WO2020204001A1 - Procédé de production d'une composition de suspension aqueuse et composition de suspension aqueuse - Google Patents

Procédé de production d'une composition de suspension aqueuse et composition de suspension aqueuse Download PDF

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Publication number
WO2020204001A1
WO2020204001A1 PCT/JP2020/014676 JP2020014676W WO2020204001A1 WO 2020204001 A1 WO2020204001 A1 WO 2020204001A1 JP 2020014676 W JP2020014676 W JP 2020014676W WO 2020204001 A1 WO2020204001 A1 WO 2020204001A1
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Prior art keywords
aqueous suspension
suspension composition
rebamipide
mass
particles
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PCT/JP2020/014676
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English (en)
Japanese (ja)
Inventor
橋本　真一
辻畑　茂朝
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富士フイルム株式会社
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Priority to JP2021512136A priority Critical patent/JPWO2020204001A1/ja
Publication of WO2020204001A1 publication Critical patent/WO2020204001A1/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
    • A61K31/435—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
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4704—2-Quinolinones, e.g. carbostyril
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents

Definitions

  • the present disclosure relates to a method for producing an aqueous suspension composition and an aqueous suspension composition.
  • Rebamipide or a salt thereof is useful as an anti-ulcer or anti-inflammatory agent.
  • Rebamipide or a salt thereof protects the mucosal epithelium by promoting the secretion of mucosa produced by the mucosal epithelium such as the stomach wall, and promotes the blood flow of the gastric mucosa by promoting the production of prostaglandins, resulting in gastritis and gastric ulcer. It is known that it has functions such as promoting the healing of TNF- ⁇ and exerting an anti-inflammatory effect by suppressing the production of inflammatory cytocans such as TNF- ⁇ and IL-8. Furthermore, in recent years, attention has been paid to the mucosal repair action of rebamipide or a salt thereof.
  • Rebamipide has functions such as increasing the goblet cells of the eye, increasing the mucus of the cornea and conjunctiva of the eye, and stabilizing the tear film, and is therefore useful as a therapeutic agent for dry eye, that is, the xerophthalmia group. It is known that there is, and it is actually formulated.
  • Rebamipide is poorly soluble or insoluble in water, and is mainly present as rebamipide particles (crystals) of several micrometers in commercial products. Therefore, when orally administered, the dissolution rate is slow and the oral absorbability is low. There is. Further, when rebamipide is used as an eye drop, the rebamipide particles settle during storage and need to be resuspended before instillation, which causes a problem that it takes time and effort to use. From the viewpoint of improving the oral absorbability and eliminating the need for the resuspension operation, it is desired that the fine particles and the stability of the fine particles are good.
  • Japanese Patent Application Laid-Open No. 2014-77012 states that the drug substance of rebamipide is dissolved in an alkali, an acid containing a water-soluble polymer or the like is added to the solution, and jet mill pulverization is performed to obtain a major axis of rebamipide of 1000 nm.
  • a method for obtaining acicular crystals of rebamipide below to prepare an aqueous suspension applicable as an ophthalmic preparation is described.
  • Japanese Unexamined Patent Publication No. 2014-77012 discloses hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyoxyethylene polyoxypropylene glycol, polysorbate 80 and the like as water-soluble polymers and the like used for dispersion.
  • Japanese Unexamined Patent Publication No. 2016-94417 contains rebamipide having an average particle size of 500 nm or less, a dispersant, and a viscosity enhancer, and has an oral mucosal disorder having a drug solution viscosity in the range of 10 mPa ⁇ s to 500 mPa ⁇ s.
  • Therapeutic pharmaceutical compositions are disclosed.
  • the method for producing a pharmaceutical composition in JP-A-2016-94417 is the same as the method described in JP-A-2014-77012.
  • the rebamipide particles can be made finer to some extent.
  • three steps of an alkali dissolution step, an acid precipitation step and a jet mill pulverization step, a dialysis step for desalting, a levamipid concentration measuring step and a volume are obtained. This is a method with a large number of steps that go through 6 steps of adjustment steps.
  • the dispersion stability of fine dispersed particles over time has not been investigated.
  • the particle size is 213 nm even when dialysis is performed after storing the rebamipide 2% by mass aqueous suspension at 60 ° C. for 2 weeks.
  • the particle size after storage is 459 nm when dialysis is not performed.
  • the particle size of the fine particles cannot be maintained during storage.
  • rebamipide needs to be alkali-soluble, and the rebamipide concentration in the rebamipide aqueous suspension composition before concentration is limited to 2% by mass. .. Therefore, an aqueous suspension composition having a rebamipide concentration of more than 2% by mass cannot be prepared without undergoing a concentration step such as dialysis.
  • Rebamipide particles have an average particle diameter of 200 nm or less, and by achieving fine particle stabilization and fine particle stabilization, the specific surface area of the rebamipide particles is increased, which improves the rate of dissolution of rebamipide in the intestinal tract and allows oral absorption of rebamipide. It can be expected that the sex will improve.
  • fine rebamipide particles having an average particle diameter of 200 nm or less tears associated with lacrimal passage obstruction and lacrimal passage obstruction, which are presumed to be caused by containing rebamipide particles of about 10 micrometer.
  • Various advantages can be expected, such as the possibility of suppressing the occurrence of pouchitis and the possibility of filtration sterilization using a filtration filter having a pore size of 200 nm in the sterilization operation required for the production of eye drops.
  • the problem to be solved by one embodiment of the present invention is a method for producing an aqueous suspension composition containing fine rebamipide particles having an average particle diameter of 200 nm or less and maintaining the fine particle diameter for a long period of time. Is to provide.
  • An object of another embodiment of the present invention is to provide an aqueous suspension composition containing fine rebamipide particles of 200 nm or less and maintaining a fine particle diameter for a long period of time.
  • Means for solving the above problems include the following embodiments. ⁇ 1> A step A of preparing a mixture containing at least one selected from levamipide and a salt thereof, a water-soluble dispersant having a viscosity of a 2% by mass aqueous solution at 25 ° C. of 15 mPa ⁇ s or less, and water.
  • a method for producing an aqueous suspension composition which comprises step B of pulverizing the mixture with a wet bead mill and having an average particle size of at least one particle selected from levamipide and a salt thereof having an average particle size of 200 nm or less.
  • ⁇ 2> The aqueous suspension composition according to ⁇ 1>, wherein the total content of rebamipide and a salt thereof with respect to the total mass of the mixture in steps A and B is greater than 2% by mass and 40% by mass or less. Production method. ⁇ 3> The aqueous suspension composition according to ⁇ 1> or ⁇ 2>, wherein the total content of rebamipide and a salt thereof with respect to the total mass of the mixture in steps A and B is 3% by mass to 30% by mass. How to make things.
  • aqueous suspension composition according to any one of ⁇ 1> to ⁇ 3>, wherein the water-soluble dispersant contains at least one selected from a vinyl polymer having a hydrophilic group and a cellulose derivative.
  • Manufacturing method ⁇ 5>
  • the above-mentioned cellulose derivative contains at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate, according to ⁇ 4>.
  • ⁇ 6> The method for producing an aqueous suspension composition according to ⁇ 4>, wherein the cellulose derivative is methyl cellulose or hydroxypropyl cellulose.
  • the vinyl polymer having a hydrophilic group contains at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, copovidone, polymethacrylic acid derivative and polyacrylic acid derivative, ⁇ 4> to The method for producing an aqueous suspension composition according to any one of ⁇ 6>.
  • ⁇ 8> The method for producing an aqueous suspension composition according to any one of ⁇ 4> to ⁇ 6>, wherein the vinyl polymer having a hydrophilic group is polyvinylpyrrolidone.
  • aqueous suspension according to any one of ⁇ 1> to ⁇ 8> further comprising step C for adjusting the pH of the mixed solution in the range of 3.5 to 7.5 after the above step B.
  • a method for producing a turbid liquid composition ⁇ 10>
  • the cellulose derivative as the dispersion stabilizer is at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate.
  • a water-soluble suspension composition comprising a water-soluble dispersant having a total content of 0.02 parts by mass to 2 parts by mass with respect to 1 part by mass of the total content of particles, and water.
  • aqueous suspension composition containing fine rebamipide particles having an average particle size of 200 nm or less and maintaining the fine particle size for a long period of time. it can.
  • an aqueous suspension composition containing fine rebamipide particles of 200 nm or less and maintaining a fine particle size for a long period of time it is possible to provide an aqueous suspension composition containing fine rebamipide particles of 200 nm or less and maintaining a fine particle size for a long period of time.
  • the combination of preferred embodiments is a more preferred embodiment.
  • the amount of each component in the composition is the total amount of the plurality of substances present in the composition unless otherwise specified, when a plurality of substances corresponding to each component are present in the composition. means.
  • the term "process” is included in this term not only as an independent process but also as long as the intended purpose of the process is achieved even if it cannot be clearly distinguished from other processes. In the present disclosure, it may be referred to as "particle dispersion stability" that the increase in particle size and the precipitation of particles due to the aggregation of dispersed particles are suppressed and the fine particle size is maintained for a long period of time.
  • the "suspension” in the present disclosure refers to a dispersion in which water-insoluble particles having an average particle diameter of 200 nm or less measured by a dynamic light scattering method are dispersed in a liquid. Even if the average particle size of the particles is small and the particles are transparently visible by visual observation, if the dispersion liquid contains the water-insoluble particles in a dispersed state, the "suspension" in the present disclosure. include. The method for measuring the average particle size of the dispersed particles in the suspension will be described later.
  • the method for producing an aqueous suspension composition of the present disclosure (hereinafter, may be simply referred to as the production method of the present disclosure) has a viscosity of at least one selected from levamipide and a salt thereof at 25 ° C. of a 2% by mass aqueous solution.
  • the average particle size of the seed particles is 200 nm or less.
  • rebamipide or a salt thereof may be referred to as “rebamipide”.
  • rebamipide in the present disclosure is used to include the salt thereof, and “rebamipide particles” or “rebamipide particles” are used to include the particles of rebamipide and the particles of the salt of rebamipide. Used.
  • Step A is a step of preparing a mixture containing rebamipide or a salt thereof, a water-soluble dispersant having a viscosity of a 2% by mass aqueous solution at 25 ° C. of 15 mPa ⁇ s or less, and water.
  • the mixture in step A comprises rebamipide.
  • Rebamipide is useful as an anti-ulcer agent and is 2- (4-Chlorobenzoylamino) -3- (2-oxo-1,2-dihydroquinolin-4-yl) propanoic acid [2- (4-chlorobenzoylamino) -3. -(2-Quinolone-4-yl) propionic acid] is also called.
  • Rebamipide has been used, for example, in the treatment of gastritis and gastric ulcer therapeutic agents, dry eye, that is, xerophthalmia.
  • Rebamipide is also known to be used in pharmaceutical compositions for promoting saliva secretion.
  • oral rebamipide has an interleukin-8 production inhibitory effect, and one of its applications includes treatment for stomatitis.
  • the levamipide salt include alkali metal salts (sodium, potassium, etc.), calcium salts, metal salts (aluminum, iron, zinc, copper, bismuth, etc.), triethanolamine salts, and tromethamol (tris [hydroxymethyl] aminomethane).
  • Examples thereof include salts, meglumin salts, diethanolamine salts, tetramethylethanediamine salts, nicotine amide salts and ammonium salts (hexadecyltrimethylammonium, benzalconium, benzethonium, cetylpyridinium, etc.).
  • ammonium salts hexadecyltrimethylammonium, benzalconium, benzethonium, cetylpyridinium, etc.
  • hexamethyltrimethylammonium salt, benzalkonium salt, benzethonium salt, cetylpyridinium salt, calcium salt, iron salt and the like are preferable as the salt from the viewpoint of low water solubility and fine processing in the pulverization step.
  • the mixture may contain only one type of rebamipide or may contain two or more types of rebamipide.
  • rebamipide single substance
  • a salt of rebamipide may be contained, or two or more kinds of rebamipide different from each other may be contained.
  • the rebamipide used in the production method of the present disclosure is not particularly limited, and may be obtained by synthesis or can be obtained as a commercially available product.
  • rebamipide can be synthesized by the method described in JP-A-63-35623 or the method described in JP-A-2004-131506.
  • JP-A-63-35623 and JP-A-2004-131506 are incorporated in the present disclosure by reference.
  • a commercially available product of rebamipide can be obtained from, for example, Tokyo Chemical Industry Co., Ltd.
  • the content of rebamipide with respect to the total mass of the mixture is preferably larger than 2% by mass and 40% by mass or less, and the content is more preferably 3% by mass to 30% by mass, and 5% by mass to 20%. It is more preferably by mass%.
  • the contact frequency between the solid rebamipide and the pulverized medium in the wet bead mill pulverization of the step B performed following the step A Is a preferable range.
  • the contact frequency between rebamipide and the pulverized media is within a preferable range, the pulverization efficiency of rebamipide becomes better, the pulverization rate becomes faster, and nano-order fine particles can be easily obtained, and the obtained particles can be obtained.
  • the stability is also good. Furthermore, when the mixture contains a sufficient amount of rebamipide as an active ingredient, the medicinal effect of rebamipide in the obtained aqueous suspension composition can be expected.
  • the mixture in step A includes "a water-soluble dispersant having a viscosity of a 2% by mass aqueous solution of 15 mPa ⁇ s or less" (hereinafter, may be referred to as a specific dispersant).
  • the water-soluble dispersant in the present disclosure refers to a dispersant that dissolves in water at 25 ° C. in an amount of 2% by mass or more.
  • the specific dispersant has a viscosity of a 2% by mass aqueous solution at 25 ° C. of 15 mPa ⁇ s or less.
  • the viscosity of the 2% by mass aqueous solution of the specific dispersant can be measured by the following method.
  • a 2% by mass aqueous solution of the specific dispersant is obtained by dissolving 200 mg of the specific dispersant in water at 25 ° C. to make the total amount 10 g.
  • the obtained aqueous solution is allowed to stand for 1 hour in an environment having an ambient temperature of 25 ° C., and then the viscosity can be measured using a vibration viscometer.
  • the viscosity at 25 ° C. indicates the viscosity measured with the temperature of the aqueous solution of the specific dispersant at 25 ° C. as the measurement target.
  • the viscosity is a value measured using a vibrating viscometer (model name: VM-10A) manufactured by SEKONIC CORPORATION.
  • the viscosity of a 2% by mass aqueous solution of the specific dispersant measured at 25 ° C. is 15 mPa ⁇ s or less, preferably 12 mPa ⁇ s or less, more preferably 10 mPa ⁇ s or less, and 5 mPa ⁇ s or less. It is more preferable to have.
  • the lower limit of the viscosity of the 2 mass% aqueous solution measured at 25 ° C. is not particularly limited, but can be 0.8 mPa ⁇ s or more from the viewpoint of improving the efficiency of bead mill pulverization.
  • the specific dispersant preferably contains at least one selected from vinyl polymers having a hydrophilic group and cellulose derivatives.
  • the "vinyl polymer having a hydrophilic group” in the present disclosure includes a structural unit derived from a vinyl group, and as the hydrophilic group, a hydroxyl group, an amide group, a carboxyl group, a polyoxyethyl group, a phosphonic acid group, a phosphinic acid group, and the like.
  • Sulfate group ammonium group, guanidinium group, pyridinium group, imidazolinium group, phosphonium group, phosphatidylcholine group, thiolate group, sulfonium group, nitro group, imide group, carbamate group, carbonate group, ester group, carbonyl group, sulfide group, Refers to a water-soluble compound having at least one selected from the group consisting of a sulfoxide group, a sulfone group, and a heteroaryl group.
  • the "cellulose derivative" in the present disclosure is a water-soluble compound containing a cellulose skeleton, which is a compound containing a cellulose skeleton and having a hydrophilic partial structure, or a compound containing a cellulose skeleton and being hydrophilic. Refers to a compound having a group.
  • the cellulose derivative which is a preferable example of the specific dispersant includes methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxyethyl methyl cellulose, ethyl cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, potassium carboxymethyl cellulose and hydroxypropyl. It is preferable to contain at least one selected from the group consisting of methylcellulose phthalate and hydroxypropylmethylcellulose acetate ester succinate, among which methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulosephthalate and hydroxypropylmethylcellulose acetate. It is more preferable to contain at least one selected from the group consisting of succinate, and further preferably methyl cellulose or hydroxypropyl cellulose.
  • the specific dispersant is a vinyl polymer having a hydrophilic group. More specifically, the vinyl polymer having a hydrophilic group preferably contains at least one selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, carboxyvinyl polymer, copovidone, polymethacrylic acid derivative and polyacrylic acid derivative. , Polyvinylpyrrolidone is more preferable.
  • the "polymethacrylic acid derivative" in the present disclosure includes a structural unit derived from methacrylic acid, and includes an ester, an amide, and a copolymer with another polymer.
  • the "polyacrylic acid derivative” in the present disclosure includes a structural unit derived from acrylic acid, and includes an ester, an amide, and a copolymer with another polymer.
  • Examples of the polymethacrylic acid derivative and the polyacrylic acid derivative ester include methyl ester, ethyl ester, butyl ester, dimethylamino ester, trimethylammonium chloride ester, octyl ester, 2-ethylhexyl ester, 2-ethylpropyl ester and starch ester. Includes glycidyl ester and acetoacetoxyethyl.
  • Amides of polymethacrylic acid derivatives and polyacrylic acid derivatives include unsubstituted (acrylamide or methacrylamide), isopropylamide, diacetoneamide, 2-methylpropanesulfonic acid amide, and tert-butylamide.
  • Examples of the copolymer with other polymers include copolymers of acrylic acid and acrylic acid ester, copolymers of methacrylic acid and methacrylic acid ester, copolymers of acrylic acid and methacrylic acid ester, and methacrylic acid and acrylate ester.
  • At least one selected from the vinyl polymer having a hydrophilic group and a cellulose derivative is a condition that "the viscosity of a 2% by mass aqueous solution at 25 ° C. is 15 mPa ⁇ s or less" specified in the present disclosure, depending on the molecular weight. Some compounds do not meet the requirements.
  • the specific dispersant in the present disclosure refers to the above-mentioned preferable exemplary compound and a compound satisfying the condition that "the viscosity of a 2% by mass aqueous solution measured at 25 ° C. is 15 mPa ⁇ s or less".
  • the specific dispersant in the present disclosure refers to the above-mentioned preferable exemplary compound and a compound satisfying the condition that "the viscosity of a 2% by mass aqueous solution measured at 25 ° C. is 15 mPa ⁇ s or less".
  • a compound having a viscosity of more than 15 mPa ⁇ s measured at 25 ° C. in a 2 mass% aqueous solution is not included in the specific dispersant in the present disclosure.
  • a commercially available product may be used as the specific dispersant.
  • the viscosity shown in parentheses which is also described in the following commercial product name, is the viscosity of the 2% by mass aqueous solution of the specific dispersant.
  • Commercially available products include polyvinylpyrrolidone K25 (PVP-K25) [Kollidon® 25), viscosity: 1.3 mPa ⁇ s], polyvinylpyrrolidone K30 (PVP-K30) [Kollidon® 30, viscosity: 1.
  • polyvinylpyrrolidone 90F [Kollidon® 90F, viscosity: 8.7 mPa ⁇ s] or higher, manufactured by BASF Co., Ltd., methylcellulose SM4 (MC-SM4) [Metroze (registered trademark) ) SM-4, viscosity: 3.6 mPa ⁇ s] or higher, manufactured by Shin-Etsu Chemical Industry Co., Ltd.], hydroxypropylmethyl cellulose TC5E (HPMC-TC5E) [hypromellose (registered trademark) TC-5E, viscosity: 2.7 mPa ⁇ s ], Hydroxypropylmethylcellulose TC5M (HPMC-TC5M) [Hypromellose (registered trademark) TC-5M, viscosity: 3.8 mPa ⁇ s], hydroxypropylmethylcellulose TC5R (HPMC-TC5R) [hyp
  • the mixture in step A may contain only one type of specific dispersant, or may contain two or more types of the specific dispersant.
  • the viscosity of the 2% by mass aqueous solution measured as a mixture of two or more kinds must be 15 mPa ⁇ s or less.
  • the content of the specific dispersant with respect to the total mass of the mixture is preferably 0.1% by mass to 10% by mass, and more preferably 0.2% by mass to 8% by mass.
  • the mass ratio of the content of rebamipide to the specific dispersant in the mixture is preferably 1: 0.02 to 1: 1, more preferably 1: 0.02 to 1: 0.5, and 1: 0.1 to 1. 1: 0.5 is more preferable.
  • the mixture in step A contains water.
  • the water used for preparing the mixture is preferably ion-exchanged water, pure water, ultrapure water, water for injection, purified water, or the like from the viewpoint of having few impurities.
  • an aqueous solution in which the specific dispersant is dissolved in water in advance is obtained, rebamipide is added to the obtained aqueous solution, and then water is further added to adjust the content of rebamipide contained in the mixture. It is preferable to adjust the range to 40% by mass or less, which is larger than the above 2% by mass.
  • the mixed solution may further contain known additives such as a pH adjuster, a buffer, a surfactant, an isotonic agent, and a preservative, depending on the purpose. The details of the additive will be described later.
  • Step B is a step of pulverizing the mixture obtained in Step A with a wet bead mill. By going through step B, an aqueous suspension composition containing rebamipide particles having an average particle diameter of 200 nm or less can be obtained.
  • the mixture obtained in step A is mechanically dispersed using a solid disperser, solid rebamipide is pulverized in a dispersion medium, and dispersion containing fine particles of rebamipide is dispersed.
  • Wet bead mill pulverization is included in a wet dispersion treatment method using a medium, and a mixture containing solid rebamipide is mixed with beads which are media having a material and a particle size selected according to a purpose to disperse the mixture. How to do it.
  • the energy transmitted from the power source to the crushing media becomes a force such as compression, impact, shear, and friction and is applied to the solid levamipid, causing stress in the solid levamipide to deform and destroy it.
  • This can be pulverized to prepare a dispersion containing fine dispersion particles of levamipid.
  • a batch method and a circulation method continuous method
  • both methods can be applied to step B.
  • beads are used from the viewpoint that finer dispersed particles can be obtained.
  • the material of the beads used for dispersion is inorganic such as zirconia, ittria stabilized zirconia, alumina, steatite, silicon carbide, silicon nitride, silica, sand, menor, steel ball, stainless steel, glass, low alkaline glass, and non-alkali glass.
  • examples thereof include compounds, polystyrene, polymethylmethacrylate, polytetrafluoroethylene, polyamide, polyethylene, polypropylene, polyetheretherketone (PEEK), polymer resins such as polyimide, and ice.
  • Yttria-stabilized zirconia is sometimes referred to simply as zirconia.
  • zirconia beads including yttria-stabilized zirconia beads are preferable from the viewpoints of strong dispersibility, excellent durability, and less concern about contamination of impurities due to media.
  • Media dispersers that add kinetic force to media are classified into various dispersers according to a stirring method, a media separation mechanism, a vertical type or a horizontal type, a cooling method, and the like.
  • a bead mill provided with a separation mechanism for fine beads having a diameter of 0.1 mm or less is particularly preferable.
  • Commercially available bead mill dispersers with a micro-bead separation mechanism such as 0.1 mm or less in diameter include Ultra Apex Mill (manufacturer: Hiroshima Metal Machinery Co., Ltd.) and Star Mill (manufacturer: Ashizawa Finetech Co., Ltd.).
  • the dispersion device that can be used for the dispersion processing is not limited to the above-mentioned example.
  • the particle size of the beads as a medium used for dispersion is preferably small from the viewpoint of reducing the reached particle size.
  • the particle size of the beads is large from the viewpoint of high crushing speed of coarse particles of several tens of micrometers or more and easy separation of the crushed beads and suspension. Larger is preferable.
  • the beads used for pulverization are preferably beads having a diameter of 0.02 mm or more and 1 mm or less, more preferably 0.05 mm or more and 0.3 mm or less, and 0.05 mm or more and 0. from the viewpoint of easily producing finer dispersed particles. It is more preferably 1 mm or less. Of these, zirconia beads having the above diameter are preferable.
  • the filling amount of the beads is 7.5 parts by mass to 60 parts by mass with respect to 1 part by mass of rebamipide from the viewpoint of increasing the rebamipide pulverization efficiency regardless of whether the batch type or the continuous circulation type is used as the disperser. It is more preferable, it is more preferably 15 parts by mass to 60 parts by mass, and further preferably 30 parts by mass to 60 parts by mass. 7.5 to 60 parts by mass with respect to 1 part by mass of rebamipide means that the filling amount of beads with respect to rebamipide is 7.5 to 60 times by mass ratio.
  • the bead filling amount means the bead filling amount with respect to 1 part by mass of rebamipide contained in the crushing chamber.
  • the bead packing density can be 1 kg to 4 kg in 1 L (liter) of the container, and is preferably in the range of 1.5 kg to 3.0 kg.
  • the bead packing density can be 0.1 kg to 3.7 kg in 1 L (liter) of the crushing chamber, and can be in the range of 1.0 kg to 3.0 kg. It is preferably in the range of 2.0 kg to 3.0 kg, more preferably.
  • the rotation speed of the crushing device can be 500 rpm (revolutions per minute, the same applies hereinafter) to 3000 rpm, preferably 1000 rpm to 2000 rpm.
  • the object to be dispersed is circulated in the crushing chamber of the device at a speed of 10 g / min to 500 g / min, preferably 100 g / min to 200 g / min, and the number of rotations is increased.
  • Wet bead mill pulverization is preferably performed under the conditions of 400 rpm to 6000 rpm, preferably 2000 rpm to 3000 rpm.
  • the crushing time can be 2 hours to 24 hours, preferably 4 hours to 18 hours, and more preferably 8 hours to 16 hours.
  • the crushing time can be 2 hours to 12 hours, preferably 4 hours to 7 hours.
  • the temperature in the pulverization treatment is preferably lower than room temperature (25 ° C), preferably 3 ° C to 8 ° C as the outside temperature, and when the entire apparatus is cooled with cooling water, the temperature of the cooling water is 3 ° C.
  • the temperature is preferably ⁇ 8 ° C.
  • Dispersers that do not have a bead separation mechanism can be used in the production method of the present disclosure by adding a post-step of bead filtration after the dispersion and pulverization treatment.
  • Dispersers that do not have a bead separation mechanism that can be used in the manufacturing methods of the present disclosure include ball mills, sand grinder mills, and planetary ball mills.
  • a ball mill is a dispersion device in which a pot made of a material selected from porcelain, nylon, polymer, stainless steel, etc. containing slurry and beads is placed on a turntable and rotated.
  • the planetary ball mill has a structure in which the slurry and the vessel containing the balls revolve while rotating, and the dispersion efficiency is superior to that of a general ball mill.
  • Examples of the planetary ball mill include a planetary ball mill (trade name: Fritsch), a rotation / revolution nano crusher NP-100 (trade name: Shinky), and the like.
  • the media dispersion treatment using zirconia beads when the solid rebamipide is pulverized to prepare dispersed particles, two or more stages of multi-stage dispersion treatment can be performed, and three or more stages can be performed. You may perform the multi-stage dispersion processing of.
  • the rebamipide particles are pulverized into fine particles to a target average particle diameter of 200 nm or less to obtain a dispersed dispersion. I wish I could.
  • it is preferable that a dispersion of fine molecules can be produced in one step.
  • the production method of the present disclosure when performing multi-step dispersion, it is preferable to include a wet bead mill pulverization and dispersion treatment method at any stage, and in the final stage dispersion treatment of the multi-step dispersion, It is more preferable to carry out a wet bead mill pulverization and dispersion treatment method using beads as a medium.
  • a disperser other than a media disperser that can be used as an auxiliary for coarse dispersion processing, which is the first-stage dispersion processing is a rheology shearing force type disperser.
  • Homo mixer, dispersion mixer, ultra mixer, stirrer such as Clairemix (trade name: M-Technique), ultrasonic homogenizer, high pressure homogenizer and the like can be used.
  • High-pressure homogenizers include Microfluidizer (trade name: Microfluidics), Nanomizer (trade name: Yoshida Kikai Kogyo), Starburst (trade name: Sugino Machine), Gorin Homogenizer (trade name: APV), Lanier Homogenizer (product name) Name: Lanier), High Pressure Homogenizer (Product Name: Niro Soabi), Homogenizer (Product Name: Sanwa Machinery), High Pressure Homogenizer (Product Name: Izumi Food Machinery), Ultra High Pressure Homogenizer (Product Name: Squid), etc. ..
  • the mechanical dispersion process may be a multi-stage dispersion process having three or more stages.
  • a dispersion of fine particles having an average particle diameter of 200 nm or less is produced by coexisting a specific dispersant with solid levamipide as a raw material.
  • the obtained particles have good particle size stability, the increase in particle size due to the aggregation of particles with time is suppressed, and the dispersion stability is excellent.
  • the specific dispersant is adsorbed on at least a part of the crushed surface of the crushed rebamipide particles by preparing the dispersion by coexisting the solid rebamipide and the specific dispersant. By continuing the pulverization, the specific dispersant is further adsorbed on the new crushed surface of the rebamipide particles, and the finely divided particles become particles such that at least a part of the surface thereof is coated with the specific dispersant.
  • the reaggregation and recrystallization of adjacent dispersed particles in a dispersion medium containing water is effectively suppressed by the presence of the specific dispersant adsorbed on at least a part of the particle surface.
  • the viscosity of the 2% by mass aqueous solution of the specific dispersant at 25 ° C. is 15 mPa ⁇ s or less, which means that the molecules of the specific dispersant are less entangled.
  • the obtained particles are fine and have excellent dispersion stability. If the viscosity of the 2% by mass aqueous solution of the dispersant at 25 ° C. is too high, the effect of pulverization due to contact between rebamipide and the beads as a medium during the bead mill pulverization treatment is hindered, and the pulverization efficiency is lowered. Further, since the viscosity of the aqueous dispersant solution is high, the adhesion of the dispersant to the new surface of the crushed particles is also lowered, so that it is considered difficult to achieve stabilization of the obtained dispersed particles.
  • the aqueous suspension composition containing the rebamipide particles obtained by the production method of the present disclosure has an average particle size of the rebamipide particles of 200 nm or less on the nano-order, and is excellent in particle dispersibility and dispersion stability. ..
  • the average particle size of the obtained rebamipide particles can be set to 200 nm or less by performing the dispersion treatment by the wet bead mill pulverization method.
  • the average particle size of the rebamipide particles is more preferably 50 nm to 180 nm, still more preferably 50 nm to 150 nm.
  • the average particle size of the rebamipide particles in the present disclosure can be measured by a dynamic light scattering method. The measurement is performed under the condition of a set temperature of 25 ° C. The obtained particle size distribution is analyzed by the analysis method: CONTIN and the distribution: scattered light intensity distribution, and the particle size giving a cumulative distribution frequency of 50% (d50 value) is adopted as the average particle size.
  • the average particle size of the levamipid particles in the present disclosure is determined by a multi-sample nanoparticle measurement system (for example, nanoSAQLA / auto sampler AS50, manufactured by Otsuka Electronics Co., Ltd.) or a concentrated particle size analyzer (for example, FPAR-1000AS, Otsuka Electronics Co., Ltd.
  • the measurement results can be regarded as the same regardless of which of these is used for measurement.
  • the average particle size of the same sample was measured using a multi-sample nanoparticle measurement system and a concentrated particle size analyzer and different results were obtained due to the influence of measurement error, etc., this disclosure was obtained. The smaller value is adopted as the average particle size of the levamipid particles contained in the aqueous suspension composition.
  • the manufacturing method of the present disclosure may further include an arbitrary step in addition to the above-mentioned steps A and B.
  • an optional step for example, after step B, the step of adjusting the pH of the mixed solution to the range of 3.5 to 7.5, and after step B, a step of adding at least one dispersion stabilizer.
  • step B water is added to adjust the levamipide concentration in the aqueous suspension composition, the obtained aqueous suspension composition is sterilized, and the obtained aqueous suspension composition is pulverized.
  • the process to be performed can be mentioned.
  • Step C which is an arbitrary step, is performed after step B described above, and is a step of adjusting the pH of the mixed solution in the range of 3.5 to 7.5.
  • the pH can be adjusted using a known pH adjuster.
  • the pH adjuster can be used without particular limitation as long as it is a biocompatible acid or alkaline agent. Examples of known pH adjusters include sodium hydroxide (NaOH), hydrochloric acid (HCl), aqueous NaOH, aqueous HCl and the like, which are appropriately used depending on the intended purpose.
  • the method for producing an aqueous suspension composition of the present disclosure can further include a step of adding at least one dispersion stabilizer to the aqueous suspension composition obtained in step B.
  • the dispersion stabilizer at least one selected from the above-mentioned specific dispersants can be used.
  • the step of adding the dispersion stabilizer is a cellulose derivative as a dispersion stabilizer in the aqueous suspension composition obtained in step B. It is preferable that the step D is shown below in which at least one selected from the above is added.
  • Step D is a step of adding at least one selected from cellulose derivatives as a dispersion stabilizer to the aqueous suspension composition obtained in Step B.
  • the cellulose derivative the same cellulose derivative as the cellulose derivative mentioned as a preferable example of the specific dispersant can be used.
  • the cellulose derivative as a dispersion stabilizer is preferably at least one selected from the group consisting of methyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methyl cellulose phthalate and hydroxypropyl methyl cellulose acetate succinate. ..
  • the cellulose derivative as a dispersion stabilizer is preferably added in an amount of 0.02 parts by mass to 2 parts by mass with respect to 1 part by mass of the total content of rebamipide or a salt thereof.
  • the amount to be added is more preferably 0.03 part by mass to 0.5 part by mass, and further preferably 0.05 part by mass to 1 part by mass with respect to 1 part by mass of the total content of rebamipide or a salt thereof.
  • the cellulose derivative After preparing the aqueous suspension composition in steps A and B, by further adding at least one cellulose derivative as a dispersion stabilizer, the cellulose derivative is formed on at least a part of the surface of the fine particles of rebamipide. Combined with the effect of the specific dispersant that adheres and adheres to at least one part of the surface of the rebamipide particles dispersed through the wet bead mill pulverization treatment of step B, it is three-dimensional on the surface of the fine particles of rebamipide. It is considered that the reaggregation suppressing effect and the recrystallizing suppressing effect become better.
  • Examples of the combination of the specific dispersant and the cellulose derivative as the dispersion stabilizer include a combination of polyvinylpyrrolidone as a specific dispersant and methylcellulose as a dispersion stabilizer, and a dispersion stable with methylcellulose as a specific dispersant. Examples thereof include a combination with hydroxymethylpropyl cellulose as a constant dispersant, a combination of polyvinylpyrrolidone as a specific dispersant, and hydroxypropyl methylcellulose as a dispersion stabilizer.
  • step C and step D either step may be performed first or may be performed at the same time.
  • step C may be performed to adjust the pH to the range of 3.5 to 7.5
  • step D may be performed to add a cellulose derivative as a dispersion stabilizer.
  • the pH may be adjusted by adding a cellulose derivative as a dispersion stabilizer and a pH adjuster to the mixed solution (dispersion solution) obtained in 1. In either order, the effect of dispersion stabilization on the cellulose derivative becomes better.
  • the production method of the present disclosure may include a step of sterilizing the obtained aqueous suspension composition.
  • the method of sterilization treatment is not particularly limited, and a known sterilization treatment can be appropriately applied.
  • sterilization treatment sterilization treatment by dry heat treatment, autoclave sterilization treatment by steam which is an example of moist heat sterilization treatment, filtration sterilization treatment, plasma sterilization treatment, sterilization treatment using chemicals such as sterilizer, sterilization gas such as ethylene oxide gas are used.
  • sterilization treatment using chemicals such as sterilizer, sterilization gas such as ethylene oxide gas are used.
  • sterilization process used and the sterilization process of irradiating radiation such as gamma rays.
  • the use of chemicals or sterilizing gas for sterilization is concerned about the effects of residual components and by-products.
  • undesired decomposition products may be generated even in the sterilization process of irradiating radiation.
  • the sterilization treatment is preferably an autoclave sterilization treatment, a dry heat sterilization treatment, or a filtration sterilization treatment, and more preferably an autoclave sterilization treatment.
  • the mixture to be wet pulverized in step B is preferably autoclaved before the wet pulverization.
  • the autoclave sterilization process is usually carried out by heat sterilization in which the aqueous suspension composition is treated at a temperature of 122 ° C. for 20 minutes.
  • Rebamipide itself has heat resistance to withstand heat treatment. Therefore, when the aqueous suspension composition of the present disclosure is sterilized, heat sterilization can be performed in order to perform a reliable sterilization treatment. However, when the aqueous suspension composition is applied to eye drops, heating may reduce the dispersion stability of the fine particles and facilitate the aggregation of the particles. Therefore, when applying the obtained aqueous suspension composition to eye drops, it is also preferable to perform filtration sterilization treatment. In addition to eye drops, it is also advantageous to be able to perform filtration sterilization when a component that cannot withstand heat sterilization is used in combination.
  • Filters used for filtration sterilization often have an average opening of 200 nm or less, and if the average particle size of the particles contained in the aqueous suspension composition exceeds 200 nm, filtration sterilization becomes difficult. ..
  • the aqueous suspension composition obtained by the production method of the present disclosure can obtain fine particles having an average particle size of 200 nm or less, and can maintain an average particle size of 200 nm or less until filtration. Therefore, it can be suitably applied to filtration sterilization.
  • filters used for filtration sterilization include, for example, a Merck polyether sulfone filter (PES / Merck) [trade name: Merck Millipore Express (registered trademark) SHF, pore diameter: 0.2 ⁇ m], a Merck polyvinylidene fluoride filter (P).
  • PES / Merck Merck polyether sulfone filter
  • PHF Merck Millipore Express
  • PVC Merck polyvinylidene fluoride filter
  • PVDF / Merck [Product name: Durapore (registered trademark), Pore diameter: 0.22 ⁇ m], PALL polyether sulfone filter (PES / PALL) [Product name: Super (registered trademark) EX ECV, Pore diameter: 0.2 ⁇ m] , Zartorius, cellulose acetate filter (CA / Sarto) [trade name: Sartobran (registered trademark) P, pore size 0.22 ⁇ m] and the like.
  • the aqueous suspension composition obtained by the production method of the present disclosure described above is a dispersion in which fine rebamipide particles are stably dispersed in a dispersion medium containing water.
  • the aqueous suspension composition is a composition that does not need to be resuspended because the rebamipide particles do not settle during storage.
  • the increase in the dispersed particle size over time due to the reaggregation of the particles is suppressed, and the average particle size of the levamipid particles contained in the aqueous suspension composition is maintained at 200 nm or less for a long period of time.
  • the suspension composition can be suitably used for various uses.
  • the rebamipide particles do not settle during storage and are suitably used as eye drops that do not need to be resuspended.
  • the aqueous suspension composition obtained by the production method of the present disclosure is suitably used as an eye drop.
  • it can be expected to have an effect of suppressing lacrimal passage obstruction, which is considered to be caused by the large particle size, which is a problem with existing drugs.
  • improvement in the absorption in the body when orally administered can be expected.
  • the aqueous suspension composition of the present disclosure is at least one selected from levamipide particles and levamipide salt particles having an average particle diameter of 200 nm or less, and at least one selected from methyl cellulose and hydroxypropyl cellulose. It contains a water-soluble dispersant having a total content of 0.02 parts by mass to 2 parts by mass with respect to 1 part by mass of the total content of the particles of levamipide and the particles of the salt of levamipide, and water.
  • the aqueous suspension composition of the present disclosure preferably further comprises polyvinylpyrrolidone.
  • the particles of rebamipide and the particles of salt of rebamipide are appropriately collectively referred to as "particles of rebamipide”.
  • the rebamipide used as a raw material for the particles of rebamipide in the aqueous suspension composition of the present disclosure is the same as the rebamipide contained in the mixture in the production method of the present disclosure described above, and the preferred examples are also the same.
  • the average particle size of the rebamipide particles contained in the aqueous suspension composition is 200 nm or less, preferably 50 nm to 180 nm, and more preferably 50 nm to 150 nm.
  • the aqueous suspension composition of the present disclosure contains a water-soluble dispersant selected from methyl cellulose and hydroxypropyl cellulose.
  • a water-soluble dispersant selected from methyl cellulose and hydroxypropyl cellulose the same compounds as the above-mentioned specific dispersants such as methyl cellulose and hydroxypropyl cellulose can be used, and preferred examples and commercially available products that can be used are also the same. ..
  • Methyl cellulose and hydroxypropyl cellulose as water-soluble dispersants contained in the aqueous suspension composition are water-soluble dispersants having a viscosity of a 2% by mass aqueous solution at 25 ° C. of 15 mPa ⁇ s or less, similar to the above-mentioned specific dispersants. Is.
  • the content of the water-soluble dispersant in the aqueous suspension composition of the present disclosure is in the range of 0.02 parts by mass to 2 parts by mass with respect to 1 part by mass of the total content of the particles of rebamipide.
  • the content of the water-soluble dispersant is more preferably 0.03 parts by mass to 1 part by mass, still more preferably 0.05 parts by mass to 0.5 parts by mass, based on 1 part by mass of the total content of the levamipide particles. , 0.1 part by mass to 0.3 part by mass is particularly preferable.
  • the content of the water-soluble dispersant is 0.02 parts by mass or more with respect to the total content of 1 part by mass of the levamipide particles, the dispersibility of the fine levamipide particles having an average particle diameter of 200 nm or less is good.
  • the amount is 2 parts by mass or less, the decrease in the dispersibility and dispersion stability of the particles is suppressed.
  • the aqueous suspension composition of the present disclosure comprises water as a dispersion medium.
  • water ion-exchanged water, pure water, ultrapure water, water for injection, purified water and the like are preferable from the viewpoint of having few impurities.
  • the aqueous suspension composition of the present disclosure preferably further contains polyvinylpyrrolidone as a dispersant in addition to the above water-soluble dispersant.
  • the polyvinylpyrrolidone that can be used in the aqueous suspension composition of the present disclosure has a viscosity of 15 mPa ⁇ s at 25 ° C. of a 2% by mass aqueous solution exemplified as a preferable compound of the specific dispersant used in the above-mentioned production method of the present disclosure.
  • the following polyvinylpyrrolidone The following polyvinylpyrrolidone.
  • the aqueous suspension composition of the present disclosure further contains the above-mentioned polyvinylpyrrolidone, the dispersion stability of the rebamipide particles becomes better.
  • the content of polyvinylpyrrolidone is not particularly limited, but is preferably in the range of 0.02 parts by mass to 2 parts by mass with respect to 1 part by mass of the total content of the rebamipide particles.
  • the average particle size of the rebamipide particles contained in the aqueous suspension composition of the present disclosure is 200 nm or less, preferably 50 nm to 180 nm, and more preferably 50 nm to 150 nm.
  • the average particle size of the rebamipide particles is 200 nm or less, and the average particle size of 200 nm or less is maintained even after a lapse of time, so that the aqueous suspension composition of the present disclosure can be subjected to filtration sterilization. Filters used for filtration sterilization often have an average opening of 200 nm or less, and if the average particle size of the particles contained in the aqueous suspension composition exceeds 200 nm, filtration sterilization becomes difficult. ..
  • the aqueous suspension composition of the present disclosure can be suitably applied to filtration sterilization because the average particle size of the rebamipide particles is 200 nm or less.
  • the content of rebamipide in the aqueous suspension composition of the present disclosure is appropriately set according to the purpose of treatment or prevention within a pharmaceutically acceptable range when the aqueous suspension composition is applied to a pharmaceutical composition. You can choose.
  • the aqueous suspension composition of the present disclosure may further contain various components acceptable as a pharmaceutical composition, depending on the intended purpose.
  • the aqueous suspension composition of the present disclosure may further contain a surfactant.
  • Surfactants may function as dispersion aids or dispersion stabilizers.
  • As the surfactant a known surfactant that can improve the dispersibility and dispersion stability of solid particles can be used without particular limitation.
  • Examples of the surfactant include anionic surfactants, cationic surfactants, amphoteric surfactants, nonionic surfactants and the like.
  • polyoxyethylene hydrogenated sardine oil for example, polyoxyethylene hydrogenated sardine oil 40, polyoxyethylene hydrogenated sardine oil 50, polyoxyethylene hydrogenated sardine oil 60, etc.
  • polysorbate 80 polysorbate 65, polysorbate 40, polysorbate 20, poly Oxyethylene sorbitan monolaurate, polyethylene glycol monostearate, polyoxyethylene lauryl ether (eg lauromacrogol BL-9, lauromacrogol BL-25), polyoxyethylene polyoxypropylene glycol (poloxamer, pluronics, eg , Poloxamer 188, poloxamer 407), polyoxyethylene hydroxystearate, sodium lauryl sulfate, sodium deoxycholate and the like.
  • polyoxyethylene hydrogenated sardine oil for example, polyoxyethylene hydrogenated sardine oil 40, polyoxyethylene hydrogenated sardine oil 50, polyoxyethylene hydrogenated sardine oil 60, etc.
  • polysorbate 80 polysorb
  • the surfactant is selected from the group consisting of polyoxyethylene polyoxypropylene glycol, lauromacrogol, sodium deoxycholate, polyoxyethylene hydrogenated castor oil, polyoxyethylene hydroxystearate, polysorbate 20, and polysorbate 80. It is preferable to contain at least one kind, and more preferably to contain at least one kind selected from polyoxyethylene polyoxypropylene glycol and polyoxyethylene hydrogenated castor oil.
  • the content of the surfactant is 0.01 parts by mass to 40 parts by mass with respect to 1 part by mass of the content of levamipide in the aqueous suspension composition. It is preferably parts by mass, more preferably 0.1 parts by mass to 10 parts by mass.
  • the content of the surfactant in the aqueous suspension composition is within the above range, the effect of improving the dispersion stability of the levamipide particles by the surfactant can be sufficiently obtained, and the content of the surfactant is also obtained. It is unlikely that the effect of the surfactant on the living body, which is a concern when the amount is too large, will occur.
  • the aqueous suspension composition of the present disclosure can be applied to a pharmaceutical composition containing rebamipide as an active ingredient.
  • the dosage form when the aqueous suspension composition is applied to the pharmaceutical composition is not particularly limited as long as it is in a form that can be administered to a living body.
  • Examples of the dosage form include liquid preparations and syrup preparations in which the aqueous suspension composition is used in a liquid state.
  • Examples of the liquid preparation include liquid preparations used for oral administration, oral mucosa protection and repair agents, eye drops (ophthalmic preparations), and the like.
  • a solid preparation can also be obtained by drying the aqueous suspension composition.
  • Examples of the solid preparation include dosage forms such as tablets, granules, powders, and fine granules, which can be administered orally.
  • Tablets include chewable tablets, lozenges, drop agents, granules that rapidly dissolve or disintegrate in the oral cavity and can be taken without water, so-called orally disintegrating tablets, and effervescent tablets that are dissolved and used before use. Includes resolving tablets.
  • Granules, powders and fine granules include dry syrups that are dissolved and used before use, and also include granules that rapidly dissolve or disintegrate in the oral cavity and can be taken without water, so-called orally disintegrating tablets. Liquids and syrups may further contain various pharmaceutically acceptable dispersion media other than water.
  • the powder preparation in the present disclosure includes granules containing the powder preparation and an excipient, tablets obtained by tableting the powder preparation, coated tablets coated with the obtained tablets, and capsules of the powder preparation. Includes forms such as capsules encapsulated in.
  • the powder preparation has good manufacturability and storage stability, is easily portable, and has an advantage that it is easy to take the required amount.
  • the mass per agent of the preparation is preferably 700 mg or less, further preferably 600 mg or less, from the viewpoint of ease of administration. preferable.
  • aqueous suspension composition of the present disclosure When the aqueous suspension composition of the present disclosure is applied to a pharmaceutical composition to be orally administered, it may contain various commonly used pharmaceutical additives as long as the effect is not impaired.
  • the formulation additive include excipients, disintegrants, binders, lubricants, colorants, flavoring agents, sweeteners and flavoring agents, pH adjusters and the like.
  • Excipient When the pharmaceutical composition to which the aqueous suspension composition of the present disclosure is applied is a powder preparation containing tablets, it is preferable to contain an excipient in order to maintain a stable dosage form.
  • Excipients include sugars (eg glucose, lactose, sucrose, maltose, trehalose, starch, cyclodextrin, etc.), sugar alcohols (eg, mannitol, erythritol, isomalto, lactitol, martitol, sorbitol, xylitol, inositol, etc.).
  • sugars eg glucose, lactose, sucrose, maltose, trehalose, starch, cyclodextrin, etc.
  • sugar alcohols eg, mannitol, erythritol, isomalto, lactitol, martitol, sorbitol, xylitol, inos
  • Starch eg, corn starch, potato starch, rice starch, wheat starch, etc.
  • crystalline cellulose eg, calcium salts (eg, anhydrous calcium phosphate, light anhydrous silicic acid, light anhydrous calcium silicate, calcium silicate, calcium sulfate, calcium carbonate.
  • Calcium silicate magnesium aluminometasilicate, silicic anhydride, amino acids (eg, glycine, alanine, asparagine, triprophan, etc.) and the like.
  • Mannitol is an optically active substance, and d-form, l-form, racemic form, and the like are present, but d-mannitol, which is abundant in nature, is suitable as an excipient.
  • sugars or sugar alcohols are preferable.
  • aqueous suspension composition of the present disclosure is dried into a solid preparation, for example, a powder preparation, a granule, a capsule or a tablet, d-mannitol, sucrose, lactose, trehalose, erythritol, etc. It preferably contains at least one excipient selected from the group consisting of mannitol and sucrose.
  • a disintegrant When the aqueous suspension composition is applied to a solid pharmaceutical composition, a disintegrant may be contained.
  • the dosage form of the pharmaceutical composition is tablets, granules, etc.
  • the inclusion of the disintegrant in the pharmaceutical composition causes the orally ingested preparation to disintegrate more quickly, resulting in a faster effect of improving solubility in the digestive tract. Can be expected to appear.
  • the disintegrant include carmellose, crospopidone, carmellose calcium, croscarmellose sodium and the like.
  • the pharmaceutical composition to which the aqueous suspension composition of the present disclosure is applied contains a lubricant, a colorant, a flavoring agent, a sweetening agent, a flavoring agent, etc. for the purpose of improving the appearance and the feel when ingested orally.
  • a lubricant include magnesium stearate, calcium stearate, talc, and sucrose fatty acid ester.
  • the colorant include edible colorants such as edible yellow No. 5 dye, edible red No. 2 dye, edible blue No. 2 dye, edible lake dye, yellow iron sesquioxide, and titanium oxide.
  • the flavoring agent include oranges, lemons, and various other orally ingestible flavors.
  • sweetener examples include aspartame, stevia, thaumatin, sodium saccharin, dipotassium glycyrrhizinate and the like.
  • flavoring agent examples include L-menthol, camphor, peppermint, sodium L-glutamate, disodium inosinate, magnesium chloride and the like.
  • the above-mentioned formulation additives may be appropriately added in an appropriate step when the aqueous suspension composition is applied to the pharmaceutical composition.
  • aqueous suspension composition [Use of aqueous suspension composition]
  • the above-mentioned aqueous suspension composition of the present disclosure can be used for various pharmaceutical compositions utilizing the medicinal properties of rebamipide.
  • the aqueous suspension composition of the present disclosure contains rebamipide, which is an active ingredient, as fine dispersed particles having an average particle diameter of 200 nm or less, and suppresses an increase in the particle size of the particles over time. Therefore, the aqueous suspension composition is used as it is for ophthalmology. It can be used as a preparation (for example, eye drops). Eye drops are also referred to as eye drops or eye drops.
  • the eye drops in the present disclosure include eye drops that can be instilled while wearing contact lenses.
  • the ophthalmic preparations in the present disclosure include eye wash agents, eye ointments (water-soluble eye ointments or oil-soluble eye ointments), contact lens wearing solutions, intraocular injections (for example, intravitreal injections), contact lens solutions. It can also be used as a preservative for excised eye tissue such as a cleaning solution, a preservative solution, or a disinfectant solution, or a multipurpose solution, or as a perfusate during surgery.
  • the "contact lens” in the present disclosure includes a hard contact lens and a soft contact lens.
  • Soft contact lenses include both ionic and nonionic, including both silicone hydrogel contact lenses and non-silicone hydrogel contact lenses.
  • the dosage form is preferably an eye drop, an eye wash, an eye ointment (water-soluble eye ointment or an oil-soluble eye ointment), a contact lens wearing solution.
  • Contact lens solution cleaning solution, preservative solution, or disinfectant solution, or multipurpose solution
  • eye drops eye wash, contact lens wearing solution, contact lens solution (cleaning solution, preservative solution, or (Disinfectant solution or multi-purpose solution) and the like can be mentioned, more preferably eye drops or eye wash, and particularly preferably eye drops.
  • the usage form of the aqueous suspension composition of the present disclosure may be a single-use unit dose, a multi-dose that can be used repeatedly, or a multi-dose that may be contained in a container for use.
  • the aqueous suspension compositions of the present disclosure may be contained (eg, filled, injected, or encapsulated) in a container.
  • the container may be a package having a portion (ie, surface) in contact with the composition (ie, formulation).
  • the container may be composed of, for example, a container main body portion for accommodating a composition (for example, a liquid composition), a portion including an extraction port of the container (nozzle, inner plug), a suction tube, a cap, and the like.
  • the material constituting the container can be selected from a wide range, and examples thereof include an example in which at least a part or all of the contact portion with the composition is made of a material selected from a metal such as plastic, glass, and aluminum. ..
  • plastics include olefin resins, styrene resins, acrylic resins, polyester resins, polycarbonate resins, fluororesins, chlorine resins such as polyvinyl chloride, polyamide resins, polyacetal resins, and modified polyphenylene ethers.
  • the container may be made of a single material or two or more kinds of materials.
  • olefin resin examples include ethylene resin [for example, polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.). Ethylene-propylene copolymer, etc.], propylene resin [for example, polypropylene (PP) (including isotactic polypropylene, syndiotactic polypropylene, atactic polypropylene, etc.), propylene-ethylene copolymer, etc.], methylpentene-based Examples include resins (eg, polymethylpentene, etc.).
  • ethylene resin for example, polyethylene (including high density polyethylene, low density polyethylene, ultra low density polyethylene, linear low density polyethylene, ultra high molecular weight polyethylene, etc.). Ethylene-propylene copolymer, etc.]
  • propylene resin for example, polypropylene (PP) (including isotactic polypropylene, syndiotactic polyprop
  • the material of the container glass, plastic, etc. are preferable. Therefore, at least a part of the container (or the material of the container) may be made of glass, plastic, or the like.
  • plastics such as olefin resin, styrene resin, and polyester resin (that is, plastic containers) are particularly preferable, and ethylene resin, propylene resin, alkylene terephthalate resin, and polystyrene are more preferable.
  • ethylene resin, propylene resin, alkylene terephthalate resin, and polystyrene are more preferable.
  • polypropylene, polyethylene terephthalate, or polystyrene is more preferable, and polyethylene terephthalate is particularly preferable.
  • aqueous suspension composition as an eye drop may further contain a known component used for an ophthalmic preparation.
  • a known component used for an ophthalmic preparation e.g., a known component used for an ophthalmic preparation.
  • optional ingredients that can be used in ophthalmic preparations will be described.
  • a known surfactant which is applicable for ophthalmology, has good biocompatibility, and is less irritating can be used without particular limitation.
  • a nonionic surfactant is preferable.
  • nonionic surfactant examples include polymers of alkylaryl polyether alcohol, for example, tyroxapole; polyoxyethylene polyoxypropylene polymer (poroxamer), for example, pluronic (trade name, BASF), rutrol (trade name, BASF); Polyoxyethylene alkylphenyl ether, for example, Triton X-100 (trade name, Dow Chemical, etc.); Polyoxyethylene fatty acid ester, for example, polyoxyethylene monostearic acid ester (also referred to as polyoxyl stearate); polyoxyethylene sorbitan fatty acid.
  • polyoxyethylene polyoxypropylene polymer for example, pluronic (trade name, BASF), rutrol (trade name, BASF)
  • Polyoxyethylene alkylphenyl ether for example, Triton X-100 (trade name, Dow Chemical, etc.)
  • Polyoxyethylene fatty acid ester for example, polyoxyethylene monostearic acid ester (also referred to as polyoxyl stearate); poly
  • Esters such as polyoxyethylene sorbitan monooleic acid ester, polyoxyethylene sorbitan monolauric acid ester, polyoxyethylene sorbitan monopalmitic acid ester and polyoxyethylene sorbitan monostearic acid ester; polyoxyethylene hydrogenated castor oil; sorbitan fatty acid ester, For example, sorbitan monooleic acid ester, sorbitan monolauric acid ester, sorbitan monopalmitic acid ester and sorbitan monostearic acid ester; polyoxyethylene bean oil, for example polyoxyl 35 bean oil; polyoxyethylene alkyl ether, for example, polyoxyethylene lauryl ether.
  • the content may be 0.005% by mass to 1.0% by mass with respect to the total mass of the aqueous suspension composition. preferable.
  • the aqueous suspension composition as an ophthalmic preparation can further contain an isotonic agent.
  • the tonicity agent include sodium chloride, glycerol (also referred to as "concentrated glycerin" as a quasi drug), glucose, mannitol, sorbitol and the like, which are commonly used in eye drops.
  • sodium chloride has excellent dispersibility when formulated, suppresses the formation of aggregates of rebamipide particles in an aqueous suspension composition, and expresses physical properties having excellent redispersibility. It is preferable as an isotonic agent because it is useful for.
  • the tonicity agent has an osmotic pressure equivalent to that of tears in an aqueous ophthalmic composition, specifically, an osmotic pressure ratio (ratio of osmotic pressure to physiological saline) of an aqueous ophthalmic preparation of 0.5 to 1. It is preferably added in an amount in the range of 5, and more preferably added in an amount in the range of 0.8 to 1.2.
  • the aqueous suspension composition as an ophthalmic formulation can further contain a buffer.
  • buffers are acetates such as sodium acetate; citrates such as sodium citrate, disodium citrate, trisodium citrate; sodium dihydrogen phosphate, disodium hydrogen phosphate, potassium dihydrogen phosphate.
  • Phosphates such as dipotassium hydrogen phosphate; ⁇ -aminocaproic acid; amino acid salts such as sodium citrate; citric acid and salts thereof; and mixtures thereof.
  • the aqueous suspension composition as an ophthalmic preparation can further contain a pH adjuster.
  • the pH adjuster may be the same as or different from the pH adjuster used for improving the dispersibility described above.
  • the pH adjuster used in ophthalmic preparations is sterilized and filtered to adjust the pH of the preparation to a pH suitable for biocompatibility, etc., and to suppress the reaggregation and recrystallization of levamipid particles during storage. At that time, it is used for the purpose of adjusting the pH so that it can easily pass through the filtration filter.
  • Examples of the pH adjuster include hydrochloric acid, citric acid, phosphoric acid, acetic acid, tartaric acid, sodium hydroxide, potassium hydroxide, sodium carbonate, sodium hydrogencarbonate and the like.
  • Ophthalmic preparations are generally preferably adjusted to a pH in the range of 3.5-10, which is less irritating to the mucous membranes of the eye, more preferably in the pH range of 3.5-7.5.
  • the pH is more preferably in the range of 4.5 to 7.0, and the pH is particularly preferably in the range of 4.5 to 6.5.
  • the pH is 3.5 or more, the chargeability of the rebamipide particles is increased, the adsorption to the filtration filter is inhibited, and the filterability is further improved.
  • the amount of rebamipide dissolved in water can be kept low, and the reaggregation and recrystallization of rebamipide particles during storage of the aqueous suspension composition can be more effectively suppressed. be able to.
  • -Chelating agent- Aqueous suspension compositions as ophthalmic formulations can contain chelating agents.
  • the chelating agent include disodium edetate, trisodium edetate, tetrasodium edetate, diethyleneamine pentaacetic acid, and mixtures thereof. Of these, disodium edetate is preferable.
  • the content of the chelating agent is preferably 0.001% by mass to 0.1% by mass with respect to the total mass of the aqueous suspension composition.
  • antioxidants include ascorbic acid; ascorbic acid salts such as sodium ascorbate; tocopherol; sodium sulfite, potassium sulfite, magnesium sulfite, calcium sulfite, sodium bisulfite, potassium bisulfite, magnesium sulfite, calcium sulfite, Examples thereof include sulfites such as sodium metabisulfite, potassium metabisulfite, calcium metabisulfite, sodium thiosulfite, and sodium hydrogensulfite.
  • Preservative- Aqueous suspension compositions as ophthalmic formulations may contain preservatives to prevent contamination by microorganisms such as fungi and bacteria.
  • preservatives include boric acid; boar sand; quaternary ammonium salts such as benzalkonium chloride and benzethonium chloride; cationic compounds such as chlorhexidine gluconate; methyl p-hydroxybenzoate, ethyl p-hydroxybenzoate, p.
  • P-Hydroxybenzoate esters such as propyl hydroxybenzoate and butyl p-hydroxybenzoate; alcohol compounds such as chlorobutanol and benzyl alcohol; sorbic acid and salts thereof; sodium dehydroacetate; thiomersal; and mixtures thereof. Be done.
  • a preservative selected from boric acid and borax is preferable from the viewpoint of less irritation to dry eye patients.
  • the quaternary ammonium salt is preferable because it suppresses the formation of aggregates of levamipide fine particles, prevents a decrease in pH, and provides a composition having excellent redispersibility and stability.
  • the content of the preservative selected from boric acid and borax is preferably in the range of 0.1% by mass to 2.5% by mass with respect to the total mass of the aqueous suspension composition of the present disclosure. It is more preferably in the range of 0.5% by mass to 2.0% by mass, and further preferably in the range of 1.0% by mass to 2.0% by mass.
  • the content of the quaternary ammonium salt as a preservative is preferably in the range of 0.001% by mass to 0.05% by mass with respect to the total mass of the aqueous suspension composition of the present disclosure, and is 0. More preferably, it is in the range of .002% by mass to 0.01% by mass.
  • Aqueous suspension compositions as ophthalmic preparations are composed of polyethylene glycol, polyvinyl alcohol (partially saponified), polyvinyl alcohol (completely saponified), carboxyvinyl polymer, etc. It can contain alginic acid, sodium chondroitin sulfate and the like. From the viewpoint of actual use as eye drops, the aqueous suspension composition preferably contains at least one selected from polyvinyl alcohol (partially saponified), carboxyvinyl polymer and polyethylene glycol.
  • the viscosity of the ophthalmic preparation is preferably in the range of 0.8 mPa ⁇ s to 200 mPa ⁇ s at a liquid temperature of 25 ° C. It is more preferably in the range of 8 mPa ⁇ s to 100 mPa ⁇ s.
  • the viscosity of the ophthalmic preparation can be measured by the method described in the 16th revision of the Japanese Pharmacopoeia.
  • ⁇ Treatment method> Another embodiment of the present disclosure is to instill the aqueous suspension composition of the present disclosure containing fine particles of rebamipide as an active ingredient into an application subject to be treated as an ophthalmic preparation, an aqueous suspension.
  • the composition can be orally administered as it is or as a solid preparation, locally administered in the body to retain rebamipide particles and sustained release of rebamipide molecules, or locally administered in the body to retain rebamipide particles and rebamipide molecules. Also includes therapeutic methods including sustained release of.
  • HPC-SSL Hydroxypropyl cellulose
  • HPC-SL Hydroxypropyl cellulose SSL
  • NISSO HPC SSL Manufacturer: Nippon Soda Corporation
  • HPC-SL Hydroxypropyl cellulose SL
  • Viscosity of 2% aqueous solution of water-soluble dispersant Each water-soluble dispersant was dissolved in water, and the viscosity of a 2% aqueous solution of the water-soluble dispersant was measured. Specifically, 200 mg of the water-soluble dispersant was dissolved in water to make the total amount 10 g, thereby obtaining a 2% aqueous solution of the water-soluble dispersant. The viscosity of a 2% aqueous solution of a water-soluble dispersant was measured using a vibrating viscometer (model name: VM-10A) manufactured by SEKONIC Corporation in an environment with an ambient temperature of 25 ° C. The results are shown in Table 1.
  • water-soluble dispersant is described by the abbreviation described in parentheses of the water-soluble dispersant.
  • polyvinylpyrrolidone K25 is described as "PVP-K25". The same applies to other water-soluble dispersants.
  • Example 1 [Preparation of aqueous suspension composition] To a 15 mL container, 500 mg of PVP-K25 as the specific dispersant 1 and 8.5 g of water were added, stirred and dissolved to obtain an aqueous solution of PVP-K25. To a 2 mL container, 100 mg of rebamipide (hereinafter, abbreviated as REB), 36 mg of the above-mentioned PVP-K25 aqueous solution and 864 mg of water were added to prepare a mixture.
  • REB rebamipide
  • Step A Using the obtained mixture as a dispersion, 3 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium were mixed, and the mixture was heated to an outside temperature of 5 ° C. For 16 hours, the mixture was treated by wet bead mill pulverization using a medium to obtain an aqueous suspension containing the pulverized REB particles. The REB content in the obtained aqueous suspension is 10 parts, and the PVP-K25 content is 0.2 parts. (Step B) The REB content, PVP-K25 (dispersant) content, and bead mill pulverization time in the obtained aqueous suspension are shown in Table 2.
  • an aqueous suspension composition used for evaluation was prepared. That is, a pH adjuster and water are added to the obtained aqueous suspension of REB particles (REB content: 10 parts), and an aqueous suspension composition containing REB particles (REB content: 2 parts, pH: 5). .5) was obtained.
  • the aqueous suspension composition was adjusted to the desired pH by appropriately selecting the types and amounts of the four types of pH adjusting agents described above and the amount of water added.
  • the particle size distribution was measured by a dynamic light scattering method using a multi-sample nanoparticle measurement system (nanoSAQLA / Auto Sampler AS50, manufactured by Otsuka Electronics Co., Ltd.) for 0.5 mL of the evaluation sample solution (Auto Sampler). Set temperature: 25 ° C).
  • the average particle size was defined as the particle size giving a cumulative distribution frequency of 50% (d50 value) of the obtained particle size distribution (analysis method: CONTIN, distribution: scattered light intensity distribution).
  • the measurement results are shown in Table 2.
  • AAA The average particle size is 100 nm or less.
  • AA The average particle size is more than 100 nm and 120 nm or less.
  • A The average particle size exceeds 120 nm and is 150 nm or less.
  • B The average particle size exceeds 150 nm and is 200 nm or less.
  • C The average particle size is more than 200 nm and 250 nm or less.
  • D The average particle size exceeds 250 nm and is 350 nm or less.
  • E The average particle size exceeds 350 nm and is 1000 nm or less.
  • F The average particle size exceeds 1000 nm.
  • rank AAA, AAA, A and B are levels that do not cause a problem in practical use, and rank AAA, AAA, and A are preferable.
  • the results of the evaluation criteria for the dispersed particles are also shown in Table 2 as "evaluation of miniaturization".
  • Examples 2 to 16 Comparative Examples 1 to 3> REB particle-containing aqueous suspension in the same manner as in Example 1 except that the content of REB, the type of specific dispersant or comparative dispersant, the content in the mixture, and the pulverization time by the wet bead mill were changed as shown in Table 2. Obtained liquid. With respect to the obtained aqueous suspension, an aqueous suspension composition was obtained in the same manner as in Example 1, and the average particle size at the start of storage and after storage at 60 ° C. for 2 weeks was measured, and further refined. The degree of was evaluated according to the above evaluation criteria. The results are shown in Table 2 below.
  • the average particle size of each of the aqueous suspension compositions (REB content: 2 parts) of Examples 1 to 16 at the start of storage (initial stage) was 200 nm or less. .. Among them, it can be seen that when the contents of REB and the specific dispersant are at the same level, an aqueous suspension composition containing fine REB particles can be obtained when polyvinylpyrrolidone (PVP) is used as the specific dispersant. .. In addition, the average particle size of the REB particles after storage at 60 ° C. for 2 weeks (after aging) was also 200 nm or less.
  • PVP polyvinylpyrrolidone
  • Example 17 [Preparation of aqueous suspension composition] To a 30 mL container, 500 mg of the specific dispersant (PVP-K25) and 8.5 g of water were added, stirred and dissolved to obtain an aqueous solution of PVP-K25. To each of 30 2 mL containers, 100 mg of rebamipide (REB), 360 mg of the above-mentioned PVP-K25 aqueous solution and 540 mg of water were added to obtain a mixture.
  • PVP-K25 specific dispersant
  • REB rebamipide
  • Step A Using each of the obtained mixtures as a dispersion, 3 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium are mixed, and the mixture is heated to the outside temperature. The treatment was carried out by wet bead mill pulverization using a medium at 5 ° C. for 8 hours. The aqueous suspension containing the crushed REB particles obtained in each of the 30 2 mL containers was put into one container, mixed, and the aqueous suspension composition containing the REB particles (REB content: 10). Part, PVP-K25 content: 2 parts) was obtained.
  • Step B Next, with respect to 600 mg of the obtained aqueous suspension composition (REB content: 10 parts) containing REB particles, PVP-K25 18 mg as a dispersion stabilizer, mannitol 135 mg as an isotonic agent, and pH adjustment The agent and water were added to obtain 3 g (REB content: 2 parts, pH: 5.0) of an aqueous suspension composition containing REB particles.
  • Step C and Step D
  • Examples 18 to 43> The content of REB, the specific dispersant used, the type and content of the water-soluble dispersant as the dispersion stabilizer added in step D, the content in the mixture, the type and content of the tonicity agent, and the step C REB particle-containing aqueous suspension composition (REB content: 2 parts, pH: 4) in the same manner as in Example 17, except that at least one of the pH values adjusted by the pH adjuster was changed. .4 to 5.6: as shown in Table 3).
  • the average particle size at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.) was measured in the same manner as in Example 1, and further. The miniaturization of particles was evaluated. The results are shown in Table 3 below.
  • aqueous suspension compositions of Examples 26 to 32 used have the same level of stability during storage as compared with the aqueous suspension composition of Example 36, which is at the same level except for the addition or absence of the dispersion stabilizer. A better aqueous suspension composition was obtained.
  • aqueous solution of PVP-K25 was obtained by adding 800 mg of PVP-K25 and 17.2 g of water as a specific dispersant to a 30 mL container, stirring and dissolving the mixture.
  • rebamipide REB
  • the total amount of the PVP-K25 aqueous solution obtained above and 18.0 g of water were added to obtain a mixture.
  • Step A 240 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium were mixed with the obtained mixture.
  • a stirring disk was connected to a bead mill device (batch type ready mill, vertical bead mill “RMB”, IMEX), and a 100 mL vessel containing a mixture and media was crushed at a rotation speed of 1500 rpm while cooling with cooling water at 7 ° C. Treatment was performed by wet bead mill pulverization under the condition of time of 2 hours to obtain an aqueous suspension composition (REB content: 10 parts) containing the pulverized REB particles.
  • a bead mill device batch type ready mill, vertical bead mill "RMB”, IMEX
  • Step B Next, in a 110 mL container, 20 g of the aqueous suspension composition (REB content: 10 parts) containing the REB particles obtained above, 300 mg of MC-SM4 as a dispersion stabilizer, and mannitol 4 as an isotonic agent. .50 g, pH adjuster and water added, 100 g of aqueous suspension composition containing REB particles (REB content: 2 parts, PVP-K25 content: 0.4 parts, MC-SM4 content: 0.3 Part, pH: 5.5) was obtained. (Step C and Step D)
  • the filter used for filtration was a Merck polyether sulfone filter (PES / Merck) [trade name: Merck Millipore Express (registered trademark) SHF, pore diameter: 0.2 ⁇ m] (indicated as “PES / Merck” in the table). Is.
  • the filterability was evaluated based on the following criteria based on the amount of filtered passage.
  • ranks "A" and "B” are levels at which there is no practical problem, and it is preferable that the rank is "A”.
  • -Evaluation criteria - A: Passes the whole amount B: Passes 50g or more but does not pass the whole amount and blocks in the middle C: The passing amount is less than 50g and blocks in the middle
  • Example 44 The measurement of the average particle size of the REB particles and the evaluation of the particle size in the obtained aqueous suspension composition were carried out in the same manner as in Example 1.
  • Example 44 in addition to the storage start (initial), after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.), a storage test (60 ° C. 2) up to 60 ° C. for 2 months, which is a more severe condition (Months later) was also done. The results are shown in Table 4 below.
  • Examples 45 to 47 REB aqueous suspension (REB content: 2 parts, pH: 5.5) in the same manner as in Example 44, except that the pulverization time and the bead diameter of the media used for wet bead mill pulverization were changed as shown in Table 4.
  • Got The average particle size of the obtained aqueous suspension composition containing REB particles was measured at the start of storage, after storage at 60 ° C. for 2 weeks, and after storage at 60 ° C. for 2 months in the same manner as in Example 44. The results are shown in Table 4 below.
  • aqueous suspension composition An aqueous solution of PVP-K25 was obtained by adding 1.75 g of the specific dispersant PVP-K25) and 77.0 g of water to each of four 100 mL containers, stirring and dissolving the mixture. 8.75 g of rebamipide (REB) was added to each container and stirred. All the mixed solutions in these four containers were put into a 1 L container to obtain a mixture.
  • Step A Using the obtained mixture as a dispersion, zirconia beads having a diameter of 0.1 mm as a medium were placed in a crushing chamber (volume 170 mL) of a bead mill device (continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.). (Apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) While filling a 1 L container containing 510 g and containing the object to be dispersed with cooling water at 7 ° C, 140 g / min in the crushing chamber.
  • a crushing chamber volume 170 mL
  • a bead mill device continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.
  • Step B Next, in a 110 mL container, 20 g of the obtained aqueous suspension composition (REB content: 10 parts) containing REB particles, 300 mg of MC-SM4 as a dispersion stabilizer, and mannitol as an isotonic agent.
  • Step C and Step D Further, in the same operation as in Example 44, using a PALL-made polyether sulfone filter (PES / PALL) [trade name: Super® EX ECV, pore diameter: 0.2 ⁇ m]. Pressurization filtration was performed to obtain a filtered liquid (passing the entire amount).
  • PES / PALL polyether sulfone filter
  • Example 48 the aqueous suspension composition was produced on a larger scale than in Example 1.
  • the aqueous suspension composition obtained in Example 48 was evaluated by the evaluation method shown below.
  • the particle size distribution was measured by a dynamic light scattering method using a concentrated particle size analyzer (FPAR-1000AS, manufactured by Otsuka Electronics Co., Ltd.) for 2 mL of the evaluation sample solution (autosampler set temperature: 25 ° C.). ).
  • the average particle size was defined as the particle size giving a cumulative distribution frequency of 50% (d50 value) of the obtained particle size distribution (analysis method: CONTIN, distribution: scattered light intensity distribution). The results are shown in Table 5.
  • the average particle size of REB particles at the start of storage, after storage at 60 ° C. for 1 week, and after storage at 60 ° C. for 1 month was determined in the same manner as in Example 48. It was measured. The results are shown in Table 5 below.
  • aqueous suspension composition An aqueous solution of MC-SM4 was obtained by adding 1.16 g of a water-soluble dispersant (MC-SM4) and 87.17 g of water to each of three 100 mL containers, stirring and dissolving the mixture. 11.67 g of rebamipide (REB) was added to each container and stirred. The liquid composition and 50 g of water in these three containers were all put into a 1 L container to obtain a mixture.
  • MC-SM4 water-soluble dispersant
  • REB rebamipide
  • Step A Using the obtained mixture as a dispersion, zirconia beads having a diameter of 0.1 mm as a medium were placed in a crushing chamber (volume 170 mL) of a bead mill device (continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.). (Apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) While filling a 1 L container containing 510 g and containing the object to be dispersed with cooling water at 7 ° C, 140 g / min in the crushing chamber.
  • a crushing chamber volume 170 mL
  • a bead mill device continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.
  • REB content: 10 parts was obtained.
  • Step B Next, 20 g of an aqueous suspension composition (REB content: 10 parts) containing REB particles, 4.50 g of mannitol as an isotonic agent, a pH adjuster and water are added to a 110 mL container, and the REB particles are contained. 100 g of an aqueous suspension composition was obtained.
  • Step C and Step D For the obtained aqueous suspension, the average particle size was measured at the start of storage, after storage at 60 ° C. for 1 week, and after storage at 60 ° C. for 1 month in the same manner as in Example 48, and the fineness of the particles was evaluated. did. The results are shown in Table 5 below.
  • Examples 52 to 53 An aqueous suspension composition (REB content: 2 parts, pH: 5.5 or 6.0: as described in Table 5) was obtained in the same manner as in Example 51 except that the pH adjustment value was changed. .. The average particle size of the obtained aqueous suspension composition was measured at the start of storage, after storage at 60 ° C. for 1 week, and after storage at 60 ° C. for 1 month in the same manner as in Example 51, and the particles were made finer. Was evaluated. The results are shown in Table 5 below.
  • the average particle diameter of each of the aqueous suspension compositions (REB content: 2 parts) containing the REB particles of Examples 48 to 53 was 200 nm or less.
  • the average particle size after storage at 60 ° C. for 1 week and after storage at 60 ° C. for 1 month was also 200 nm or less. Therefore, the aqueous suspension compositions of Examples 48 to 53, which have been scaled up during production, have the dispersibility of REB particles in both the case where the step D is performed and the case where the step D is not performed. And it can be seen that the dispersion stability is good.
  • Example 51 to 53 in which Step B was carried out in the presence of methylcellulose (MC) as a specific dispersant the average particle size of the rebamipide particles was 150 nm or less after storage, and the dispersion was excellent. Showed stability. According to the production methods of Examples 48 to 50, which contained polyvinylpyrrolidone (PVP) in step B and methylcellulose (MC) as a dispersion stabilizer in step D, the stability during storage was better. It can be seen that an aqueous suspension composition is obtained.
  • PVP polyvinylpyrrolidone
  • Example 54 [Preparation of aqueous suspension composition] To a 30 mL container, 500 mg of a water-soluble dispersant (PVP-K25) and 8.5 g of water were added, and the mixture was stirred and dissolved to obtain an aqueous PVP-K25 solution. To each of 30 2 mL containers, 100 mg of rebamipide (REB), 360 mg of the PVP-K25 aqueous solution obtained above and 540 mg of water were added to obtain a mixture.
  • PVP-K25 water-soluble dispersant
  • REB rebamipide
  • Step A Using the obtained mixture as a dispersion, 3 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium were mixed, and the mixture was heated to an outside temperature of 5 ° C. Was treated by wet bead mill pulverization using a medium for 8 hours. The aqueous suspension composition containing REB particles in all the crushed containers is mixed into one, and the aqueous suspension composition containing REB particles (REB content: 10 parts, PVP-K25 content: 2 parts) is mixed. ) Was obtained.
  • Step B Next, 20 g of the obtained aqueous suspension composition (REB content: 10 parts), a pH adjuster and water were added to a 110 mL container, and the aqueous suspension composition containing REB particles (100 g, REB content: REB content: Two parts, pH: 4.5) were obtained. (Step C)
  • the average particle size and the dispersibility of REB particles of the obtained aqueous suspension composition were evaluated in the same manner as in Example 1.
  • the particle diameter giving the cumulative distribution frequency of 50% (d50 value) and the cumulative distribution frequency of 90% (d90 value) of the particle size distribution was defined as the particle size.
  • the results are shown in Table 6.
  • Example 55 to 59 Example 54-B, Example 56-B, Example 58-B, Comparative Example 4> An aqueous suspension composition containing REB particles (REB content:: Two parts, pH: 4.5-6.0: as described in Table 6) were obtained.
  • REB aqueous suspension the filter was changed to the filter shown in Table 6, and the filtration passage amount and the filterability were evaluated in the same manner as in Example 54, respectively.
  • the results are shown in Table 6 below.
  • Example 54-B is an example in which the amount of the aqueous suspension composition having the same formulation as that of Example 54 was evaluated by using different filters, and Examples 56 and 56-B, and Examples Example 58 and Example 58-B also show different evaluation results with different filters.
  • an aqueous suspension composition (REB) containing REB particles of Examples 54 to 59 having a cumulative 90% particle size of less than 200 nm in addition to the average particle size (cumulative 50% particle size). Content: 2 parts) was filtered through 50 g or more regardless of the type of filter. For example, from the comparison between Example 54 and Example 54-B, it can be seen that the amount of filtration through may be improved by changing the filter used for filtration. From the evaluation results of the aqueous suspension compositions of Examples 54, 55, 56 and 57, the pH value was adjusted from 4.5 to 5.1, 5.5, and 6.0.
  • Example 55 By changing each of them, the amount of passing through the filtration was improved, and in Example 55, Example 56 and Example 57, the entire amount of the filter for sterilization could be passed from the passing amount of 64 g in Example 54. From this, it can be seen that adjusting the pH of the aqueous suspension composition obtained in step C is also effective for further improving the dispersibility and dispersion stability of the REB particles.
  • aqueous solution of PVP-K25 was obtained by adding 200 mg of PVP-K25 and 8.80 g of water, which are specific dispersants, to a 15 mL container and dissolving the mixture with stirring. To a 2 mL container, 100 mg of rebamipide (REB) and 900 mg of the PVP-K25 aqueous solution obtained above were added to obtain a mixture.
  • REB rebamipide
  • Step A 1.5 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium is mixed with the obtained mixture, and the mixture is heated at an outside temperature of 5 ° C. Treatment was performed by wet bead mill pulverization using a medium for 16 hours to obtain a pulverized REB aqueous suspension.
  • the REB content in the obtained aqueous suspension is 10 parts by weight, and the PVP-K25 content is 2 parts by weight.
  • Example 61-Example 63 REB particle-containing aqueous suspension composition (REB content: 2 parts, pH: 5) in the same manner as in Example 60 except that the content of REB, the content of the specific dispersant and the content of zirconia beads were changed. .5) was obtained. With respect to the obtained aqueous suspension composition, the average particle size at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.) was measured in the same manner as in Example 1, and further. The miniaturization of particles was evaluated. The results are shown in Table 7.
  • Table 7 also shows the evaluation results of Example 29 in which the content of zirconia beads is 30 times the amount of REB particles.
  • the aqueous suspension composition (REB content: 2 parts, PVP-K25 content: 0.4 parts, MC-SM4 content: 0.3 parts) obtained in Example 29 was diluted with water and REB.
  • the content of the particles is 2% by mass, the level is the same as that of the aqueous suspension composition obtained in Example 60.
  • aqueous solution of PVP-K25 was obtained by adding 500 mg of PVP-K25 and 9.50 g of water, which are specific dispersants, to a 15 mL container and dissolving the mixture with stirring.
  • a mixture was obtained by adding 50 mg of rebamipide (REB), 200 mg of the above-mentioned PVP-K25 aqueous solution and 750 mg of water to each of two 2 mL containers.
  • REB rebamipide
  • Step A To the obtained mixture, 3.0 g of zirconia beads (apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) having a diameter of 0.1 mm as a medium was mixed, and the mixture was heated at an outside temperature of 5 ° C. The treatment was carried out by wet bead mill pulverization using a medium for 16 hours. The aqueous suspension containing the crushed REB particles obtained in each of the two 2 mL containers was put into one container, mixed, and the aqueous suspension composition containing the REB particles (REB content: 5). Part, PVP-K25 content: 1 part) was obtained.
  • Example 65 to Example 67 REB particle-containing aqueous suspension composition (REB content) in the same manner as in Example 64 except that the content of REB, the type and content of the specific dispersant, or the type and content of the dispersion stabilizer were changed. : 2 parts, pH: 5.5) was obtained. With respect to the obtained aqueous suspension composition, the average particle size at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.) was measured in the same manner as in Example 1, and further. The miniaturization of particles was evaluated. The results are shown in Table 8.
  • aqueous suspension compositions of Examples 64 to 67 had an average particle size of 200 nm or less at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after aging). It was. Among them, the aqueous suspension compositions of Examples 64 and 65 containing polyvinylpyrrolidone (PVP) in step B and methylcellulose (MC) in step D had a REB content of 3% in step B. And even in the case of 5%, it can be seen that an aqueous suspension composition having better stability during storage can be obtained.
  • PVP polyvinylpyrrolidone
  • MC methylcellulose
  • Example 68 A REB particle-containing aqueous suspension composition (REB content: 2 parts, pH: 5.5) was obtained in the same manner as in Example 29 except that the diameter of the zirconia beads used for pulverization was changed in step B. .. With respect to the obtained aqueous suspension composition, the average particle size at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.) was measured in the same manner as in Example 29, and further. The miniaturization of particles was evaluated. The results are shown in Table 9. As a control example, the evaluation results of Example 29 having a zirconia bead diameter of 0.1 mm are also shown in Table 9.
  • Example 68 and Example 69 both had an average particle size of 200 nm or less at the start of storage (initial stage) and after storage at 60 ° C. for 2 weeks (after aging). It was. From the comparison between Example 29 and Examples 68 and 69, in the range of bead diameters in the range of 0.1 mm to 0.5 mm, by using beads having a smaller diameter, the average particle size after pulverization is smaller in water. There was a tendency to obtain suspension compositions.
  • aqueous suspension composition An aqueous solution of PVP-K25 was obtained by adding 1.75 g of PVP-K25 and 77.0 g of water, which are specific dispersants, to each of four 100 mL containers, stirring and dissolving the mixture. 8.75 g of rebamipide (REB) was added to each container and stirred. All the mixed solutions in these four containers were put into a 1 L container to obtain a mixture.
  • REB rebamipide
  • Step A Using the obtained mixture as a dispersion, zirconia beads having a diameter of 0.1 mm as a medium were placed in a crushing chamber (volume 170 mL) of a bead mill device (continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.). (Apparent density: 6 g / cm 3 , packing density: 3.7 kg / l) While filling a 1 L container containing 510 g and containing the object to be dispersed with cooling water at 7 ° C, 140 g / min in the crushing chamber.
  • a crushing chamber volume 170 mL
  • a bead mill device continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.
  • Step B Next, in a 110 mL container, 20 g of the obtained aqueous suspension composition (REB content: 10 parts) containing REB particles, 300 mg of MC-SM4 as a dispersion stabilizer, and boric acid as a preservative (Fujifilm). Wako Pure Chemical Industries, Ltd.) 1.75 g, a pH adjuster and water were added to obtain an aqueous suspension composition containing REB particles (100 g, REB content: 2 parts, pH: 5.0).
  • the obtained aqueous suspension composition was subjected to storage at the start (initial stage), after storage at 60 ° C. for 1 week (60 ° C. for 1 week), after storage at 60 ° C. for 2 weeks (after 60 ° C. for 2 weeks), and at 60 ° C.
  • the average particle size after storage for 4 weeks (after 4 weeks at 60 ° C.) was measured, and further, the fineness of the particles was evaluated. The results are shown in Table 10.
  • Example 71 to Example 76 The REB particle-containing aqueous suspension composition (REB content: 2) was the same as in Example 70 except that the boric acid content and the pH value of the aqueous suspension composition were changed to the values shown in Table 10. Part, pH: 5.5 to 6.5) was obtained.
  • the obtained aqueous suspension composition was stored at the start of storage (initial stage), after storage at 60 ° C. for 1 week (after 1 week at 60 ° C.), after storage at 60 ° C. for 2 weeks (after 2 weeks at 60 ° C.), and at 60 ° C.
  • the average particle size after storage for 4 weeks (after 4 weeks at 60 ° C.) was measured, and further, the fineness of the particles was evaluated. The results are shown in Table 10.
  • aqueous suspension composition An aqueous solution of MC-SM4 was obtained by adding 0.88 g of MC-SM4 and 77.87 g of water, which are specific dispersants, to each of four 100 mL containers, stirring and dissolving the mixture. 8.75 g of rebamipide (REB) was added to each container and stirred. All the mixed solutions in these four containers were put into a 1 L container to obtain a mixture.
  • REB rebamipide
  • Step A Using the obtained mixture as a dispersion, zirconia beads having a diameter of 0.1 mm as a medium were placed in a crushing chamber (volume 170 mL) of a bead mill device (continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.). (Apparent density: 6 g / cm 3 , filling density: 3.7 kg / l) While filling a 1 L container containing 510 g and containing the object to be dispersed with cooling water at 7 ° C., 140 g / min in the crushing chamber.
  • a crushing chamber volume 170 mL
  • a bead mill device continuous circulation type, horizontal bead mill "LMZ", Ashizawa Finetech Co., Ltd.
  • Step B Next, in a 110 mL container, 20 g of the obtained aqueous suspension composition (REB content: 10 parts) containing REB particles, boric acid as a preservative (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.) 1.75 g, pH A regulator and water were added to obtain an aqueous suspension composition containing REB particles (100 g, REB content: 2 parts, pH: 5.5).
  • REB content 10 parts
  • boric acid as a preservative manufactured by Fujifilm Wako Pure Chemical Industries, Ltd.
  • the obtained aqueous suspension composition was subjected to storage at the start (initial stage), after storage at 60 ° C. for 1 week (60 ° C. for 1 week), after storage at 60 ° C. for 2 weeks (after 60 ° C. for 2 weeks), and at 60 ° C.
  • the average particle size after storage for 4 weeks (after 4 weeks at 60 ° C.) was measured, and further, the fineness of the particles was evaluated. The results are shown in Table 10.

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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Ophthalmology & Optometry (AREA)
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Abstract

L'invention concerne un procédé de production d'une composition de suspension aqueuse et la composition de suspension aqueuse, le procédé comprenant une étape A de préparation d'un mélange contenant au moins un élément choisi parmi le rébamipide et un sel de celui-ci ; un dispersant soluble dans l'eau ayant une viscosité à 25 °C, en tant que solution aqueuse à 2 % en masse, inférieure ou égale à 15 mPa·s, et de l'eau, et une étape B de pulvérisation du mélange obtenu par broyage à billes humides, le diamètre de particule moyen des particules dudit élément choisi parmi le rébamipide et un sel de celui-ci étant d'au moins 200 nm.
PCT/JP2020/014676 2019-03-29 2020-03-30 Procédé de production d'une composition de suspension aqueuse et composition de suspension aqueuse WO2020204001A1 (fr)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS523355B2 (fr) * 1970-06-26 1977-01-27
WO2005009474A1 (fr) * 2003-07-24 2005-02-03 Shionogi & Co., Ltd. Agent pharmaceutique sec pour sirop, difficilement soluble dans l'eau
WO2016140219A1 (fr) * 2015-03-02 2016-09-09 武田薬品工業株式会社 Suspension ou composition contenant des nanocristaux et son procédé de production
JP2019077644A (ja) * 2017-10-25 2019-05-23 富士フイルム株式会社 医薬組成物及び医薬組成物の製造方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS523355B2 (fr) * 1970-06-26 1977-01-27
WO2005009474A1 (fr) * 2003-07-24 2005-02-03 Shionogi & Co., Ltd. Agent pharmaceutique sec pour sirop, difficilement soluble dans l'eau
WO2016140219A1 (fr) * 2015-03-02 2016-09-09 武田薬品工業株式会社 Suspension ou composition contenant des nanocristaux et son procédé de production
JP2019077644A (ja) * 2017-10-25 2019-05-23 富士フイルム株式会社 医薬組成物及び医薬組成物の製造方法

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HANAWA,TAKEHISA: "Development and characterization of the spray for oral cavity containing micronized rebamipide", ADVANCES IN PHARMACEUTICAL SCIENCES, vol. 29, 2013, pages 77 - 81 *
KAWANO, Y. ET AL.: "Development and characterization of a suspension containing nanoparticulated rebamipide for a mouth wash for stomatitis.", J.PHARM.SCI.TECHNOL.JPN., vol. 77, no. 2, 2017, pages 104 - 115, XP055746416 *
KAWANO, Y. ET AL.: "Development of Hospital Formulations Based on Medical Need.", YAKUGAKU ZASSHI, vol. 139, no. 10, October 2019 (2019-10-01), pages 1275 - 1280, XP055746449 *
NAGAI, N. ET AL.: "Size effect of rebamipide ophthalmic nanodispersions on its therapeutic efficacy for corneal wound healing.", EXPERIMENTAL EYE RESEARCH, vol. 151, 2016, pages 47 - 53, XP029749500, DOI: 10.1016/j.exer.2016.07.003 *
NAGAI, NORIAKI, SAKAMOTO RYUSUKE, YAMAMOTO SEIJI, DEGUCHI SAORI, OTAKE HIROKO, TANINO TADATOSHI: "Solid Nanocrystals of Rebamipide Promote Recovery from Indomethacin-Induced Gastrointestinal Bleeding.", INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, vol. 20, no. 20, October 2019 (2019-10-01), pages 1 - 14, XP055746434, DOI: 10.3390/ijms20204990 *

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