WO2017119506A1 - Particules et préparation pharmaceutique - Google Patents

Particules et préparation pharmaceutique Download PDF

Info

Publication number
WO2017119506A1
WO2017119506A1 PCT/JP2017/000333 JP2017000333W WO2017119506A1 WO 2017119506 A1 WO2017119506 A1 WO 2017119506A1 JP 2017000333 W JP2017000333 W JP 2017000333W WO 2017119506 A1 WO2017119506 A1 WO 2017119506A1
Authority
WO
WIPO (PCT)
Prior art keywords
scattering
particles
active ingredient
surfactant
acid
Prior art date
Application number
PCT/JP2017/000333
Other languages
English (en)
Japanese (ja)
Inventor
大地 川村
松本　泉
隆之 赤峰
紗織 利根
和志 伊藤
阿部　佳子
Original Assignee
積水化学工業株式会社
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 積水化学工業株式会社 filed Critical 積水化学工業株式会社
Priority to JP2017560445A priority Critical patent/JPWO2017119506A1/ja
Publication of WO2017119506A1 publication Critical patent/WO2017119506A1/fr

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/02—Cosmetics or similar toiletry preparations characterised by special physical form
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles

Definitions

  • the present invention relates to particles containing active ingredients and preparations containing the same.
  • Patent Documents 1 and 2 a preparation using particles (active ingredient-containing particles) formed by combining a phase containing a hydrophilic active ingredient and a phase containing a surfactant to form an aggregate, so-called S / O (Solid in Oil) formulation has been reported.
  • S / O Solid in Oil
  • the inventors of the present invention have been analyzing the active ingredient-containing particles, and found that even when the active ingredient is made into particles with a surfactant, the absorbability may not be improved or the absorbability may be decreased. It was.
  • an object of the present invention is to provide active ingredient-containing particles having a higher absorbability of active ingredients into the body.
  • the present inventors have found that the cohesiveness of the active ingredient in the active ingredient-containing particles varies from particle to particle, and further, this cohesiveness is related to the absorption into the body. I found out. Furthermore, as a result of further research, we found an aggregating parameter (aggregation index) associated with the absorption in the body, and found that if it is within a certain range, the absorption in the body can be further increased. .
  • the present invention has been completed through further trial and error based on this finding, and includes the following aspects.
  • Item 1 Particles comprising a first fraction containing an active ingredient and a second fraction containing a surfactant, wherein the cohesiveness index X represented by the following formula (1) is 30 or less.
  • S 1 represents the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of the particles.
  • Sr 1 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the particles.
  • S 0 represents the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • Sr 0 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • Item 2. The particle according to Item 1, wherein a part or all of the surface of the first fraction is covered with the second fraction.
  • Item 3. Item 3.
  • Item 4. Item 4. The particle according to any one of Items 1 to 3, wherein the active ingredient has an octanol water partition coefficient of -2 to 6.
  • Item 5. A preparation comprising the particle according to any one of Items 1 to 4.
  • Item 6. Item 6.
  • Item 7. Item 7.
  • Item 8. Item 7.
  • a cosmetic comprising the preparation according to item 5 or 6.
  • FIG. 1A shows a typical scattering profile of an active ingredient-containing particle and a surfactant
  • FIG. 1B shows a scattering profile obtained by normalizing the scattering profile.
  • the downward arrow indicates the point where the change in the scattering intensity I starts from increasing to decreasing.
  • the horizontal axis represents the magnitude of the scattering vector q [nm ⁇ 1 ], and the vertical axis (common logarithmic axis) represents the scattering intensity I.
  • FIG. 2 shows the normalized scattering profile of the particles of Examples 1 to 3 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 3 shows the normalized scattering profile of the particles of Examples 4 to 6 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 4 shows the normalized scattering profiles of the particles of Examples 7 to 9 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 3 shows the normalized scattering profile of the particles of Examples 4 to 6 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 4 shows the normalized scattering profiles of the particles of Examples 7 to 9 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 3 shows the normalized scattering profile of the particles of Examples 4 to 6 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 5 shows the normalized scattering profiles of the particles of Examples 10 to 12 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 6 shows normalized scattering profiles of the particles of Examples 13 to 15 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 7 shows the normalized scattering profile of the particles of Comparative Examples 1 and 2 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 8 shows the normalized scattering profile of the particles of Comparative Examples 3 to 5 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 9 shows the normalized scattering profiles of the particles of Comparative Examples 6 to 8 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 10 shows the normalized scattering profiles of the particles of Example 19 and Comparative Examples 9 to 10 and sucrose erucic acid ester (ER-290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 9 shows the normalized scattering profiles of the particles of Comparative Examples 6 to 8 and sucrose erucic acid ester (ER290) obtained by the small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 10 shows the normalized scattering profiles of the particles of Example 19 and Comparative Examples 9 to 10 and sucrose erucic acid ester (ER-290)
  • FIG. 11 shows the normalized scattering profile of the particles of Examples 20 to 21 and sucrose oleate (O-170) obtained by small-angle X-ray scattering analysis of Test Example 1.
  • FIG. 12 shows the normalized scattering profiles of the particles of Examples 16 to 18 and Examples 22 to 24 and oleic acid diethanolamide (Stahome DOS) obtained by the small angle X-ray scattering analysis of Test Example 1.
  • FIG. 13 is a simplified diagram of the drug skin permeation test cell used in Test Example 2.
  • absorbability to the body
  • skin permeability skin permeability
  • absorption through the skin for example, eye drops
  • nasal, intravaginal rectal
  • absorption via internal (suppository) subcutaneous, intradermal, intramuscular
  • the particles of the present invention include at least two fractions: a first fraction containing an active ingredient and a second fraction containing a surfactant.
  • the first fraction and the second fraction may be combined with each other (preferably by intermolecular force) to form an aggregate.
  • grains which have such a structure may be shown as "active ingredient containing particle
  • 30% or more of the surface of the first fraction preferably 50% or more, more preferably 70% or more, still more preferably 85% or more, still more preferably 95% or more, particularly preferably 99% or more is the second fraction. It is desirable to be directly or indirectly coated with the fraction.
  • S 1 represents the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of the active ingredient-containing particles.
  • Sr 1 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the active ingredient-containing particles.
  • S 0 indicates the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • Sr 0 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • the scattering profile is obtained by irradiating a sample (a sample made of active ingredient-containing particles or a sample made of a surfactant) with X-rays and detecting the position and intensity of the scattered X-rays with a detector. Based on this, it is a two-dimensional graph obtained by plotting the scattering intensity I (q) against the scattering vector q. Typically, it is a two-dimensional graph in which the horizontal axis (common logarithmic axis) represents the magnitude of the scattering vector q [nm ⁇ 1 ], and the vertical axis (common logarithmic axis) represents the scattering intensity I.
  • FIG. 1 (a) shows typical scattering profiles of a sample composed of particles containing active ingredients and a sample composed of a surfactant.
  • the X-ray source is not particularly limited, and synchrotron radiation X-rays and rotating Cu cathode characteristic X-rays can be used. Of these, synchrotron radiation X-rays are preferably used.
  • synchrotron radiation is light emitted synchrotron along with electron synchrotron.
  • Synchrotron radiation includes electromagnetic waves of various wavelengths having characteristics such as monochromatic, high luminance, and high directivity, and the X-ray region also includes monochromatic, high luminance, and high directivity X-rays. . For this reason, by using this X-ray, it is possible to acquire a scattering profile including more information than when using a normal X-ray using an X-ray tube or the like.
  • synchrotron radiation includes, for example, SPring-8 of the High Brightness Optical Science Research Center, PF ring of the High Energy Accelerator Research Organization, UVSOR of the Molecular Science Research Institute, HiSOR of the Hiroshima University Synchrotron Radiation Research Center, etc. It can be used in synchrotron radiation facilities.
  • Detection and data analysis can be performed using an apparatus generally used in the small-angle X-ray scattering method.
  • the maximum value of the scattering intensity is the point at which the change in the scattering intensity I starts from increasing to decreasing when the scattering profile I changes from the smaller side of the scattering vector q in the scattering profile (in FIG. 1, the downward arrow indicates The scattering intensity I at the point indicated).
  • the maximum value usually appears when the scattering vector q is 1.0 [nm ⁇ 1 ] or more.
  • the maximum value is preferably a maximum value within the range of the scattering vector q of 1.0 to 3.0 [nm ⁇ 1 ] from the viewpoint that the effects of the present invention can be more reliably exhibited.
  • a specific peak indicating a crystalline state appears in a relatively high angle region (for example, q ⁇ 4.0 [nm ⁇ 1 ]), but this peak is included in the above maximum value. Not.
  • the surfactant constituting the active ingredient-containing particles of the “scattering profile to be obtained” may be different from the surfactant, but is preferably the same from the viewpoint that the effects of the present invention can be more reliably exhibited. That is, when the former surfactant is surfactant A, the latter surfactant is also preferably surfactant A.
  • the cohesiveness index X is a value obtained by dividing the scattering profile of the active ingredient-containing particles and the scattering profile of the surfactant (FIG. 1 (a)) with the value of the scattering intensity I so that the maximum value of both is the same value ( ⁇ ).
  • Normalized scattering profile (FIG. 1 (b) (when ⁇ 1) obtained by correction (that is, [ ⁇ / maximum value of scattering intensity] multiplied by scattering intensity in each scattering vector)
  • the lower limit of the cohesiveness index X is not particularly limited, and is 0.1, for example. From the viewpoint that the effects of the present invention can be more reliably exhibited, the lower limit of the cohesiveness index X is preferably 0.2, more preferably 0.4, and still more preferably 0.6.
  • the upper limit of the cohesiveness index X is not particularly limited as long as it is 30 or less. From the viewpoint that the effects of the present invention can be more reliably exhibited, the upper limit of the cohesiveness index X is preferably 30, more preferably 25, and even more preferably 22.
  • the cohesiveness index X can be obtained by increasing the weight ratio of active ingredient to surfactant (active ingredient weight: surfactant weight) or reducing the molecular weight of the surfactant, for example. Can be reduced.
  • the active ingredient is preferably amorphous.
  • the shape retention of the particles can be further enhanced, so that leakage of the active ingredient can be further suppressed, and as a result, even higher absorbability can be exhibited.
  • a specific sharp peak indicating a crystalline state appears in a relatively high angle region (for example, q ⁇ 4.0) of the scattering profile. It is preferable that it does not appear in.
  • the number average particle diameter of the particles of the present invention is not particularly limited.
  • the number average particle diameter is, for example, 1 nm to 500 nm, preferably 1 nm to 100 nm, more preferably 1 nm to 50 nm.
  • the shape of the particles is not particularly limited. Examples of the shape include a spherical shape, a rod shape, a cubic shape, a lens shape, and a sea urchin shape.
  • the number average particle diameter of the particles is a number average diameter calculated by a dynamic light scattering method when a solvent (for example, squalane or the like) is dispersed.
  • a solvent for example, squalane or the like
  • the water content of the particles is preferably 20% by weight or less, more preferably 10% by weight or less, even more preferably 5% by weight or less, still more preferably 1% by weight or less, and particularly preferably the particles are substantially water. Does not contain. That is, the particles of the present invention are different from the particles in the W / O emulsion.
  • the first fraction is preferably a solid.
  • the stability in the base mentioned later improves further. Therefore, a formulation having an S / O (Solid in Oil) type structure can be formed by dispersing the particles in a base phase that is an oil phase.
  • the first fraction contains at least an active ingredient.
  • the active ingredient is not particularly limited as long as it is a physiologically active ingredient.
  • it is a component blended for the purpose of exerting its physiological activity.
  • those having physiological activity but not blended for the purpose of exerting the physiological activity are not included in the active ingredient from the viewpoint of blending amount, blending method and the like.
  • blended as an active ingredient in a pharmaceutical, cosmetics etc. is mentioned, for example. Since many active ingredients of pharmaceuticals and cosmetics are organic substances, the active ingredients may be organic substances.
  • any of those requiring a systemic action and those requiring a local action can be used.
  • the active ingredient included in the pharmaceutical are not particularly limited, for example, dementia therapeutics, antiepileptic drugs, antidepressants, antiparkinsonian drugs, antiallergic drugs, anticancer drugs, diabetes therapeutic drugs, antihypertensive drugs, Examples thereof include ED therapeutic agents, skin disease agents, local anesthetics, peptide drugs, and pharmaceutically acceptable salts thereof.
  • the pharmaceutically acceptable salt is not particularly limited, and any of an acidic salt and a basic salt can be employed.
  • acid salts include inorganic acid salts such as hydrochloride, hydrobromide, sulfate, nitrate, and phosphate, acetate, propionate, tartrate, fumarate, maleate, apple Organic acid salts such as acid salts, citrate salts, methanesulfonate salts, benzenesulfonate salts, and paratoluenesulfonate salts.
  • Examples of basic salts include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt and magnesium salt.
  • salt of the active ingredient examples include memantine hydrochloride, donepezil hydrochloride, rivastigmine tartrate, galantamine hydrobromide, clomipramine hydrochloride, diphenhydramine hydrochloride, nalfurafine hydrochloride, metoprolol tartrate, fesoterodine fumarate, rudenafil Hydrochloride hydrate, Nalflaphine hydrochloride, Tandospirone citrate, Beraprost sodium, Lurasidone hydrochloride, Nefazodone hydrochloride, Benidipine hydrochloride, Doxazosin mesylate, Nicardipine hydrochloride, Formoterol fumarate, Lomeridine hydrochloride, Amlodipine besil Examples include acid salts.
  • the active ingredient blended in the cosmetic is not particularly limited as long as skin permeation is required.
  • vitamin ingredients such as vitamin C and vitamin E
  • moisturizing ingredients such as hyaluronic acid, ceramide and collagen
  • tranexamic acid examples include whitening components such as arbutin, hair growth components such as minoxidil, cosmetic components such as FGF (fibroblast growth factor) and EGF (epidermal growth factor), and salts and derivatives thereof.
  • the active ingredient is preferably an acidic salt or a basic salt.
  • the acid salt is preferably an inorganic acid salt.
  • a hydrophilic one is preferable.
  • the active ingredient is not particularly limited when it is hydrophilic, but typically has the following characteristics.
  • the molecular weight is 10,000 or less
  • the octanol water partition coefficient is ⁇ 6 to 6.
  • the molecular weight is preferably 5000 or less, more preferably 2000 or less, and still more preferably 1000 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50 or more.
  • the octanol water distribution coefficient is preferably ⁇ 3 to 6, more preferably ⁇ 2 to 6, and further preferably ⁇ 2 to 5 from the viewpoint that the effects of the present invention can be more reliably exhibited. is there.
  • the octanol water partition coefficient is calculated by the following formula from the drug concentration of each phase after adding the drug into a flask containing octanol and an aqueous buffer solution of pH 7 and then shaking. .
  • Octanol water partition coefficient Log 10 (concentration in octanol phase / concentration in water phase)
  • the amount of the active ingredient contained in the particles of the present invention depends on the type of the active ingredient.
  • the raw material charge weight is 0.1 to 30% by weight (based on the total weight of all the raw materials contained in the particles) ).
  • the active ingredients can be used alone or in combination of any two or more.
  • the first fraction may further contain at least one other component in addition to the active component.
  • at least one other component for example, a stabilizer, an absorption promoter, a stimulus reducing agent, a preservative, etc. are mentioned.
  • the stabilizer has a function of stabilizing the particle structure, prevents unintended early collapse of the particle structure, and ensures a sustained release effect of the active ingredient.
  • the stabilizer is not particularly limited, and specific examples include polysaccharides, proteins, and hydrophilic polymer materials.
  • a stabilizer may contain 1 type, or 2 or more types.
  • the content of the stabilizer in the first fraction can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the active ingredient and the stabilizer is 1: 0.1 to 1:10. It can also be blended.
  • the absorption promoter is not particularly limited, and specifically includes higher alcohols, N-acyl sarcosine and salts thereof, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, 2 to 10 carbon atoms. And divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid.
  • the absorption promoter may contain 1 type (s) or 2 or more types.
  • the content of the absorption enhancer in the first fraction can be appropriately set depending on the type, but for example, the weight ratio of the active ingredient to the absorption enhancer is 1: 0.01 to 1:50. It can also be blended.
  • the irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples include acids, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole.
  • the irritation reducing agent may contain one kind or two or more kinds.
  • the content ratio of the irritation reducing agent in the first fraction can be set as appropriate depending on the type of the agent, but for example, it can be blended so as to be 0.1 wt% to 50 wt%.
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • the content of the preservative in the first fraction can be set as appropriate depending on the type of the preservative, but it can also be blended so as to be, for example, 0.01 wt% to 10 wt%.
  • preservative may contain 1 type (s) or 2 or more types.
  • the second fraction contains at least a surfactant.
  • the surfactant one having a weighted average value of HLB values of 10 or less, preferably 5 or less, more preferably 3 or less can be used.
  • an HLB abbreviation of Hydrophile Lipophile Balance
  • HLB Hydrophile Lipophile Balance
  • HLB value 20 ⁇ ⁇ (molecular weight of hydrophilic portion) / (total molecular weight) ⁇
  • the weighted average value of the HLB value is calculated as follows.
  • surfactant raw materials having HLB values A, B, and C
  • the weighted average value is calculated as (xA + yB + zC) / (x + y + z) when the respective weights are x, y, and z.
  • the surfactant is preferably one having a melting point of 50 ° C. or lower, more preferably 40 ° C. or lower in terms of absorbability.
  • the surfactant is not particularly limited and can be appropriately selected depending on the application. For example, it can be widely selected from those that can be used as pharmaceuticals and cosmetics. A plurality of types of surfactants may be used in combination.
  • the surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant and an amphoteric surfactant.
  • Nonionic surfactants include, but are not limited to, fatty acid esters, fatty alcohol ethoxylates, polyoxyethylene alkyl phenyl ethers, alkyl glycosides and fatty acid alkanolamides, and polyoxyethylene castor oil and hydrogenated castor oil. .
  • the fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. Specific examples include esters of fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid, and behenic acid and sugars (preferably sucrose).
  • anionic surfactant examples include alkyl sulfate ester salts, polyoxyethylene alkyl ether sulfate ester salts, alkylbenzene sulfonate salts, fatty acid salts, and phosphate ester salts.
  • Examples of the cationic surfactant include alkyl trimethyl ammonium salts, dialkyl dimethyl ammonium salts, alkyl dimethyl benzyl ammonium salts, and amine salts.
  • amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.
  • sucrose fatty acid ester As the surfactant, sucrose fatty acid ester, polyoxyethylene sorbite fatty acid ester, polyoxyethylene castor oil and hydrogenated castor oil are particularly preferably used.
  • the surfactant is not particularly limited, but may have a hydrocarbon chain (an alkyl chain, an alkenyl chain, an alkynyl chain, etc.).
  • the hydrocarbon chain length is not particularly limited, but can be selected widely from 8 to 30 carbon atoms on the main chain.
  • the molecular weight of the surfactant is preferably 600 or less from the viewpoint of further reducing the cohesiveness index X and further increasing the permeation amount.
  • Surfactants can be used singly or in combination of any two or more.
  • the second fraction may further contain at least one other component in addition to the surfactant.
  • at least one other component for example, an irritation
  • the irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, glycyrrhetin Examples include acids, BHT, BHA, vitamin E and derivatives thereof, vitamin C and derivatives thereof, benzotriazole, propyl gallate, and mercaptobenzimidazole.
  • the irritation reducing agent may contain one kind or two or more kinds.
  • the content ratio of the irritation reducing agent in the second fraction can be set as appropriate depending on the type, but it can also be blended so as to be, for example, 0.1 wt% to 50 wt%.
  • the analgesic is not particularly limited, and specific examples include local anesthetics such as procaine, tetracaine, lidocaine, dibucaine and prilocaine, and salts thereof.
  • An analgesic may contain 1 type (s) or 2 or more types.
  • the content ratio of the analgesic agent in the second fraction can be appropriately set depending on the type of the analgesic agent, but it can also be blended to be, for example, 0.1 wt% to 30 wt%.
  • the absorption promoter is not particularly limited, and specifically includes higher alcohols, N-acyl sarcosine and salts thereof, higher monocarboxylic acids, higher monocarboxylic acid esters, aromatic monoterpene fatty acid esters, 2 to 10 carbon atoms. And divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphates and salts thereof, lactic acid, lactic acid esters, and citric acid.
  • the absorption promoter may contain 1 type (s) or 2 or more types.
  • the content ratio of the absorption accelerator in the second fraction can be appropriately set depending on the type, but it can also be blended to be, for example, 0.1 wt% to 30 wt%.
  • the stabilizer has a function of stabilizing the core-shell structure, prevents unintended early collapse of the core-shell structure, and ensures a sustained release effect of the active ingredient.
  • the stabilizer is not particularly limited, and specifically, fatty acids and salts thereof, parahydroxybenzoates such as methylparaben and propylparaben, alcohols such as chlorobutanol, pendyl alcohol, and phenylethyl alcohol, thimerosal , Acetic anhydride, sorbic acid, sodium hydrogen sulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl- ⁇ -tocopherol, protein and polysaccharides.
  • a stabilizer may contain 1 type, or 2 or more types.
  • the content of the stabilizer in the second fraction can be appropriately set depending on the type of the stabilizer. For example, the weight ratio of the sucrose fatty acid ester to the stabilizer is 1: 0.01 to 1:50. It can also be blended.
  • Preservatives are not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol.
  • preservative may contain 1 type (s) or 2 or more types.
  • the content of the preservative in the second fraction can be set as appropriate depending on the type of the preservative, but for example, it can be blended so as to be 0.01 wt% to 10 wt%.
  • formulation of the present invention contains at least the particles of the present invention.
  • the content ratio of the particles in the preparation is not particularly limited, but in the case of a patch, ointment, cream, or gel, it is preferably 10% by weight to 70% by weight, more preferably 20% by weight to 50% by weight. It is as follows.
  • the weight ratio between the active ingredient and the surfactant can be appropriately set within the range where the effects of the present invention are exhibited. 3 to 1: 100. From the viewpoint that the effects of the present invention can be exhibited more reliably, the weight ratio is preferably 1: 5 to 1:70, more preferably 1: 5 to 1:50, and 1:10 to 1 : 40 is more preferable, and 1:15 to 1:35 is even more preferable.
  • the preparation of the present invention is a preparation intended for percutaneous absorption or transmucosal absorption, such as external preparations (for example, external preparations for skin, eye drops, nasal drops, suppositories, oral preparations, etc.) or cosmetics, depending on the type of active ingredient. It can be used for a wide range of applications such as injections.
  • external preparations for example, external preparations for skin, eye drops, nasal drops, suppositories, oral preparations, etc.
  • cosmetics depending on the type of active ingredient. It can be used for a wide range of applications such as injections.
  • the preparation of the present invention is not particularly limited, but is usually sustained for 1 day to 1 week, and in a preferred embodiment, it is used so as to be applied once a day to 1 week.
  • the target disease varies depending on the type of active ingredient.
  • the preparation of the present invention is not particularly limited, and is a tape agent (reservoir type, matrix type, etc.) such as a plaster agent or a plaster agent, a patch, a patch agent, a patch such as a microneedle, an ointment, an external liquid agent (liniment agent). , Lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enemas, etc. Can be used.
  • a tape agent such as a plaster agent or a plaster agent, a patch, a patch agent, a patch such as a microneedle, an ointment, an external liquid agent (liniment agent). , Lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal
  • the preparation of the present invention preferably has a water content of 20% by weight or less, and more preferably contains substantially no water. As a result, it is possible to further improve the shape retention of the particles of the present invention, and it is possible to further suppress the leakage of the active ingredient from the particles and thus the crystallization of the active ingredient, resulting in a further higher absorption. It is possible to demonstrate the nature. From this point of view, the preparation of the present invention is an agent whose water content is adjusted to 20% by weight or less (more preferably an agent that does not substantially contain water), such as a plaster agent, patch agent, ointment agent, gel agent and the like. It is preferable to be used as
  • the preparation of the present invention may further contain a phase (base phase) containing a base, and the base phase may contain the particles. At this time, the particles are dispersed or dissolved in the base phase.
  • the base is not particularly limited, and can be widely selected from drugs that can be used as pharmaceuticals (especially external medicines) and cosmetics.
  • the base can be appropriately selected from those suitable for dispersing or dissolving the particles according to the purpose of use, and is not particularly limited.
  • the particles used in the present invention preferably have a solid first fraction.
  • an S / O (Solid in Oil) type preparation can be formed by dispersing such particles in the base phase that is the oil phase.
  • the S / O type preparation can be obtained, for example, by dispersing particles obtained by a production method including a step of drying a W / O emulsion described later in an oil phase.
  • the base is not particularly limited, and examples thereof include an oily base and an aqueous base.
  • the oily base include elastomers, vegetable oils, animal oils, neutral lipids, synthetic fats and oils, sterol derivatives, waxes, hydrocarbons, monoalcohol carboxylic acid esters, oxyacid esters, polyhydric alcohol fatty acid esters, silicone , Higher alcohols, higher fatty acids, fluorine oils, and the like.
  • the aqueous base include water and (polyhydric) alcohol.
  • the elastomer is not particularly limited, but styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-ethylene-butylene-styrene block copolymer (SEBS), Examples thereof include rubbers such as polyisobutylene (PIB) and isoprene rubber (IR), silicones such as silicone rubber, and urethanes.
  • SIS styrene-isoprene-styrene block copolymer
  • SBS styrene-butadiene-styrene block copolymer
  • SEBS styrene-ethylene-butylene-styrene block copolymer
  • PIB polyisobutylene
  • IR isoprene rubber
  • silicones such as silicone rubber, and urethanes.
  • the vegetable oil is not particularly limited, and examples thereof include soybean oil, sesame oil, olive oil, palm oil, balm oil, rice bran oil, cottonseed oil, sunflower oil, rice bran oil, cacao butter, corn oil, bean flower oil, castor oil and rapeseed oil. Can be mentioned.
  • Animal oil is not particularly limited, and examples thereof include mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, and salmon squalane.
  • the neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.
  • Synthetic fats and oils are not particularly limited, and examples thereof include phospholipids and azones.
  • the sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.
  • waxes examples include candelilla wax, carnauba wax, rice wax, beeswax, beeswax, montan wax, ozokerite, ceresin, paraffin wax, microcrystalline wax, petrolatum, Fischer-Tropsch wax, polyethylene wax, and ethylene / propylene copolymer. Is mentioned.
  • hydrocarbons examples include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, ⁇ -olefin oligomer, polyisobutene, hydrogenated polyisobutene, polybutene, squalane, olive-derived squalane, squalene, petrolatum and solid paraffin. It is done.
  • Monoalcohol carboxylates include octyldodecyl myristate, hexyl decyl myristate, octyl dodecyl isostearate, cetyl palmitate, octyl dodecyl palmitate, cetyl octoate, hexyldecyl octoate, isotridecyl isononanoate, isononanoyl isononanoate, Octyl isononanoate, isotridecyl isononanoate, isodecyl neopentanoate, isotridecyl neopentanoate, isostearyl neopentanoate, octyldodecyl neodecanoate, oleyl oleate, octyl dodecyl oleate, octyldodecy
  • oxyesters examples include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearate.
  • Polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, glyceryl tri (caprylic acid / capric acid), tri (caprylic acid / capric acid / myristic acid / stearic acid) ) Glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl behenate, trimethylolpropane trioctanoate, trimethylolpropane triisostearate, neopentylglycol dioctanoate, neopentyl glycol dicaprate Pentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrate
  • Silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl.
  • Polyether modification such as dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cation-modified silicone, dimethicone copolyol Silicone, polyglycerin modified silicone, sugar modified silicone, carboxylic acid modified silicone, phosphoric acid modified silicone , Sulfuric acid modified silicone, alkyl modified silicone, fatty acid modified silicone, alkyl ether modified silicone, amino acid modified silicone, peptide modified silicone, fluorine modified silicone, cation modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or poly Examples thereof include ether-modified silicones and polysiloxane / oxyalkylene copolymers.
  • Examples of higher alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, cetostearyl alcohol, stearyl alcohol, aralkyl alcohol, behenyl alcohol, jojoba alcohol, chimyl alcohol, ceralkyl alcohol, batyl alcohol, hexyldecanol, isostearyl alcohol, Examples include 2-octyldodecanol and dimer diol.
  • Higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitoleic acid, oleic acid, linoleic acid, linolenic acid, erucic acid, docosahexaenoic acid Eicosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid and hydrogenated dimer acid.
  • Fluorinated oils include perfluorodecane, perfluorooctane and perfluoropolyether.
  • Polyhydric alcohol includes ethanol, isopropanol, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol and the like.
  • bases are not particularly limited, but include patches (plasters, plasters and other tapes (reservoir type, matrix type, etc.), poultices, patches, microneedles, etc.), ointments, external use Liquids (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enemas Examples include bases used for agents.
  • the preparation of the present invention may contain other additive components depending on the dosage form, purpose of use, and the like.
  • Additive components are not particularly limited, but include excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, Buffering agents, pH adjusting agents, gelling agents, pressure-sensitive adhesives, antioxidants, absorption accelerators, stimulus relaxation agents, preservatives, chelating agents, dispersing agents and the like can be mentioned.
  • the preparation of the present invention when the base phase is not included, the particles are included, or when the base phase is included, the base phase in which the particles are included (hereinafter collectively referred to as “particles”). It may be referred to as “containing basic component”), and may be dispersed in other components.
  • the preparation of the present invention is provided by mixing and dispersing or emulsifying particles or particle-containing basic components in a component in which particles or particle-containing basic components are not completely dissolved. It can be appropriately selected depending on the dosage form, and is not particularly limited.
  • a patch a plaster, a plaster, a tape (reservoir, matrix, etc.), a cataplasm, a patch, a microneedle, etc.), an ointment, etc.
  • particles or particle-containing basic components can be mixed and dispersed or emulsified in the base used in each dosage form.
  • the particles of the present invention are not particularly limited, but can be produced, for example, by a method including a step of drying a W / O emulsion containing an active ingredient in an aqueous phase.
  • the W / O emulsion is not particularly limited as long as it is a so-called water-in-oil emulsion, specifically, an emulsion in which droplets of an aqueous solvent are dispersed in an oily solvent.
  • the W / O emulsion containing the active ingredient in the aqueous phase is, for example, an aqueous solvent containing the active ingredient (eg, water, buffered aqueous solution, etc.) and an oily solvent containing a surfactant (eg, cyclohexane, hexane, toluene, etc.) Can be obtained by mixing.
  • the aqueous solvent containing the active ingredient may contain additive components such as a stabilizer, an absorption accelerator, and an irritation reducing agent, if necessary, in addition to the active ingredient.
  • the oily solvent containing the surfactant may contain additional components such as an irritation reducing agent, an analgesic agent, an absorption accelerator, and a stabilizer, as necessary, in addition to the active ingredient.
  • the mixing method is not particularly limited as long as it is a method capable of forming a W / O emulsion, and examples thereof include stirring with a homogenizer or the like.
  • the conditions at the time of stirring the homogenizer are, for example, about 5000 to 50000 rpm, more preferably about 10,000 to 30000 rpm.
  • the weight ratio between the active ingredient and the surfactant in the W / O emulsion is not particularly limited, and is, for example, 1: 3 to 1: 100. From the viewpoint that the effects of the present invention can be exhibited more reliably, the weight ratio is preferably 1: 5 to 1:70, more preferably 1: 5 to 1:50, and 1:10 to 1 : 40 is more preferable, and 1:15 to 1:35 is even more preferable.
  • the method for drying the W / O emulsion is not particularly limited as long as it is a method capable of removing the solvent (aqueous solvent and oily solvent) in the emulsion.
  • aqueous solvent and oily solvent aqueous solvent and oily solvent
  • freeze-drying, reduced-pressure drying, and the like are preferable. Can be mentioned.
  • the particle cohesiveness index X is determined by the weight ratio between the active ingredient and the surfactant during particle formation, the octanol water partition coefficient of the active ingredient, and the salt type (or effective) of the active ingredient.
  • the component is a free form, it is considered that it may vary depending on the type of salt that it can form.
  • the weight ratio of the active ingredient to the surfactant is too low or too high, the cohesion index X tends to increase.
  • the appropriate weight ratio may vary depending on the active ingredient.
  • the active ingredient is an acid salt (or a free form capable of forming an acid salt), or has an octanol water partition coefficient within a predetermined range (preferably ⁇ 3 to 6, more preferably ⁇ 2 to 6, more preferably ⁇ In the case of 2 to 5), the desired cohesiveness index X of the present invention can be easily obtained. On the other hand, in other cases, it is possible to obtain the particles of the present invention exhibiting the desired cohesiveness index X by appropriately setting the conditions (for example, adjusting the weight ratio to an appropriate range). .
  • the particles of the present invention may be used as they are, but may be used by dispersing in the above-mentioned base or the like.
  • a preparation can be produced by a solution coating method.
  • a solvent such as hexane, toluene, or ethyl acetate is used so that additional components such as an absorption accelerator, a thickener, and a gelling agent are added at a predetermined ratio as desired. And stir to prepare a homogeneous solution.
  • the solid content concentration in the solution is preferably 10 to 80% by weight, more preferably 20 to 60% by weight.
  • a release liner silicone-treated polyester film, etc.
  • a coating machine such as a knife coater, comma coater, or reverse coater, and dried.
  • An absorption-type preparation can be obtained by completing a drug-containing layer and laminating a support on the drug-containing layer.
  • a release liner may be laminated on the surface of the drug-containing layer.
  • the particles of the present invention may be added and mixed with additives such as a base, an absorption accelerator, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • additives such as a base, an absorption accelerator, a stabilizer, a thickener, and a gelling agent as necessary, depending on the use.
  • Natural fabric members such as gauze or absorbent cotton, synthetic fiber fabric members such as polyester or polyethylene, or a combination of these appropriately processed into a woven fabric or nonwoven fabric, or laminated or impregnated on a permeable membrane, etc. It can also be used by covering it with an adhesive cover material or the like.
  • the thus obtained absorption preparation is appropriately cut into an oval shape, a circular shape, a square shape, a rectangular shape or the like according to the intended use. Moreover, you may provide an adhesive phase etc. in the periphery as needed.
  • Example 1 except that donepezil hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient 4.3) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 0.5 g.
  • Particles were prepared as follows.
  • Particles were prepared in the same manner as in Example 4 except that the amount of sucrose erucic acid ester was changed to 3.0 g.
  • Example 1 except that diphenhydramine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient 3.1) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 0.5 g.
  • Particles were prepared as follows.
  • Particles were prepared in the same manner as in Example 7 except that the amount of sucrose erucic acid ester was 1.0 g.
  • Particles were prepared in the same manner as in Example 7 except that the amount of sucrose erucic acid ester was changed to 3.0 g.
  • Example 10 Example except that vardenafil hydrochloride trihydrate (manufactured by Atomax Chemicals, water octanol partition coefficient 3.2) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 1.0 g. Particles were prepared as in 1.
  • Particles were prepared in the same manner as in Example 10 except that the amount of sucrose erucic acid ester was changed to 3.0 g.
  • Particles were prepared in the same manner as in Example 10 except that the amount of sucrose erucic acid ester was 5.0 g.
  • Example 1 except that octreotide acetate (BACHEM, water octanol partition coefficient -1.2) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 1.5 g. The particles were prepared.
  • BACHEM water octanol partition coefficient -1.2
  • risedronate sodium 2.5 hydrate manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient -5.0
  • memantine hydrochloride the amount of sucrose erucic acid ester was 5.0 g
  • Particles were prepared in the same manner as in Comparative Example 1 except that the amount of sucrose erucic acid ester was 10 g.
  • Diclofenac sodium manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient 13.4
  • BSA bovine serum albumin
  • 0.067 g were added to 40 g of phosphate buffer (pH 8.0).
  • Particles were prepared in the same manner as in Comparative Example 3 except that the amount of sucrose erucic acid ester was changed to 0.833 g.
  • Particles were prepared in the same manner as in Comparative Example 3 except that the amount of sucrose erucic acid ester was 1.667 g.
  • Example 1 except that ascorbic acid (manufactured by Wako Pure Chemical Industries, Ltd., water octanol partition coefficient -2.2) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 0.3 g. Particles were prepared in the same manner.
  • Particles were prepared in the same manner as in Comparative Example 6 except that the amount of sucrose erucic acid ester was changed to 0.5 g.
  • Particles were prepared in the same manner as in Comparative Example 6 except that the amount of sucrose erucic acid ester was 1.0 g.
  • Test Example 1 Small-angle X-ray scattering analysis Surfactant (sucrose erucic acid ester (ER-290) used for the preparation of the particles of Examples and Comparative Examples, and the particles of Examples and Comparative Examples by small-angle X-ray scattering )) was analyzed.
  • the analysis conditions are as follows.
  • X-ray source High-intensity Photoscience Research Center Spring-8 Beamline BL40B2 Camera length: 1.25m X-ray wavelength: 0.71 mm Beam size (full width at half maximum): 0.2 mm x 0.2 mm Measurement time: 10 to 60 seconds / 1 sample Measurement temperature: 25 ° C
  • the created scattering profile was normalized based on the maximum value of the scattering intensity. Specifically, in each scattering profile, [ ⁇ / maximum value of scattering intensity] was multiplied by the scattering intensity in each scattering vector to obtain a normalized scattering profile. That is, in this normalized scattering profile, the maximum value of the scattering intensity is ⁇ . Normalized scattering profiles are shown in FIGS.
  • the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the normalized scattering profile of the particle is determined, and the scattering vector q in the normalized profile of the surfactant is 0.2 [nm ⁇ 1]. ] was calculated as a cohesiveness index.
  • the cohesiveness index is shown in Table 1.
  • Equation (1) S 1 / Sr 1) / (S 0 / Sr 0) (1)
  • S 1 represents the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of particles.
  • Sr 1 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the particles.
  • S 0 indicates the scattering intensity when the scattering vector q is 0.2 [nm ⁇ 1 ] in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • Sr 0 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the surfactant.
  • Test Example 2 Hairless Rat Skin Permeability Test Hairless rat skin (extracted from Japan SLC, HWY / Slc, 8 weeks old) was set in a drug skin permeation test cell (FIG. 13).
  • particles of Examples and Comparative Examples or active ingredients memantine hydrochloride, donepezil hydrochloride, diphenhydramine hydrochloride, vardenafil hydrochloride trihydrate, octreotide acetate, risedronate sodium 2.5 hydrate , Diclofenac sodium, ascorbic acid and fenoterol hydrobromide
  • Plastibase Talaisho Pharmaceutical Co., Ltd.
  • 0.3 g (about 3.14 cm 2 ) of the formulation is applied, and in the lower receptor layer, NaH 2 PO 4 is 5 ⁇ 10 ⁇ 4 M, Na 2 HPO 4 is 2 ⁇ 10 ⁇ 4 M, NaCl in distilled water.
  • the 1.5 ⁇ 10 -4 M, gentamicin sulfate (manufactured by Wako Pure Chemical Industries, Ltd., G1658) a liquid which contains 10ppm with NaOH to pH7 Put 2 was adjusted to buffer and installing equipment in a constant temperature bath kept at 32 ° C. than after start of the test. 48 hours after the start of the test, 1 ml of the liquid in the tank was collected from the lower receptor layer, and immediately after that, 1 ml of the same composition was replenished.
  • HPLC high performance liquid chromatography
  • the magnification magnification permeation rate magnification
  • the cumulative permeation amount after 48 hours was calculated as the value obtained by dividing the cumulative permeation amount after 48 hours when only the active ingredient was applied ( ⁇ g / cm 2 )]. The results are shown in Table 2.
  • the particles of the comparative example did not improve the skin permeability due to the formation of the active ingredient (magnification permeation rate magnification ⁇ 1.0).
  • the particles of the examples had improved skin permeability due to the formation of active ingredients (magnification permeation rate magnification> 1.0).
  • octreotide acetate manufactured by BACHEM, water octanol partition coefficient -1.2
  • oleic acid diethanolamide manufactured by NOF Corporation, Stahome DOS
  • a solution dissolved in 80 g of cyclohexane was added, followed by homogenizer stirring (10,000 rpm). This was followed by lyophilization for 2 days to obtain particles containing the active ingredient and surfactant.
  • 0.1 g of octreotide acetate BACHEM, water octanol partition coefficient -1.2
  • 0.02 g of N-lauroyl sarcosine sodium Nacalai Tesque
  • DODO manufactured by NOF Corporation, Stahome DOS
  • Particles were prepared in the same manner as in Example 17 except that a phospholipid-like water-soluble polymer (manufactured by NOF Corporation, Medicinal Lipidure-PMB, molecular weight of about 600,000) was used in place of N-lauroyl sarcosine sodium.
  • a phospholipid-like water-soluble polymer manufactured by NOF Corporation, Medicinal Lipidure-PMB, molecular weight of about 600,000
  • Particles were prepared in the same manner as in Example 17, except that sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) was used instead of oleic acid diethanolamide.
  • Fenoterol hydrobromide manufactured by Wako Pure Chemical Industries, Ltd., water octanol partition coefficient -0.3
  • sucrose oleate Mitsubishi Chemical Foods
  • oleic acid diethanolamide Particles were prepared in the same manner as in Example 16 except that O-170; HLB value 1) was used.
  • Particles were prepared in the same manner as in Example 16 except that fenoterol hydrobromide (manufactured by Wako Pure Chemical Industries, Ltd., water octanol partition coefficient -0.3) was used instead of octreotide acetate.
  • Particles were prepared in the same manner as in Example 16 except that sucrose erucic acid ester (ER-290; HLB value 2 manufactured by Mitsubishi Chemical Foods Co., Ltd.) was used instead of oleic acid diethanolamide.
  • sucrose erucic acid ester ER-290; HLB value 2 manufactured by Mitsubishi Chemical Foods Co., Ltd.
  • Particles were prepared in the same manner as Example 20 except that sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) was used instead of sucrose oleate.
  • the particles of the comparative example did not improve the skin permeability due to the formation of the active ingredient (magnification permeation rate magnification ⁇ 1.1).
  • the particles of the examples had improved skin permeability due to the formation of active ingredients (magnification permeation ratio> 1.1).

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Birds (AREA)
  • Medicinal Preparation (AREA)
  • Cosmetics (AREA)

Abstract

La présente invention concerne la fourniture de particules contenant une substance active présentant une absorption supérieure de la substance active dans un corps. Les particules comprennent une première infraction contenant une substance active et une deuxième fraction contenant un tensioactif, l'indice d'agrégabilité X des particules représenté par la formule (1) étant de 30 ou moins. Formule (1) : X = (S1/Sr1)/(SO/Sr0) [Dans la formule (1) : S1 représente l'intensité de diffusion lorsque le vecteur de diffusion q dans un profil de diffusion obtenu par diffusion des rayons X aux petits angles dans les particules est de 0,2 [nm-1]; Sr1 représente la valeur maximale de l'intensité de diffusion dans le profil de diffusion obtenu par diffusion des rayons X aux petits angles dans les particules; S0 représente l'intensité de diffusion lorsque le vecteur de diffusion q dans un profil de diffusion obtenu par diffusion des rayons X aux petits angles dans le tensioactif est de 0,2 [nm-1]; et Sr0 représente une valeur maximale de l'intensité de diffusion dans le profil de diffusion obtenu par diffusion des rayons X aux petits angles dans le tensioactif.]
PCT/JP2017/000333 2016-01-06 2017-01-06 Particules et préparation pharmaceutique WO2017119506A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2017560445A JPWO2017119506A1 (ja) 2016-01-06 2017-01-06 粒子及び製剤

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2016-000870 2016-01-06
JP2016000870 2016-01-06

Publications (1)

Publication Number Publication Date
WO2017119506A1 true WO2017119506A1 (fr) 2017-07-13

Family

ID=59273665

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP2017/000333 WO2017119506A1 (fr) 2016-01-06 2017-01-06 Particules et préparation pharmaceutique

Country Status (2)

Country Link
JP (1) JPWO2017119506A1 (fr)
WO (1) WO2017119506A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019155992A1 (fr) * 2018-02-07 2019-08-15 積水化学工業株式会社 Structure cœur-écorce et préparation
JP2021059521A (ja) * 2019-10-09 2021-04-15 積水化学工業株式会社 製剤

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009057808A1 (fr) * 2007-11-02 2009-05-07 Aspion Co., Ltd. Produit complexe de substance médiocrement soluble-agent tensio-actif, et son procédé de fabrication
WO2009139506A1 (fr) * 2008-05-15 2009-11-19 Ａｓｐｉｏｎ株式会社 Combinaison de médicaments ayant différentes propriétés physiques en une seule forme pharmaceutique
JP2014172840A (ja) * 2013-03-07 2014-09-22 Lintec Corp 貼付剤
WO2016043323A1 (fr) * 2014-09-19 2016-03-24 積水化学工業株式会社 Formulation et son procédé de production
WO2016047757A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Poudre fine hautement dispersible de composé métallique alcalino-terreux, film optique, dispositif afficheur d'image, procédé de fabrication de poudre fine hautement dispersible de composé métallique alcalino-terreux, procédé d'évaluation de la dispersibilité de la poudre fine, et dispositif d'évaluation de la dispersibilité de la poudre fine
WO2016098857A1 (fr) * 2014-12-19 2016-06-23 積水化学工業株式会社 Préparation
JP2016179962A (ja) * 2015-03-24 2016-10-13 積水化学工業株式会社 コアシェル構造体を含有する製剤
WO2017002865A1 (fr) * 2015-06-29 2017-01-05 積水化学工業株式会社 Structure noyau/enveloppe et agent topique

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2009057808A1 (fr) * 2007-11-02 2009-05-07 Aspion Co., Ltd. Produit complexe de substance médiocrement soluble-agent tensio-actif, et son procédé de fabrication
WO2009139506A1 (fr) * 2008-05-15 2009-11-19 Ａｓｐｉｏｎ株式会社 Combinaison de médicaments ayant différentes propriétés physiques en une seule forme pharmaceutique
JP2014172840A (ja) * 2013-03-07 2014-09-22 Lintec Corp 貼付剤
WO2016043323A1 (fr) * 2014-09-19 2016-03-24 積水化学工業株式会社 Formulation et son procédé de production
WO2016047757A1 (fr) * 2014-09-26 2016-03-31 宇部興産株式会社 Poudre fine hautement dispersible de composé métallique alcalino-terreux, film optique, dispositif afficheur d'image, procédé de fabrication de poudre fine hautement dispersible de composé métallique alcalino-terreux, procédé d'évaluation de la dispersibilité de la poudre fine, et dispositif d'évaluation de la dispersibilité de la poudre fine
WO2016098857A1 (fr) * 2014-12-19 2016-06-23 積水化学工業株式会社 Préparation
JP2016179962A (ja) * 2015-03-24 2016-10-13 積水化学工業株式会社 コアシェル構造体を含有する製剤
WO2017002865A1 (fr) * 2015-06-29 2017-01-05 積水化学工業株式会社 Structure noyau/enveloppe et agent topique

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2019155992A1 (fr) * 2018-02-07 2019-08-15 積水化学工業株式会社 Structure cœur-écorce et préparation
JP2021059521A (ja) * 2019-10-09 2021-04-15 積水化学工業株式会社 製剤

Also Published As

Publication number Publication date
JPWO2017119506A1 (ja) 2018-10-25

Similar Documents

Publication Publication Date Title
JP6091721B2 (ja) 製剤
JP6148416B2 (ja) コアシェル構造体及び外用剤
JP6386691B1 (ja) コアシェル構造体、製剤、外用薬、テープ剤及び化粧品
WO2016043323A1 (fr) Formulation et son procédé de production
US20180311357A1 (en) External preparation and method for producing same
JPWO2020203733A1 (ja) コアシェル構造体、製剤、外用薬、テープ剤及び化粧品
WO2017119506A1 (fr) Particules et préparation pharmaceutique
JP2017165699A (ja) 有効成分含有粒子及び製剤
JP2017014128A (ja) コアシェル構造体及びそれを含有する製剤
JP2016179962A (ja) コアシェル構造体を含有する製剤
JP2016117681A (ja) コアシェル構造体を含有する製剤
JP7227271B2 (ja) 製剤
JP6263315B2 (ja) 粒子、製剤、外用薬及び化粧品
JP2017014129A (ja) 持続性全身作用型外用剤
WO2016006630A1 (fr) Médicament pour usage externe type à action générale durable
JP2018070535A (ja) 有効成分含有粒子、製剤、外用薬、化粧品及び注射剤
JP2016179963A (ja) コアシェル構造体を含有する製剤
JP6809784B2 (ja) 製剤
US20190388350A1 (en) Formulation
JP2017014130A (ja) 製剤

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 17736043

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2017560445

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 17736043

Country of ref document: EP

Kind code of ref document: A1