of nimodipine, and therefore it is preferable to be as short as possible. That is, step C) is preferably performed after step A) and step B) are performed.
In step D), the solution obtained in step C) is added dropwise to the dispersion obtained in step B) and subjected to coarse emulsification, and the coarse emulsified liquid is further subjected to high-pressure emulsification treatment. By performing step D), the emulsion of the present embodiment is obtained. The crude emulsification before the high-pressure emulsification treatment can be carried out, for example, by slowly dropping the solution obtained in step C) into the dispersion obtained in step B) at a constant rate, followed by heating at 5,000 to 15,000rpm at 50 to 70℃and stirring for 1 to 30 minutes. The particle size of the lipid nanoparticles contained in the emulsion obtained in the crude emulsification before the high-pressure emulsification treatment is usually in the range of 1nm to 500 nm.
The high-pressure emulsification treatment can be performed in the same manner as in step c) of the production method 1.
(other steps)
The 2 nd production method may include a step of sterilizing the emulsion in addition to the above steps as needed. The sterilization step may be performed in the same manner as described in the method of manufacturing method 1.
Examples
The present invention will be described more specifically with reference to examples. However, the present invention is not limited to the following examples.
The correspondence of the ingredients and abbreviations used in the examples are shown below.
NP: nimodipine, tokyo chemical industry Co
PC: PC-98T (trade name), kewpie Corporation (egg yolk lecithin purified to a phosphatidylcholine content of 98% or more)
PL: PL-100M (trade name), kewpie Corporation (egg yolk lecithin containing phosphatidylcholine 80%, phosphatidylethanolamine 20%)
MCT: COCONARD RK (trade name), manufactured by Kao corporation (glycerol trioctanoate)
LCT: japanese pharmacopoeia soybean oil, KANEDA co., ltd. Long chain fatty acid triglyceride having a carbon number of fatty acid of mainly 18
HA: hyaloerepair (trade name), kewpie Corporation (alkyl hyaluronate (C12-13) glyceride hydrolysis)
Tris: 2-amino-2-hydroxymethyl-1, 3-propanediol 999 (trade name) (tris-hydroxymethyl-aminomethane), fuji film and manufactured by Kagaku Co., ltd
VE: vitamin E, dl-alpha-tocopherol superfine (trade name), manufactured by Kanto chemical Co., ltd. (dl-alpha-tocopherol)
Test example 1: investigation of factors decomposing nimodipine
< preparation and stability evaluation of nimodipine-containing ethanol preparation >
Nimodipine was dissolved in ethanol to 0.2 mass%, to prepare a 0.2 mass% NP ethanol solution. After adding the components to a 10mL vial so as to have the compositions shown in table 1, the vessel was closed and stirred to prepare an ethanol preparation containing nimodipine. Preserving the prepared ethanol preparation containing nimodipine at 60 ℃ and quantifying nimodipine at proper time. The results are shown in Table 1.
< quantification of nimodipine >
Quantification of nimodipine was performed by High Performance Liquid Chromatography (HPLC) under the following conditions.
Mobile phase: water: methanol: mixed solution of acetonitrile (27:35:38)
Column: octadecylsilyl silica gel column (inner diameter 4.6mm, length 250mm, particle size 5 μm)
Temperature: 30 DEG C
The detection method comprises the following steps: ultraviolet (UV) detector (detection wavelength 237 nm)
TABLE 1
ND not determined
As shown in table 1, the decomposition of nimodipine was not promoted by ethanol or water. On the other hand, it can be seen that: decomposition of nimodipine is promoted by phospholipids (PL, PC) or neutral lipids (MCT).
Test example 2: inhibition of nimodipine decomposition of phospholipid
A search was conducted for a substance capable of inhibiting nimodipine decomposition by the phospholipid identified in test example 1. The results of the search are extracted and recorded.
< preparation and stability evaluation of nimodipine-containing ethanol preparation >
A0.2 mass% NP ethanol solution was prepared in the same manner as in test example 1. Citric acid and trisodium citrate (anhydrate, fuji film and Wako Co., ltd.) were dissolved in water so as to be 0.5 mass%, and then mixed to pH5.0, whereby a 0.5 mass% citric acid buffer (pH 5.0) was prepared. Sodium dihydrogen phosphate (anhydrous, fuji photo Co., ltd.) and disodium hydrogen phosphate (anhydrous, manufactured by Kanto chemical Co., ltd.) were dissolved in water so as to be 0.5 mass%, and then mixed to pH7.0, whereby a 0.5 mass% phosphate buffer (pH 7.0) was prepared. After dissolving Tris in water so as to be 0.5 mass%, the pH was adjusted to 9.0 with 1M hydrochloric acid to prepare 0.5 mass% Tris buffer (pH 9.0). VE was dissolved in ethanol so as to be 1% by mass, to prepare a 1% VE ethanol solution.
After adding the components to a 10mL vial so as to have the compositions shown in table 2, the vessel was closed and stirred to prepare an ethanol preparation containing nimodipine. Preserving the prepared ethanol preparation containing nimodipine at 60 ℃ and quantifying nimodipine at proper time. The nimodipine was quantified by the same method as in test example 1. The results are shown in Table 2.
TABLE 2
As shown in table 2, it can be seen that: the decomposition of nimodipine by phospholipids is inhibited by the addition of buffers or tocopherols.
Test example 3: confirmation of the decomposition inhibiting effect of nimodipine by tocopherol content
The relationship between the tocopherol content and the nimodipine decomposition inhibition effect was confirmed for tocopherol, which is a substance capable of inhibiting nimodipine decomposition caused by phospholipid, as clear in test example 2.
< preparation and stability evaluation of nimodipine-containing ethanol preparation >
A0.2 mass% NP ethanol solution and a 1 mass% VE ethanol solution were prepared in the same manner as in test example 2.
After adding the components to a 10mL vial so as to have the compositions shown in table 3, the vessel was closed and stirred to prepare an ethanol preparation containing nimodipine. Preserving the prepared ethanol preparation containing nimodipine at 60 ℃ and quantifying nimodipine at proper time. The nimodipine was quantified by the same method as in test example 1. The results are shown in Table 3.
TABLE 3
As shown in table 3, it can be seen that: the decomposition of nimodipine by phospholipid is inhibited by adding tocopherol, and even if the added amount of tocopherol is 0.01 mass%, the effect of inhibition is exhibited.
Test example 4: evaluation of emulsion stabilization Using buffering agent
An emulsion comprising lipid nanoparticles containing nimodipine was prepared and the effect of the buffer on the emulsification was evaluated.
< preparation of emulsion comprising lipid nanoparticle containing nimodipine >
An emulsion comprising lipid nanoparticles comprising nimodipine was prepared by the following method.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. Mixing MCT, LCT and VE, heating to 60deg.C for dissolving to obtain oil phase. PL and various buffers (0.5% by mass Tris buffer (pH 9.0), 0.5% by mass citric buffer (pH 6.0), 0.5% by mass phosphoric buffer (pH 7.0)) were added to pure water heated to 60℃and crude emulsification was carried out for 5 minutes to obtain crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution mixed with the oil phase before was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). The crude emulsion (2) was treated 5 times with a high-pressure emulsifying machine (Microfluidics Co., ltd.) at 150MPa, and then filled into vials. Next, an emulsion containing the lipid nanoparticles encapsulating NPs was prepared by sterilizing at 121 ℃ for 20 minutes using a heat-and-pressure sterilizer. The components were used so as to have the compositions shown in table 4.
< evaluation of particle size >
The particle size of each lipid nanoparticle was measured before and after sterilization in a autoclave. Particle size was measured by a dynamic light scattering method using a particle size measuring apparatus (manufactured by Zetasizer Nano, malvern Panalytical Co.). The results are shown in Table 4.
TABLE 4
As shown in table 4, it can be seen that: the stabilizing effect of nimodipine can be obtained by adding a buffer, but emulsion stability of an emulsion greatly varies depending on the kind of the buffer. As shown in comparative examples 4-1 and 4-2, it is clear that: the particle size of the lipid nanoparticles increases before and after sterilization, and the emulsion is unstable. On the other hand, as shown in examples 4-1 to 4-3, it is known that: tris buffer inhibits the increase in particle size of lipid nanoparticles and improves emulsion stability.
Test example 5: preparation and evaluation of emulsions comprising lipid nanoparticles comprising nimodipine
< preparation and stability evaluation of emulsion comprising lipid nanoparticles containing nimodipine >
An emulsion comprising lipid nanoparticles comprising nimodipine was prepared by the following method.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. PL, MCT, LCT, VE, concentrated glycerol and 0.5 mass% Tris buffer (pH 9.0) were added to pure water heated to 60℃and crude emulsification was carried out for 5 minutes to obtain a crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). After the crude emulsion (2) was treated 5 times with a high-pressure emulsifying machine (Microfluidics Co.) at 150MPa, the treated product was filled into vials to prepare emulsions containing lipid nanoparticles encapsulating NPs (example 5-1). The components were used so as to have the compositions shown in table 5.
NP, PL, MCT and ethanol were mixed and heated to 60℃for dissolution to prepare a lipid ethanol solution. HA as an emulsification aid was added to pure water heated to 60 ℃ and stirred for 5 minutes to prepare an aqueous phase. While stirring the aqueous phase heated to 60 ℃, a lipid ethanol solution was added dropwise, and coarse emulsification was performed for 5 minutes to obtain a coarse emulsion. After the crude emulsion was treated 5 times with a high-pressure emulsifying machine (Microfluidics Co.) at 150MPa, the treated product was filled into vials to prepare emulsions containing lipid nanoparticles encapsulating NPs (comparative example 5-1). The components were used so as to have the compositions shown in table 5.
For each emulsion, nimodipine was quantified by the same method as in test example 1 immediately after preparation and after storage at 60 ℃ for 2 weeks. The results are shown in Table 5.
TABLE 5
As shown in table 5, it can be seen that: when nimodipine is dissolved together with lipid by heating, decomposition of nimodipine is promoted, and thus the quantitative value immediately after preparation is reduced (95% in example 5-1, and 74% in comparative example 5-1). In addition, it is known that: the emulsion of comparative example 5-1 containing no Tris buffer and tocopherol has low storage stability of nimodipine (the difference between before and after storage of example 5-1 is-2% and comparative example 5-1 is-20%).
Test example 6: preparation and evaluation of emulsions comprising lipid nanoparticles comprising nimodipine
< preparation and stability evaluation of emulsion comprising lipid nanoparticles containing nimodipine >
An emulsion comprising lipid nanoparticles comprising nimodipine was prepared by the following method.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. PL, MCT, LCT, VE, concentrated glycerol and 0.5 mass% Tris buffer (pH 9.0) were added to pure water heated to 60℃and crude emulsification was carried out for 5 minutes to obtain a crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). After the crude emulsion (2) was treated 5 times with a high-pressure emulsifying machine (Microfluidics Co.) under 150MPa, the treated product was passed through a 0.2 μm membrane filter and filled into vials to prepare an emulsion containing lipid nanoparticles encapsulating NPs (example 6-1). The components were used so as to have the compositions shown in table 6.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. HA, PL, MCT, LCT, concentrated glycerol and 0.5 mass% Tris buffer (pH 9.0) were added to pure water heated to 60℃and crude emulsification was carried out for 5 minutes to obtain a crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). After the crude emulsion (2) was treated 5 times with a high-pressure emulsifying machine (Microfluidics Co.) at 150MPa, the treated product was filled into vials to prepare emulsions containing lipid nanoparticles encapsulating NPs (comparative example 6-1). The components were used so as to have the compositions shown in table 6.
For each emulsion, the nimodipine was quantified by the same method as in test example 1 immediately after preparation and after storage at 40 ℃ for 1 month. In addition, for each emulsion, immediately after preparation and after storage at 40℃for 1 month, evaluation of particle size was performed by the same method as in test example 4. The results are shown in Table 6.
TABLE 6
As shown in table 6, it can be seen that: the emulsion of example 6-1 comprising tocopherol is more excellent in storage stability.
Test example 7: preparation and evaluation of emulsions comprising lipid nanoparticles comprising nimodipine
< preparation and stability evaluation of emulsion comprising lipid nanoparticles containing nimodipine >
An emulsion comprising lipid nanoparticles comprising nimodipine was prepared by the following method.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. HA, PL, MCT, LCT, VE, sodium oleate, concentrated glycerol and 0.5 mass% Tris buffer (ph 9.0) were added to pure water heated to 60 ℃ and crude emulsification was performed for 5 minutes to obtain crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). After the crude emulsion (2) was treated 10 times with a high-pressure emulsifying machine (Microfluidics Co.) under 120MPa, the treated product was passed through a 0.2 μm membrane filter and filled into vials to prepare emulsions containing lipid nanoparticles encapsulating NPs (examples 7-1 to 7-4). The components were used so as to have the compositions shown in table 7.
For each emulsion, nimodipine was quantified by the same method as in test example 1 immediately after preparation and after storage at 60 ℃ for 2 or 4 weeks. Further, for each emulsion, immediately after the preparation and after the storage at 60℃for 2 weeks or 4 weeks, the particle size was evaluated by the same method as in test example 4. The results are shown in Table 7.
TABLE 7
It can be seen that: the emulsions of examples 7-1 to 7-4 satisfying the constitution of the present invention were excellent in storage stability and emulsion stability of nimodipine.
Test example 8: preparation and evaluation of emulsions comprising lipid nanoparticles comprising nimodipine
< preparation and stability evaluation of emulsion comprising lipid nanoparticles containing nimodipine >
An emulsion comprising lipid nanoparticles comprising nimodipine was prepared by the following method.
The NP was mixed with ethanol and heated to 60℃for dissolution to prepare an NP ethanol solution. HA, PL, MCT, LCT, VE, concentrated glycerol and 0.5 mass% Tris buffer (pH 9.0) were added to pure water heated to 60℃and crude emulsification was carried out for 5 minutes to obtain a crude emulsion (1). While stirring and heating the crude emulsion (1) to 60 ℃, an NP ethanol solution was added dropwise, and crude emulsification was performed for 5 minutes, to obtain a crude emulsion (2). After the crude emulsion (2) was treated 10 times with a high-pressure emulsifying machine (Microfluidics Co.) under 120MPa, the treated product was passed through a 0.2 μm membrane filter and filled into vials to prepare emulsions containing lipid nanoparticles encapsulating NPs (examples 8-1 to 8-2). The components were used so as to have the compositions shown in table 8.
For each emulsion, the amount of nimodipine was determined immediately after preparation and after storage at 60℃for 1 week in the same manner as in test example 1. In addition, for each emulsion, immediately after preparation and after storage at 60℃for 1 week, the particle size was evaluated in the same manner as in test example 4. The results are shown in Table 8.
TABLE 8
It can be seen that: the emulsions of examples 8-1 to 8-2 satisfying the constitution of the present invention were excellent in storage stability and emulsion stability of nimodipine.

Claims (9)

1. An emulsion comprising nimodipine, a phospholipid, a neutral lipid, a tocopherol, and water, and at least 1 selected from the group consisting of tris and salts thereof.
2. The emulsion of claim 1, wherein the phospholipid is at least 1 selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylglycerol, phosphatidylinositol, and sphingomyelin.
3. The emulsion of claim 1, wherein the neutral lipid is at least 1 selected from the group consisting of soybean oil, sesame oil, olive oil, rapeseed oil, corn oil, and medium chain fatty acid triglycerides.
4. The emulsion according to claim 1, which has a pH of 5 to 9.
5. The emulsion according to claim 1, wherein,
the content of nimodipine is more than 0.02 wt% and less than 0.2 wt% based on the total amount of the emulsion,
the content of the phospholipid is 1 to 3 wt% based on the total amount of the emulsion,
the content of neutral fat is 5 wt% to 10 wt% based on the total amount of the emulsion,
the content of at least 1 selected from the group consisting of tris (hydroxymethyl) aminomethane and salts thereof is 0.01 to 0.2 wt% based on the total amount of the emulsion,
the content of the tocopherol is 0.01-0.2 wt% based on the total emulsion.
6. The emulsion of claim 1 which is an injection.
7. The emulsion of claim 1, which is administered without dilution.
8. A method of manufacturing an emulsion comprising:
a) Heating and dissolving nimodipine in an organic solvent;
b) A step of adding phospholipids, neutral lipids, tocopherols and at least 1 selected from the group consisting of tris and salts thereof to an aqueous solvent followed by a crude emulsification; and
c) And (c) a step of adding the solution obtained in step a) dropwise to the crude emulsion obtained in step b) and dispersing the solution, and further subjecting the dispersed liquid to high-pressure emulsification treatment.
9. A method of manufacturing an emulsion comprising:
a) Heating and dissolving nimodipine in an organic solvent;
b) A step of adding at least 1 selected from the group consisting of a phospholipid and tris (hydroxymethyl) aminomethane and a salt thereof to an aqueous solvent to disperse the phospholipid;
c) A step of mixing the solution obtained in the step A) with neutral fat and tocopherol; and
d) And (C) a step of adding the solution obtained in step C) dropwise to the dispersion obtained in step B) and performing coarse emulsification, and further performing high-pressure emulsification treatment on the coarse emulsified liquid.
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Citations (2)

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