JPWO2017119506A1 - Particles and formulations - Google Patents

Abstract

To provide active ingredient-containing particles having a higher absorbability of active ingredients into the body. 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. Formula (1): X = (S1 / Sr1) / (S0 / Sr0) [In Formula (1), S1 is a scattering vector q in a scattering profile obtained by small-angle X-ray scattering of the particles of 0.2 [ nm-1] is shown. Sr1 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the particles. S0 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. Sr0 represents the maximum value of the scattering intensity in the scattering profile obtained by small-angle X-ray scattering of the surfactant. ]

Description

  The present invention relates to an active ingredient-containing particle and a preparation containing the same.

  Various techniques have been proposed to improve the absorption of active ingredients into the body. For example, in 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) formulations have been reported. In this technique, it is possible to control the pharmacokinetics of an active ingredient while improving the absorbability of the active ingredient into the body with a surfactant.

Japanese Patent No. 4334939 Japanese Patent No. 4844494

  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.

  Then, this invention makes it a subject to provide the active ingredient containing particle | grains with higher absorbability in the body of an active ingredient.

  As a result of intensive studies to solve the above problems, 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.
Wherein (1), _{S 1} is in the scattering profile obtained by small-angle X-ray scattering of the particle, showing a scattering intensity when the scattering vector q is 0.2 ^{[nm -1].} 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. 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. The particle according to Item 1 or 2, wherein the maximum value is a maximum value within a range of a scattering vector q of 1.0 to 3.0 [nm ⁻¹ ].
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. Item 5. A preparation comprising the particle according to any one of Items 1 to 4.
Item 6. Item 6. The preparation according to Item 5, wherein the weight ratio of the active ingredient to the surfactant is 1: 5 to 1: 100.
Item 7. Item 7. An external preparation containing the preparation according to Item 5 or 6.
Item 8. Item 7. A cosmetic comprising the preparation according to item 5 or 6.

  ADVANTAGE OF THE INVENTION According to this invention, the active ingredient containing particle | grains with higher absorbability in the body of an active ingredient can be provided.

FIG. 1A shows a typical scattering profile of an active ingredient-containing particle and a surfactant, and 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 small-angle X-ray scattering analysis of Test Example 1. 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 (the same applies to FIGS. 3 to 13). FIG. 3 shows normalized scattering profiles 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 profile of the particles of Examples 7 to 9 and sucrose erucic acid ester (ER290) obtained by small-angle X-ray scattering analysis of Test Example 1. FIG. 5 shows the normalized scattering profile 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 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 small-angle X-ray scattering analysis of Test Example 1. FIG. 10 shows normalized scattering profiles of the particles of Example 19 and Comparative Examples 9 to 10 and sucrose erucic acid ester (ER-290) obtained by small-angle X-ray scattering analysis of Test Example 1. 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.

  In this specification, the expression “containing” includes the concepts of “including”, “consisting essentially of”, and “consisting only of”.

  In the present specification, “absorbability (to the body)” means, for example, “percutaneous absorption (skin permeability)”, “absorption through the skin, for example, eye drops, nasal, intravaginal, rectal The concept of “absorbability via internal (suppository), subcutaneous, intradermal, intramuscular” is included.

1. Particles The present invention is a particle comprising a first fraction containing an active ingredient and a second fraction containing a surfactant, wherein the formula (1): X = (S ₁ / Sr ₁ ) / (S ₀ / Sr ₀ ) and a cohesiveness index X of 30 or less (in the present specification, sometimes referred to as “particle of the present invention”). This will be described below.

  The particles of the present invention comprise 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. In addition, the particle | grains which have such a structure may be shown as "active ingredient containing particle | grains" in this specification. In the particles of the present invention, it is preferable that part or all of the surface of the first fraction is directly or indirectly coated with the second fraction from the viewpoint of the absorbability and sustained release of the active ingredient. For example, 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. Moreover, it is desirable that part or all of the surface of the first fraction is directly covered with the second fraction. As an example of the aspect of the particles, a core-shell structure in which the first fraction is a core portion and the second fraction corresponds to a shell portion that includes the core portion.

In formula (1), definitions of S ₁ , Sr ₁ , S ₀ , and Sr ₀ are as follows.
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 size of the scattering vector q [nm ⁻¹ ], and the vertical axis (common logarithmic axis) represents the scattering intensity I. Note that q = (4π / λ) sin (θ / 2) (where the wavelength of X-ray is λ and θ is a scattering angle). FIG. 1 (a) shows typical scattering profiles of a sample composed of particles containing active ingredients and a sample composed of a surfactant.

This scattering profile contains information about the microstructure of the sample. Specifically, for example, when the scattering intensity in a relatively low angle region (for example, q = 1.0 [nm ⁻¹ ] or less) is strong, it indicates that particles due to aggregation are present in the sample. For this reason, these information can be acquired by analyzing a scattering profile.

  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.

  The synchrotron radiation is light emitted synchrotron along with the 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.

  Such 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. When there are two or more maximum values, it is preferable to employ the largest maximum value among them. When the active ingredient is crystallized, 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.

A surfactant S ₀ and "scattering profile obtained by small-angle X-ray scattering of the surfactant" in the definition of Sr _0, by small angle X-ray scattering of the "active ingredient-containing particles in the definition of S ₁ and Sr ₁ 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 (α). Normalized scattering profile (FIG. 1 (b) (when α = 1) obtained by correction (that is, [α / maximum value of scattering intensity] multiplied by scattering intensity in each scattering vector) Of the active ingredient-containing particles with respect to the scattering intensity (S ₀ / Sr ₀ = S ′ _{0 in} FIG. 1) in the low-angle region (q = 0.2 [nm ⁻¹ ]) of the surfactant in Example 1) It is the ratio of the scattering intensity (in FIG. 1, S ₁ / Sr ₁ = S ′ ₁ ) in the low angle region (q = 0.2 [nm ⁻¹ ]). Therefore, if the cohesiveness index X is high, it is considered that larger aggregated particles or more aggregated particles are formed in the active ingredient-containing particles.

  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.

  In the particles of the present invention, the active ingredient is preferably amorphous. As a result, 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. As described above, when the active component is crystallized, 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.

  In the present invention, 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.

  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.

  In the present invention, the first fraction is preferably a solid. In this case, 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.

1.2 First fraction 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. Preferably, it is a component blended for the purpose of exerting its physiological activity. In this preferred embodiment, 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. As an active ingredient, the ingredient mix | blended as an active ingredient, for example to a pharmaceutical, cosmetics, etc. is mentioned. Since many active ingredients of pharmaceuticals and cosmetics are organic substances, the active ingredients may be organic substances.

  As an active ingredient blended in a pharmaceutical, any of those requiring a systemic action and those requiring a local action can be used.

  Specific examples of 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. More specifically, memantine, donepezil, diphenhydramine, vardenafil, octreotide, rivastigmine, galantamine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, clomipramine, nalfurafine, metoprolol, fesoterodine, vardenafil, nalfurfine, tandolone , Beraprost sodium, tartilellin, lurasidone, nefazodone, rifaximin, benidipine, doxazosin, nicardipine, formoterol, lomerizine, amlodipine, teriparatide, bucladecin, cromoglycic acid, lixenatide, exenatide, liraglutitonin, lanreotide gluconide Risedronic acid Diclofenac, such as ascorbic acid or acceptable salts on these pharmaceutical thereof.

  The pharmaceutically acceptable salt is not particularly limited, and any of an acidic salt and a basic salt can be employed. Examples of 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. Examples of the salt of the active ingredient 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. For example, 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.

  From the viewpoint that the effects of the present invention can be more reliably exhibited, the active ingredient is preferably an acidic salt or a basic salt. In this case, the acid salt is preferably an inorganic acid salt.

  As an active ingredient, a hydrophilic thing is preferable.

  The active ingredient is not particularly limited when it is hydrophilic, but typically has the following characteristics. For example, the molecular weight is 10,000 or less, and the octanol water partition coefficient is -6 to 6.

  In the above, molecular weight becomes like this. Preferably it is 5000 or less, More preferably, it is 2000 or less, More preferably, it is 1000 or less. Although the minimum of molecular weight is not specifically limited, Usually, it is 50 or more.

  In the above, 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.

  In the present invention, 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, but is, for example, 0.1 to 30% by weight (based on the total weight of all the raw materials contained in the particles) ).

  An active ingredient can also be used individually by 1 type, and can also be used in combination of arbitrary 2 or more types.

  The first fraction may further contain at least one other component in addition to the active component. Although it does not specifically limit as another 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 has a role of ensuring 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.

  Although it does not specifically limit as an absorption accelerator, Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, C2-C10 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 and 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. Although the content rate in the 1st fraction of a irritation | stimulation reducing agent can be suitably set according to the kind, it can also mix | blend so that it may be 0.1 weight%-50 weight%, for example.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol. Although the content rate in the 1st fraction of an antiseptic | preservative can be suitably set according to the kind, it can also mix | blend, for example so that it may become 0.01 weight%-10 weight%. An antiseptic | preservative may contain 1 type (s) or 2 or more types.

1.3 Second Fraction The second fraction contains at least a surfactant.

  A surfactant having a weighted average value of HLB values of 10 or less, preferably 5 or less, more preferably 3 or less can be used.

  The HLB (abbreviation of Hydrophile Lyophile Balance) value in the present invention is an index for knowing whether an emulsifier is hydrophilic or lipophilic, and takes a value of 0 to 20. It shows that lipophilicity is so strong that an HLB value is small. In the present invention, it is calculated from the following Griffin equation.

HLB value = 20 × {(molecular weight of hydrophilic portion) / (total molecular weight)}
The weighted average value of the HLB value is calculated as follows.

  For example, there are surfactant raw materials having HLB values A, B, and C, and 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).

  Examples of the anionic surfactant 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.

  Examples of amphoteric surfactants include alkylamino fatty acid salts, alkylbetaines, and alkylamine oxides.

  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.

  Surfactant can also be used individually by 1 type, and can also be used in combination of arbitrary 2 or more types.

  The second fraction may further contain at least one other component in addition to the surfactant. Although it does not specifically limit as another component, For example, an irritation | stimulation reducing agent, an analgesic agent, an absorption promoter, a stabilizer, antiseptic | preservative, etc. are mentioned.

  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. Although the content rate in the 2nd fraction of an irritation | stimulation reducing agent can be suitably set according to the kind, it can also mix | blend so that it may become 0.1 to 50 weight%, for example.

  Although it does not specifically limit as an analgesic, Specifically, local anesthetics, such as procaine, tetracaine, lidocaine, dibucaine, and prilocaine, its salt, etc. are mentioned. An analgesic may contain 1 type (s) or 2 or more types. Although the content rate in the 2nd fraction of an analgesic can be suitably set according to the kind, it can also mix | blend, for example so that it may become 0.1 to 30 weight%.

  Although it does not specifically limit as an absorption accelerator, Specifically, higher alcohol, N-acyl sarcosine and its salt, higher monocarboxylic acid, higher monocarboxylic acid ester, aromatic monoterpene fatty acid ester, C2-C10 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. Although the content rate in the 2nd fraction of an absorption promoter can be suitably set according to the kind, it can also mix | blend, for example so that it may become 0.1 to 30 weight%.

  A stabilizer has the effect | action which stabilizes a core-shell structure, prevents the core shell structure from unintentionally disintegrating at an early stage, and has a role which ensures the sustained-release effect of an 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 bisulfite, L-ascorbic acid, sodium ascorbate, butylhydroxyanisole, butylhydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, protein and polysaccharides. A stabilizer may contain 1 type, or 2 or more types. Although content in the 2nd fraction of a stabilizer can be suitably set by the kind, For example, the weight ratio of sucrose fatty acid ester and stabilizer becomes 1: 0.01-1: 50. It can also be blended.

  The preservative is not particularly limited, and specific examples include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol and thymol. An antiseptic | preservative may contain 1 type (s) or 2 or more types. Although the content rate in the 2nd fraction of an antiseptic | preservative can be suitably set according to the kind, it can also mix | blend, for example so that it may become 0.01 weight%-10 weight%.

2. Formulation The 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.

  In the preparation of the present invention, the weight ratio between the active ingredient and the surfactant (active ingredient weight: surfactant weight) 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.

  Although the formulation of the present invention is not particularly limited, it 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.

  When the preparation of the present invention is an external medicine, 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). , Lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids, enemas, etc. Can be used.

  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

2.1 Base Phase 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 those that can be used as pharmaceuticals (particularly 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.

  A plurality of types of bases may be used in combination.

  As described above, the particles used in the present invention preferably have a solid first fraction. When the base phase is an oil phase, 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. Examples of 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. Examples of 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.

  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.

  Although it does not specifically limit as animal oil, For example, mink oil, turtle oil, fish oil, cow oil, horse oil, pig oil, shark squalane, etc. are mentioned.

  The neutral lipid is not particularly limited, and examples thereof include triolein, trilinolein, trimyristin, tristearin, and triarachidonin.

  Although it does not specifically limit as synthetic fats and oils, For example, a phospholipid, an azone, etc. are mentioned.

  The sterol derivative is not particularly limited, and examples thereof include dihydrocholesterol, lanosterol, dihydrolanosterol, phytosterol, cholic acid, and cholesteryl linoleate.

  Waxes 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, etc. Is mentioned.

  Examples of hydrocarbons include liquid paraffin (mineral oil), heavy liquid isoparaffin, light liquid isoparaffin, α-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, octyldodecyl ricinoleate, octyldodecyl lanolinate, hexyldecyl dimethyloctanoate , Octyldodecyl erucate, isostearic acid hydrogenated castor oil, ethyl oleate Avocado oil fatty acid ethyl, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, isopropyl lanolin fatty acid, diethyl sebacate, diisopropyl sebacate, dioctyl sebacate, diisopropyl adipate, dibutyloctyl sebacate, diisobutyl adipate, Examples include dioctyl succinate and triethyl citrate.

  Examples of oxyesters 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, pentaerythrtetraoctanoate Chill, hydrogenated rosin pentaerythrityl, triethylhexanoic acid ditrimethylolpropane, (isostearic acid / sebacic acid) ditrimethylolpropane, triethylhexanoic acid pentaerythrityl, (hydroxystearic acid / stearic acid / rosinic acid) dipentaerythrityl, diisostearic acid di Glyceryl, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostearic acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate) Dineopentanoic acid 3-methyl-1,5-pentanediol and dineopentanoic acid 2,4-diethyl-1,5-penta Diol, and the like.

  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, cationic modified or polyether modified silicone, amino modified or polyether modified silicone, alkyl modified or polyether Examples thereof include 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.

  Examples of the fluorinated oils include perfluorodecane, perfluorooctane and perfluoropolyether.

  (Polyhydric) alcohol includes ethanol, isopropanol, glycerin, propylene glycol, 1,3-butylene glycol, polyethylene glycol and the like.

  Other 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.

2.2 Other Additive Components 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.

  In addition, in 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. In this case, 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. For example, a patch (a plaster, a plaster, a tape (reservoir, matrix, etc.), a cataplasm, a patch, a microneedle, etc.), an ointment, etc. Preparations, external liquids (liniments, lotions, etc.), sprays (external aerosols, pump sprays, etc.), creams, gels, eye drops, eye ointments, nasal drops, suppositories, rectal semisolids In order to provide it as an enema, etc., particles or particle-containing basic components can be mixed and dispersed or emulsified in the base used in each dosage form.

3. Method for Producing Particles and Formulations 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 a homogenizer stirring are about 5000-50000 rpm, for example, More preferably, it is about 10000-30000 rpm.

  The weight ratio of the active ingredient to the surfactant in the W / O emulsion (active ingredient weight: surfactant weight) 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. For example, freeze-drying, reduced-pressure drying, and the like are preferable. Can be mentioned.

  Although not intended to be limited in interpretation, 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. In the case where the component is a free form, it is considered that it may vary depending on the type of salt that it can form. For example, if the weight ratio of the active ingredient to the surfactant is too low or too high, the cohesion index X tends to increase. However, the appropriate weight ratio may vary depending on the active ingredient. The active ingredient is an acidic salt (or a free form capable of forming an acidic salt), or has an octanol water partition coefficient within a predetermined range (preferably −3 to 6, more preferably −2 to 6, more preferably − 2-5), it is easier to obtain the desired cohesiveness index X of the present invention. 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.

  Moreover, a formulation can be manufactured, for example with a solution coating method using the particle | grains of this invention. In the solution coating method, in addition to the particles and the base of the present invention, 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.

  Next, the above solution containing each component is uniformly applied on a release liner (silicone-treated polyester film, etc.) using 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. Depending on the type of the support, after the drug-containing layer is formed on the support, a release liner may be laminated on the surface of the drug-containing layer.

  In addition, as another method, for example, 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. , A natural fabric member such as gauze or absorbent cotton, a synthetic fiber fabric member such as polyester or polyethylene, or a combination of these appropriately processed into a woven or non-woven 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 a shape such as an oval, a circle, a square, or a rectangle according to the intended use. Moreover, you may provide an adhesive phase etc. in the periphery as needed.

  EXAMPLES The present invention will be described in detail below based on examples, but the present invention is not limited to these examples.

Example 1 (active ingredient: surfactant = 1: 30)
Memantine hydrochloride (manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient 0.3) 0.1 g was dissolved in 40 g of pure water, and sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB) Value 2) A solution prepared by dissolving 3.0 g in 80 g of cyclohexane was added, and the mixture was stirred with a homogenizer (10,000 rpm). This was followed by lyophilization for 2 days to obtain particles containing the active ingredient and surfactant. Moreover, the number average particle diameter calculated by the dynamic light scattering method (Spectris Co., Ltd., Zetasizer Nano S) was 100 nm.

Example 2 (active ingredient: surfactant = 1: 50)
Particles were prepared in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was 5.0 g.

Example 3 (active ingredient: surfactant = 1: 100)
Particles were prepared in the same manner as in Example 1 except that the amount of sucrose erucic acid ester was 10 g.

Example 4 (active ingredient: surfactant = 1: 5)
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.

Example 5 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 4 except that the amount of sucrose erucic acid ester was 1.0 g.

Example 6 (active ingredient: surfactant = 1: 30)
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 7 (active ingredient: surfactant = 1: 5)
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.

Example 8 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 7 except that the amount of sucrose erucic acid ester was 1.0 g.

Example 9 (active ingredient: surfactant = 1: 30)
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 (active ingredient: surfactant = 1: 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.

Example 11 (active ingredient: surfactant = 1: 30)
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.

Example 12 (active ingredient: surfactant = 1: 50)
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 13 (active ingredient: surfactant = 1: 15)
Example 1 except that octreotide acetate (manufactured by 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.

Example 14 (active ingredient: surfactant = 1: 30)
Particles were prepared in the same manner as in Example 13 except that the amount of sucrose erucic acid ester was changed to 3.0 g.

Example 15 (active ingredient: surfactant = 1: 50)
Particles were prepared in the same manner as in Example 13 except that the amount of sucrose erucic acid ester was 5.0 g.

Comparative Example 1 (active ingredient: surfactant = 1: 50)
Except that risedronate sodium 2.5 hydrate (manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient -5.0) was used instead of memantine hydrochloride, and the amount of sucrose erucic acid ester was 5.0 g Prepared particles in the same manner as in Example 1.

Comparative Example 2 (active ingredient: surfactant = 1: 100)
Particles were prepared in the same manner as in Comparative Example 1 except that the amount of sucrose erucic acid ester was 10 g.

Comparative Example 3 (active ingredient: surfactant = 1: 6.67)
Diclofenac sodium (manufactured by Tokyo Chemical Industry Co., Ltd., water octanol partition coefficient 13.4) 0.1 g and bovine serum albumin (BSA) (manufactured by Sigma-Aldrich) 0.067 g were added to 40 g of phosphate buffer (pH 8.0). The solution which melt | dissolved and melt | dissolved the sucrose erucic acid ester 0.667g in the cyclohexane 80g was added to this, and the homogenizer stirring (10,000 rpm) was carried out. This was followed by lyophilization for 2 days to obtain particles containing the active ingredient and surfactant.

Comparative Example 4 (active ingredient: surfactant = 1: 8.33)
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.

Comparative Example 5 (active ingredient: surfactant = 1: 16.67)
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.

Comparative Example 6 (active ingredient: surfactant = 1: 3)
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.

Comparative Example 7 (active ingredient: surfactant = 1: 5)
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.

Comparative Example 8 (active ingredient: surfactant = 1: 10)
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 the small-angle X-ray scattering method )) Was analyzed. The analysis conditions are as follows.

X-ray source: High Brightness Optical Science 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.

Based on the obtained data, a scattering profile was created in which the horizontal axis (common logarithmic axis) represents the size of the scattering vector q [nm ⁻¹ ] and the vertical axis (common logarithmic axis) represents the scattering intensity I. Note that q = (4π / λ) sin (θ / 2) (where the wavelength of X-ray is λ and θ is a scattering angle). The created scattering profile was normalized based on the maximum value of the scattering intensity. Specifically, in each scattering profile, [α / 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 α. Normalized scattering profiles are shown in FIGS.

Furthermore, the scattering intensity when the scattering vector q is 0.2 [nm ⁻¹ ] in the normalized scattering profile of the particles is the same as the scattering intensity 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.

When α is set to 1 in the normalization method, the cohesiveness index can be calculated from the scattering profile (before normalization) by the following formula (1).
Equation _{(1): X = (S} 1 / Sr 1) / (S 0 / Sr 0) (1)
Wherein (1), _{S 1} is in the scattering profile obtained by small-angle X-ray scattering of particles, showing the scattering intensity when the scattering vector q is 0.2 ^{[nm -1].} 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). In the upper part of this apparatus, 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) were added to Plastibase (Taisho Pharmaceutical Co., Ltd.), mixed and dispersed so that the active ingredient was 1% by weight based on the total weight of the preparation. 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. Methanol was added to each collected receptor fluid sample to extract the eluted lipids and centrifuged, and then the active ingredient concentration in the supernatant was quantified by high performance liquid chromatography (HPLC) (device: system controller; Shimadzu) CBM-20A manufactured by Seisakusho Co., Ltd .; Liquid feeding unit; LC-20AD manufactured by Shimadzu Corp., column oven; CTO-20A manufactured by Shimadzu Corp., detector; SPD-20A manufactured by Shimadzu Corp.

Based on the calculated cumulative permeation amount after 48 hours (μg / cm ² ), the magnification (magnification permeation rate magnification) at which the cumulative permeation amount was changed by atomizing the active ingredient was expressed as [when particles were applied. The cumulative permeation amount after 48 hours (μg / cm ² )] was calculated as the value obtained by dividing the cumulative permeation amount after 48 hours when only the active ingredient was applied (μg / cm ² )]. The results are shown in Table 2.

  As shown in Table 2, the particles of the comparative example (aggregation index> 30) did not improve the skin permeability due to the formation of the active ingredients (magnification permeation rate magnification ≦ 1.0). In contrast, the particles of the examples (cohesiveness index ≦ 30) had improved skin permeability due to the formation of active ingredients (magnification permeation rate magnification> 1.0).

Example 16 (active ingredient: surfactant = 1: 10)
0.1 g of octreotide acetate (manufactured by BACHEM, water octanol partition coefficient -1.2) is dissolved in 40 g of pure water, and 1.0 g of oleic acid diethanolamide (manufactured by NOF Corporation, Stahome DOS) is added thereto. 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.

Example 17 (active ingredient: surfactant = 1: 10)
Octreotide acetate (BACHEM, water octanol partition coefficient -1.2) 0.1 g and N-lauroyl sarcosine sodium (Nacalai Tesque) 0.02 g were dissolved in 40 g of pure water. A solution prepared by dissolving 1.0 g of DODO (manufactured by NOF Corporation, Stahome DOS) 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.

Example 18 (active ingredient: surfactant = 1: 10)
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 instead of N-lauroyl sarcosine sodium.

Example 19 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 17 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.

Example 20 (active ingredient: surfactant = 1: 10)
Fenoterol hydrobromide (manufactured by Wako Pure Chemical Industries, Ltd., water octanol partition coefficient -0.3) was used instead of octreotide acetate, and sucrose oleate (Mitsubishi Chemical Foods, Inc.) instead of oleic acid diethanolamide Particles were prepared in the same manner as in Example 16 except that O-170; HLB value 1) was used.

Example 21 (active ingredient: surfactant = 1: 30)
Particles were prepared in the same manner as in Example 20 except that the amount of sucrose oleate was 3.0 g.

Example 22 (active ingredient: surfactant = 1: 10)
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.

Example 23 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 17 except that fenoterol hydrobromide (manufactured by Wako Pure Chemical Industries, Ltd., water octanol partition coefficient -0.3) was used instead of octreotide acetate.

Example 24 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 18 except that fenoterol hydrobromide (manufactured by Wako Pure Chemical Industries, Ltd., water octanol distribution coefficient -0.3) was used instead of octreotide acetate.

Comparative Example 9 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 16 except that sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) was used instead of oleic acid diethanolamide.

Comparative Example 10 (active ingredient: surfactant = 1: 10)
Particles were prepared in the same manner as in Example 20 except that sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) was used instead of sucrose oleate.

  For the particles obtained in Examples 16 to 24 and Comparative Examples 9 and 10, according to Test Example 1 (small angle X-ray scattering analysis) and Test Example 2 (hairless rat skin permeability test), the cohesiveness index and particle formation Permeation magnification was evaluated. The results are shown in Table 3 below.

  As shown in Table 3, the particles of the comparative example (aggregability index> 30) did not improve the skin permeability due to the formation of the active ingredient (magnification permeation rate magnification ≦ 1.1). In contrast, the particles of the examples (aggregation index ≦ 30) had improved skin permeability due to the formation of active ingredients (magnification permeation ratio> 1.1).

1 Parafilm 2 Skin 3 Formulation 4 Receptor solution (pH = 7.2 phosphate buffer)
5 Stir bar

Claims (8)

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.
Equation _{(1): X = (S} 1 / Sr 1) / (S 0 / Sr 0)
Wherein (1), _{S 1} is in the scattering profile obtained by small-angle X-ray scattering of the particle, showing a scattering intensity when the scattering vector q is 0.2 ^{[nm -1].} 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. ]   The particle according to claim 1, wherein a part or all of the surface of the first fraction is covered with the second fraction. The particle according to claim 1, wherein the maximum value is a maximum value within a range of a scattering vector q of 1.0 to 3.0 [nm ⁻¹ ].   The particle | grains of any one of Claims 1-3 whose octanol water partition coefficient of the said active ingredient is -2-6.   The formulation containing the particle | grains of any one of Claims 1-4.   The preparation according to claim 5, wherein a weight ratio of the active ingredient to the surfactant is 1: 5 to 1: 100.   An external preparation containing the preparation according to claim 5 or 6.   Cosmetics containing the preparation according to claim 5 or 6.

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