JP6809784B2 - Formulation - Google Patents

Description

The present invention relates to a preparation, and more particularly to a preparation used as an external medicine, a cosmetic, or the like.

Topical drugs that show systemic action by transferring the drug absorbed through the skin to the systemic circulation (systemic action type topical drug), or topical drugs that show local efficacy of drugs absorbed through the skin (topical action type topical drug) Medicine) is used. In addition, cosmetics (transdermal cosmetics) aimed at percutaneously absorbing the active ingredient are also used.
In these preparations, storage stability and skin permeability of the active ingredient are major technical issues, and preparations containing particles mainly composed of the active ingredient and a surfactant have been proposed. (Patent Documents 1 and 2). These particles are usually obtained by homogenizing a water (W) phase containing an active ingredient and an oil (O) phase containing a surfactant to obtain a W / O emulsion, which is freeze-dried or the like. Obtainable.

Japanese Unexamined Patent Publication No. 2009-084293 International Publication No. 2006/025583

However, the present inventors have found that in a preparation containing particles mainly composed of an active ingredient and a surfactant, the shape of the particles may change with the passage of time.

An object of the present invention is to provide a preparation containing particles containing an active ingredient and a surfactant and having excellent shape stability.

The present inventors have conducted diligent studies to solve the above problems, and by adjusting the pH of the aqueous phase containing the active ingredient during the production of particles mainly composed of the active ingredient and the surfactant. , I found that the above problem can be solved. The present invention has been completed through further trial and error based on such findings, and includes the following aspects.
Item 1.
Particles containing active ingredients, surfactants and pH regulators.
Item 2.
Contains the first and second fractions,
Item 2. The particle according to Item 1, wherein the first fraction contains the active ingredient and the pH adjuster.
Item 3.
Item 2. The particles according to Item 1 or 2, wherein the pH adjusting agent is at least one pH adjusting agent selected from the group consisting of inorganic acids, organic acids, and salts thereof.
Item 4.
Item 2. The particle according to any one of Items 1 to 3, wherein the pH adjusting agent is at least one pH adjusting agent selected from the group consisting of hydrochloric acid and hydrochloride.
Item 5.
Item 2. The particle according to any one of Items 1 to 4, wherein the pH adjuster is contained in an amount of 0.01 to 2% by weight based on the whole particle.
Item 6.
Item 2. The particle according to any one of Items 1 to 5, wherein the active ingredient is hydrophilic.
Item 7.
A preparation containing the particles according to any one of Items 1 to 6.
Item 8.
A method for producing particles containing an active ingredient, a surfactant and a pH adjuster.
(1) A step of preparing an aqueous (W) phase containing an active ingredient and a pH adjuster;
(2) A step of homogenizing the water (W) phase and the oil (O) phase containing a surfactant to obtain a W / O emulsion; and (3) a step of drying the W / O emulsion. ,Production method.

According to the present invention, it is possible to provide a preparation containing particles mainly composed of an active ingredient and a surfactant, and having excellent shape stability of the particles.

It is an observation image by the optical microscope of the preparation obtained in Example 1. It is an observation image by the optical microscope of the preparation obtained in Comparative Example 1. It is an observation image by the optical microscope of the preparation obtained in Comparative Example 2.

1. 1. Composition of Formulation The formulation of the present invention contains at least the following particles.

1.1 Particles Particles contain active ingredients and surfactants. More specifically, the particles contain at least two fractions, a first fraction containing the active ingredient and a second fraction containing the surfactant.

In the particles, the surfactant in the second fraction covers a part or the entire surface of the first fraction containing the active ingredient. When the particles have such a constitution, the preparation of the present invention can slowly release the active ingredient of the first fraction.

It is sufficient that the first fraction and the second fraction are connected to each other (preferably by intermolecular force) to form an aggregate. The entire surface of the first fraction may be covered with the second fraction, and the entire surface of the first fraction may not be covered with the second fraction.

An example of the embodiment of the particles is a core-shell structure in which the first fraction corresponds to the core portion and the second fraction corresponds to the shell portion including the core portion. In the core-shell structure, the entire surface of the core portion does not necessarily have to be covered with the shell portion.

1.1.1 First Fraction The first fraction contains at least the active ingredient and a pH regulator.

The active ingredient is not particularly limited as long as it is an ingredient having physiological activity. Preferably, it is a component compounded for the purpose of exerting its physiological activity. In this preferred embodiment, the active ingredient does not include those having a physiological activity but not being blended for the purpose of exerting the physiological activity from the viewpoint of the blending amount, blending method and the like. Examples of the active ingredient include an ingredient blended as an active ingredient in pharmaceuticals, cosmetics and the like. Since most of the active ingredients of pharmaceuticals and cosmetics are organic substances, the active ingredients may be organic substances.

The active ingredient is not particularly limited and can be widely selected.

The active ingredient is preferably hydrophilic.

The active ingredient is not particularly limited as long as it is hydrophilic, but typically, an active ingredient having the following properties can be used:
The molecular weight is 10,000 or less, and the octanol water partition coefficient is -8 to 6.

In the above, the molecular weight is preferably 5000 or less, more preferably 2000 or less. The lower limit of the molecular weight is not particularly limited, but is usually 50 or more.

In the above, the octanol water partition coefficient is preferably -6 to 5, and more preferably -5 to 4.

In the present invention, the octanol water partition coefficient is calculated by the following formula from the concentration of the active ingredient in each phase after adding the active ingredient to a flask containing an aqueous buffer solution of octanol and pH 7. And.

Octanol water partition coefficient = Log ₁₀ (octanol phase concentration / aqueous phase concentration)

The active ingredient is not particularly limited in the case of a drug, but a drug that is required to have a systemic action or a local action is preferably used.

Specific examples of the active ingredient contained in the pharmaceutical product are not particularly limited, but for example, a dementia therapeutic agent, an antiepileptic agent, an antidepressant agent, an antiparkinsonian disease agent, an antiallergic agent, an anticancer agent, an antidiabetic agent, an antihypertensive agent, Examples thereof include ED therapeutic agents, skin disease agents, local anesthetics, and pharmaceutically acceptable salts thereof. More specifically, donepezil, valdenafil, rivastigmine, duloxetine, galantamine, nitroglycerin, lidocaine, fentanyl, male hormones, female hormones, nicotine, chromipramine, diphenhydramine, nalfurafine, metoprolol, fesoterodin, valdenafil, nalfrafin, tandospirone. Examples thereof include sodium, tartilelin, lulacidone, nephazodone, rivaxetine, benidipine, doxazosin, nicardipine, formoterol, romelysin, amlodipine, octreotide, teriparatide, bucladesin and chromoglycic acid, and pharmaceutically acceptable salts thereof. The pharmaceutically acceptable salt is not particularly limited, and for example, hydrochlorides such as donepezil hydrochloride, valdenafil hydrochloride and duroxetine hydrochloride, tartrate salts such as rivastigmine tartrate, hydrobromide such as galantamine hydrobromide, and fe. Examples thereof include fumarate such as soterodin fumarate and citrate such as tandospirone citrate.

The active ingredient is not particularly limited as long as it is required to permeate the skin in the case of cosmetic use. For example, vitamin components such as vitamin C and vitamin E, moisturizing components such as hyaluronic acid, ceramide and collagen, and tranexamic acid. , Whitening components such as albutin, 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 amount of the active ingredient contained in the particles depends on the type of the active ingredient, but can be, for example, 0.1 to 50% by weight based on the whole particles.

The first fraction may contain two or more kinds of active ingredients, if necessary. In this case, at least one active ingredient can be used as a combination drug.

In the present invention, the pH adjuster refers to a compound that changes the pH of an object by adding it to the object, and is not particularly limited. Preferably, the pH adjuster is a compound (pH lowering agent) that lowers the pH by adding it to an object.

The pH adjuster is not particularly limited. For example, it may be at least one pH adjuster selected from the group consisting of inorganic acids or organic acids and salts thereof.

Specific examples of the inorganic acid are not particularly limited, and examples thereof include hydrochloric acid, sulfuric acid, phosphoric acid and the like.

Specific examples of the organic acid are not particularly limited, and examples thereof include citric acid, adipic acid, succinic acid, tartaric acid, lactic acid, fumaric acid, malic acid, benzoic acid, acetic acid and gluconic acid.

Specific examples of the pH adjuster include, but are not limited to, hydrochlorides, citrates, and the like.

The particles of the present invention preferably contain a pH adjuster so that the relative ratio to the active ingredient is as follows. That is, the particles of the present invention use these components so that the ratio of the active ingredient and the pH adjuster is lower than the pH of the aqueous solution in which the active ingredient is dissolved so that the concentration of the active ingredient is 0.5% by weight. Includes. By containing the pH adjuster in such a relative ratio, the particles of the present invention have excellent shape stability.

In the above, the degree of decrease in pH can be adjusted according to the type of active ingredient. Although not particularly limited, in general, a pH (value) decrease of 1 or more is preferable, 2 or more is more preferable, 3 or more is more preferable, and 4 or more is even more preferable.

The particles of the present invention preferably contain a pH adjuster in an amount of 0.01 to 2% by weight based on the whole particles from the viewpoint of shape stability of the particles of the present invention.

In the present invention, the pH adjuster in the particles of the present invention can be detected by a method including the following steps (1) to (5).
(1) In distilled water, NaH ₂ PO ₄ is 5 × 10 ^-4 M, Na ₂ HPO ₄ is 2 × 10 ^-4 M, NaCl is 1.5 × 10 ^-4 M, and gentamicin sulfate (manufactured by Wako Pure Chemical Industries, Ltd.). , G1658) is further adjusted to pH 7.2 with NaOH to prepare a buffer solution (4 mL).
(2) Using the particles of the present invention and using liquid paraffin as a dispersion solvent, a 7.5% S / O preparation is prepared by the method described below.
(3) The 7.5% S / O preparation (0.8 mL) obtained in (2) above is added to the buffer solution obtained in (1) above.
(4) The drug and pH adjuster in the S / O preparation are eluted into the buffer solution by stirring the solution obtained in (3) above overnight.
(5) The pH adjuster contained in the solution obtained in (4) above is detected by liquid chromatography or the like.

The first fraction may further contain at least one additional component in addition to the active ingredient and the pH adjuster.

Other components include, but are not limited to, stabilizers, transdermal absorption promoters, skin irritation reducers, preservatives, and the like.

Since the stabilizer has an action of stabilizing the structure of the particles, the sustained release effect of the active ingredient can be ensured by preventing the particles from unintentionally prematurely collapsing.

The stabilizer is not particularly limited, and specific examples thereof include polysaccharides, proteins, and hydrophilic polymer materials. The stabilizer may contain one kind or two or more kinds. The content of the stabilizer in the first fraction can be appropriately set depending on the type thereof. For example, the stabilizer is blended so that the weight ratio of the active ingredient to the stabilizer is 100: 1 to 1:10. You can also do it.

The transdermal absorption accelerator is not particularly limited, but specifically, a higher alcohol, N-acylsarcosine and a salt thereof, a higher monocarboxylic acid, a higher monocarboxylic acid ester, an aromatic monoterpene fatty acid ester, and 2 carbon atoms. Examples thereof include 10 to 10 divalent carboxylic acids and salts thereof, polyoxyethylene alkyl ether phosphoric acid esters and salts thereof, lactic acid, lactic acid esters, citric acid and the like. The percutaneous absorption promoter may contain one kind or two or more kinds. The content of the transdermal absorption promoter in the core portion can be appropriately set depending on the type thereof, but for example, the weight ratio of the active ingredient to the transdermal absorption promoter is 100: 1 to 1:50. It can also be blended.

The skin irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantethine, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium nitrite, soybean lecithin, methionine, etc. Examples thereof include glycyrrhetinic acid, BHT, BHA, vitamin E and its derivatives, vitamin C and its derivatives, benzotriazole, propyl nitrite, and mercaptobenzimidazole. The skin irritation reducing agent may contain one kind or two or more kinds. The content ratio of the skin irritation reducing agent in the first fraction can be appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.1% to 50%.

The preservative is not particularly limited, and specific examples thereof include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. The content ratio of the preservative in the first fraction can be appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.01% to 10%. The preservative may contain one or more.

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

In addition, a plurality of types of surfactants may be used in combination.

As the surfactant, one having a weighted average value of HLB (Hydrophile Hydrophilic Balance) value of 10 or less, preferably 5 or less, and more preferably 3 or less can be used.

In terms of absorbability of the preparation, the surfactant preferably has a melting point of 50 ° C. or lower, and more preferably 40 ° C. or lower.

As the surfactant, preferably, a surfactant having a weighted average value of HLB value of 10 or less and a melting point of 50 ° C. or less can be used, and more preferably, a weighted average value of HLB value of 5 or less and a melting point is used. Can be used at 50 ° C. or lower, and more preferably, a weighted average HLB value of 5 or less and a melting point of 40 ° C. or lower can be used.

The HLB value in the present invention is an index for knowing whether the emulsifier is hydrophilic or lipophilic, and has a value of 0 to 20.
The smaller the HLB value, the stronger the lipophilicity. In the present invention, it is calculated from the following Griffin formula.
HLB value = 20 × {(molecular weight of hydrophilic part) / (total molecular weight)}
The weighted average value of the HLB value is calculated as follows.
For example, the formula for calculating the weighted average value when there are surfactant raw materials having HLB values A, B, and C and the charged weights at the time of particle synthesis are x, y, and z is
(XA + yB + zC) ÷ (x + y + z)

Further, the melting point of the surfactant in the present invention is determined by the endothermic peak in the differential scanning calorimetry (DSC) measurement.

The surfactant is not particularly limited and can be appropriately selected depending on the intended use. For example, it can be widely selected from those that can be used as external medicines and cosmetics.

The surfactant may be any of a nonionic surfactant, an anionic surfactant, a cationic surfactant and an amphoteric surfactant.

The nonionic surfactant is not particularly limited, and examples thereof include fatty acid ester, fatty alcohol ethoxylate, polyoxyethylene alkyl phenyl ether, alkyl glycoside, and fatty acid alkanolamide.

The fatty acid ester is not particularly limited, but a sugar fatty acid ester is preferable. In particular, sucrose fatty acid esters are preferred. Specific examples thereof include esters of sucrose and fatty acids such as erucic acid, oleic acid, lauric acid, stearic acid and behenic acid.

The other fatty acid ester is not particularly limited, and examples thereof include an ester of at least one of glycerin, polyglycerin, polyoxyethylene glycerin, sorbitan, polyoxyethylene sorbit, and the like with a fatty acid. In particular, polyglycerin fatty acid ester is preferable.

Examples of the anionic surfactant include alkyl sulfates, polyoxyethylene alkyl ether sulfates, alkylbenzene sulfonates, fatty acid salts, phosphate salts and the like.

Examples of the cationic surfactant include alkyltrimethylammonium salt, dialkyldimethylammonium salt, alkyldimethylbenzylammonium salt and amine salts.

Examples of amphoteric surfactants include alkylamino fatty acid salts, alkyl betaines and alkyl amine oxides.

The surfactant is not particularly limited, but may have an alkyl chain. The alkyl chain length is not particularly limited, but can be widely selected from 8 to 30, and particularly preferably 10 to 24.

When only a surfactant having an alkyl chain is used, or when a surfactant having an alkyl chain is used in combination with another surfactant, the total weight ratio of the active ingredient and the alkyl chain contained in the surfactant is determined. If it is 1: 1 to 1:70, the preparation of the present invention has excellent absorbability. In this respect, it is preferable that the weight ratio is 1: 2 to 1:50.

The second fraction may further contain at least one additional component in addition to the surfactant. Other components include, but are not limited to, irritation reducing agents, analgesics, absorption promoters, stabilizers, preservatives and the like.

The irritation reducing agent is not particularly limited, but specifically, hydroquinone glycoside, pantetin, tranexamic acid, lecithin, titanium oxide, aluminum hydroxide, sodium nitrite, sodium hydrogen nitrite, soybean lecithin, methionine, and glycyrrhetin. Examples thereof include acid, BHT, BHA, vitamin E and its derivatives, vitamin C and its derivatives, benzotriazole, propyl nitrite, 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 appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.1% to 50%.

The analgesic is not particularly limited, and specific examples thereof include local anesthetics such as procaine, tetracaine, lidocaine, dibucaine and prlocaine, and salts thereof. The analgesic may contain one or more. The content ratio of the analgesic in the second fraction can be appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.1% to 30%.

The absorption accelerator is not particularly limited, but specifically, a higher alcohol, N-acylsarcosine and a salt thereof, a higher monocarboxylic acid, a higher monocarboxylic acid ester, an aromatic monoterpene fatty acid ester, and 2 to 10 carbon atoms. Divalent carboxylic acid and its salt, polyoxyethylene alkyl ether phosphoric acid ester and its salt, lactic acid, lactic acid ester, citric acid and the like. The absorption accelerator may contain one kind or two or more kinds. The content ratio of the absorption accelerator in the shell portion can be appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.1% to 30%.

The stabilizer has the effect of stabilizing the particles. Stabilizers can ensure a sustained release effect of the drug by preventing unintentional premature disintegration of the particles.

The stabilizer is not particularly limited, but specifically, fatty acids and salts thereof, parahydroxybenzoic acid esters such as methylparaben and propylparaben, alcohols such as chlorobutanol, penzyl alcohol and phenylethyl alcohol, and thimerosal. , Acetic acid anhydride, sorbic acid, sodium hydrogen sulfite, L-ascorbic acid, sodium ascorbic acid, butyl hydroxyanisole, petit hydroxytoluene, propyl gallate, tocopherol acetate, dl-α-tocopherol, proteins and polysaccharides. The stabilizer may contain one kind or two or more kinds. The content of the stabilizer in the second fraction can be appropriately set depending on the type thereof, and for example, the weight ratio of the surfactant to the stabilizer is set to 1: 0.01 to 1:50. It can also be blended in.

The preservative is not particularly limited, and specific examples thereof include methyl paraoxybenzoate, propyl paraoxybenzoate, phenoxyethanol, and thymol. The preservative may contain one or more. The content ratio of the preservative in the second fraction can be appropriately set depending on the type thereof, but for example, it can be blended so as to be 0.01% to 10%.

Formulations 1.2 groups agent phase present invention may contain a phase further comprises a base (base phase). The base phase may contain the above particles. At this time, the particles may be dispersed in the base phase.

The base can be appropriately selected from those suitable for dispersing the particles according to the purpose of use and the like, and is not particularly limited.

In addition, a plurality of types of bases may be used in combination.

The base is not particularly limited, but for example, 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. Classes, silicones, higher (polyhydric) alcohols, higher fatty acids, fluorine-based oils and the like. Further, these can be used in combination as appropriate.

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, beni flower oil and rapeseed oil. ..

The animal oil is not particularly limited, and examples thereof include mink oil, turtle oil, fish oil, cow oil, horse oil, lard, and shark squalane.

The triglyceride is not particularly limited, and examples thereof include triolein, triolein, trimyristin, tristearin, and triarachidonin.

The synthetic fats and oils are not particularly limited, and examples thereof include phospholipids and azone.

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

Examples of waxes include candelilla wax, carnauba wax, rice wax, wood wax, honey wax, montan wax, ozokerite, ceresin, paraffin wax, microcrystallin wax, petrolatum, fishertroph wax, polyethylene wax and ethylene-propylene copolymer. Can be 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, squalane, vaseline and solid paraffin. Be done.

Examples of monoalcohol carboxylic acid esters include octyldodecyl myristate, hexyldecyl myristate, octyldodecyl isostearate, cetyl parimitinate, octyldodecyl palmitate, cetyl octanate, hexyldecyl octanoate, isotridecyl isononanoate, and isononyl isononanoate. Octyl isononanoate, Isotridecyl isononanoate, Isodecyl neopentanoate, Isotridecyl neopentate, Isostearyl neopentate, Octyldodecyl neodecanoate, Oleyl oleate, Octyldodecyl lysinoleate, Octyldodecyl licinoleate, Hexyl dimethyloctane , Octyldodecyl erucate, hardened isostearic acid castor oil, ethyl oleate, ethyl avocado fatty acid, isopropyl myristate, isopropyl palmitate, octyl palmitate, isopropyl isostearate, lanolin fatty acid isopropyl, diethyl sebatate, diisopropyl sebatate, sebatin Examples thereof include dioctyl acid acid, diisopropyl adipate, dibutyloctyl sebatate, diisobutyl adipate, dioctyl succinate and triethyl citrate.

Examples of oxyacid esters include cetyl lactate, diisostearyl malate, and hydrogenated castor oil monoisostearic acid.

Examples of polyhydric alcohol fatty acid esters include glyceryl trioctanoate, glyceryl trioleate, glyceryl triisostearate, glyceryl diisostearate, tri (capric acid / capric acid) glyceryl, and tri (capric acid / capric acid / myristic acid / stearic acid). ) Glyceryl, hydrogenated rosin triglyceride (hydrogenated ester gum), rosin triglyceride (ester gum), glyceryl beecosanate, glyceryl trioctanoate, trimethylol propane triisostearate, neopentyl glycol dioctanoate, neo dicaprate Pentyl glycol, 2-butyl-2-ethyl-1,3-propanediol dioctanoate, propylene glycol dioleate, pentaerythrityl tetraoctanoate, hydrogenated rosin pentaerythrityl, ditrimethylolpropane triethylhexanoate, (isostearic acid / (Sebacic acid) ditrimethylolpropane, pentaerythricyl triethylhexanoate, (hydroxystearic acid / stearic acid / logonic acid) dipentaerythrityl, diglyceryl diisostearate, polyglyceryl tetraisostearate, polyglyceryl-10 nonaisostearate, deca (erucic acid / isostear) Acid / ricinoleic acid) polyglyceryl-8, (hexyldecanoic acid / sebacic acid) diglyceryl oligoester, glycol distearate (ethylene glycol distearate), 3-methyl-1,5-pentanediol dineopentanoate and 2,4-pentanoic acid Examples thereof include diethyl-1,5-pentanediol.

Examples of silicones include dimethicone (dimethylpolysiloxane), highly polymerized dimethicone (highly polymerized dimethylpolysiloxane), cyclomethicone (cyclic dimethylsiloxane, decamethylcyclopentasiloxane), phenyltrimethicone, diphenyldimethicone, phenyldimethicone, stearoxypropyl. Dimethylamine, (aminoethylaminopropylmethicone / dimethicone) copolymer, dimethiconol, dimethiconol crosspolymer, silicone resin, silicone rubber, amino-modified silicone such as aminopropyldimethicone or amodimethicone, cationically modified silicone, polyether-modified such as dimethicone polyol Silicone, polyglycerin-modified silicone, sugar-modified silicone, carboxylic acid-modified silicone, phosphate-modified silicone, sulfuric acid-modified silicone, alkyl-modified silicone, fatty acid-modified silicone, alkylether-modified silicone, amino acid-modified silicone, peptide-modified silicone, fluorine-modified silicone, Examples thereof include cation-modified or polyether-modified silicones, amino-modified or polyether-modified silicones, alkyl-modified or polyether-modified silicones, and polysiloxane / oxyalkylene copolymers.

Higher (polyvalent) alcohols include cetanol, myristyl alcohol, oleyl alcohol, lauryl alcohol, setostearyl alcohol, stearyl alcohol, araquil alcohol, behenyl alcohol, jojoba alcohol, chimil alcohol, seraquil alcohol, bacil alcohol, hexyldecanol, Examples thereof include isostearyl alcohol, 2-octyldodecanol and dimerdiol.

Higher fatty acids include lauric acid, myristic acid, palmitic acid, stearic acid, isostearic acid, behenic acid, undecylenic acid, 12-hydroxystearic acid, palmitic acid, oleic acid, linoleic acid, linoleic acid, erucic acid, docosahexaenoic acid. , Eikosapentaenoic acid, isohexadecanoic acid, anteisohenicosanoic acid, long-chain branched fatty acid, dimer acid, hydrogenated dimer acid and the like.

Fluorine-based oils include perfluorodecane, perfluorooctane, perfluoropolyether and the like.

The other bases are not particularly limited, and examples thereof include bases used for ointments, creams, aerosols, tapes, patches, paps, gels, microneedles, and the like.

As the base, in addition to those exemplified above, those containing other components as appropriate may be used. It may further contain an additive (gelling agent) or the like having a gelling action.
Such additives are not particularly limited, but are, for example, hydrocarbons such as resins and silicones, amino acids, cyclic peptides, epoxys, rosins, melamines, polysaccharides, pectins such as surfactants, alginic acid, carrageenan, and locusts. Bean gum, guar gum, xanthan gum, dextrin fatty acid ester, inulin fatty acid ester, glycerin fatty acid ester and the like can be used. The resin is not particularly limited, and examples thereof include polyethylene, polypropylene, polyester, polystyrene, and polyurethane. The base containing such a resin is not particularly limited, and for example, a base containing 0.1 to 50%, preferably 1 to 30% of these additives can be used. Such a base is not particularly limited, and is, for example, a hydrocarbon-based base such as liquid paraffin, cyclohexane, n-octane, toluene, and xylene, isopropyl myristate, isopropyl palmitate, cetyl ethylhexanate, and the like. The ester-based base of the above is preferably used. Specific examples of such a base include, but are not limited to, hydrocarbons such as Bristol Myers Squibb, which contains 95% liquid paraffin and 5% polyethylene resin as a gelling agent. A gel ointment base or the like can be used.

1.3 Other Additive Ingredients The preparation of the present invention may contain other additive ingredients in addition to the above particles and the above base phase, depending on the dosage form, purpose of use and the like.

Additives are not particularly limited, but are excipients, colorants, lubricants, binders, emulsifiers, thickeners, wetting agents, stabilizers, preservatives, solvents, solubilizers, suspending agents, etc. Examples thereof include buffers, pH adjusters, gelling agents, adhesives, antioxidants, absorption promoters, stimulants, preservatives, chelating agents and dispersants.

The blending amount of the surfactant in the preparation of the present invention can be appropriately set within the range in which the effect of the present invention is exhibited. For example, the weight ratio of the active ingredient in the preparation of the present invention to the blended amount can be 1: 3 to 1: 100. With such a configuration, not only the shape stability is excellent, but also the preparation having excellent absorbability can be obtained. In this respect, it is preferable that the weight ratio of the active ingredient in the preparation of the present invention to the blended amount is 1: 5 to 1:70.

2. 2. Method for Producing Formulation The preparation of the present invention is not particularly limited, but can be manufactured as follows, for example.

First, although not particularly limited, the particles of the present invention can be produced, for example, by a method including the following step (1).
(1) A step of homogenizing a water (W) phase containing an active ingredient and an oil (O) phase containing a surfactant to obtain a W / O emulsion.

It is preferable to lower the pH of the aqueous phase in the step (1) because the shape stability of the obtained particles is excellent. In the past, homogenization was often performed near neutrality for the purpose of dissolving the stabilizer. The pH is preferably 1 or more, more preferably 2 or more, still more preferably 3 or more, and even more preferably 4 or more, based on the aqueous phase containing no pH adjuster. For this pH adjustment, the above-mentioned pH adjusting agent can be used, if necessary.

The method for producing the preparation of the present invention may further include the following steps, if necessary.
(2) A step of drying the W / O emulsion obtained in the step (1).

In the step (2), the method for drying the W / O emulsion containing the active ingredient in the aqueous phase 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, vacuum-drying and the like are preferable, and freeze-drying is preferable.

The method for producing the preparation of the present invention may further include the following steps, if necessary.
(3) A step of dispersing the freeze-dried product obtained in step (2) in a base.

Specific examples of the method for producing the preparation of the present invention include the following.
The active ingredient and, if desired, additive components such as stabilizers, absorption enhancers and irritation reducers are dissolved in a solvent such as pure water or phosphate buffer. It is preferable to adjust the pH of this solvent by adding a pH adjuster as needed.
In the solution thus obtained, a solution prepared by dissolving an additive component such as a surfactant and, if desired, an irritation reducing agent, an analgesic, an absorption enhancer and a stabilizer in a solvent such as cyclohexane, hexane or toluene is added. In addition, a W / O emulsion is obtained by stirring with a homogenizer or the like.
After that, the particles of the present invention can be prepared by freeze-drying or the like, dispersing the particles in a base such as isopropyl myristate as necessary, and performing filtration treatment such as a filter, chromatography, centrifugation or the like. The formation of particles can be confirmed using particle size measurement or an optical microscope.

The particles can be used to produce, for example, the following formulations. A composition containing particles by adding and mixing particles in a predetermined ratio together with a base such as a liquid base or an ointment and additional components such as an absorption accelerator, a thickener and a gelling agent. To get. The composition thus obtained may be used as it is, or depending on the intended use, a natural woven fabric member such as gauze or absorbent cotton, a synthetic fiber woven fabric member such as polyester or polyethylene, or a woven fabric obtained by appropriately combining these. Alternatively, it can be processed into a non-woven fabric or the like, or can be used by being laminated or impregnated with a permeable film or the like to hold it, and further covered with an adhesive covering material or the like.

In addition, eye drop-type preparations can also be produced using particles. A pharmaceutically acceptable additive can be added to the ophthalmic solution as needed by using a general-purpose technique. The concentration of the active ingredient in the ophthalmic solution can usually be 0.0001 to 1% by weight, but is preferably 0.0005 to 0.5% by weight, particularly preferably 0.001 to 0.1% by weight. The preparation solution can be sterilized by filtration or other sterilization treatment. The sterilization method is not particularly limited as long as it can sterilize the obtained preparation solution, but is preferably filtration sterilization in which a filtration sterilization filter having a pore size of 0.1 to 0.5 μm is used for filtration.

Further, as another method for producing the preparation, for example, a solution coating method and the like can be mentioned. For example, first, the particles and base of the present invention, and additional components such as an absorption accelerator, a thickener, and a gelling agent are added to a solvent such as hexane, toluene, or ethyl acetate in a predetermined ratio, and stirred. To prepare a uniform 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 onto a release liner (silicone-treated polyester film, etc.) using a coating machine such as a knife coater, a comma coater, or a reverse coater, and dried. A preparation can be obtained by completing the active ingredient-containing layer and laminating a support on the layer. Depending on the type of support, after forming the layer on the support, a release liner may be laminated on the surface of the layer.

The preparation thus obtained is appropriately cut into a shape such as an ellipse, a circle, a square, or a rectangle according to the intended use. Further, an adhesive layer or the like may be provided in the periphery as needed.

3. 3. Uses of the formulation The formulation of the present invention can be used in a wide range of applications such as external medicines and cosmetics, depending on the type of active ingredient. The preparation of the present invention is not particularly limited, but can be used as a transdermal preparation. In this case, it is usually sustained for 1 day to 1 week and is preferably used to be applied once per day to 1 week.

When the preparation of the present invention is an external preparation, the target disease depends on the type of active ingredient.

The transdermal preparation of the present invention is not particularly limited, but is a tape agent (reservoir type, matrix type, etc.), ointment agent, lotion agent, aerosol agent, ointment agent, aqueous bop agent, cream agent, gel agent, aerosol agent. , Patch agent, microneedle, etc.

Hereinafter, the present invention will be described in detail with reference to Examples and Test Examples, but the present invention is not limited to these examples.

Manufacturing example 1
200 mg of donepezil hydrochloride (pKa = 8.9) is dissolved in 40 g of pure water, and 3.0 g of sucrose erucic acid ester (Mitsubishi Chemical Foods Co., Ltd., ER-290; HLB value 2) is dissolved in 80 g of cyclohexane. The solution was added. Four kinds of this solution are prepared, one is pH unadjusted (pH 5.47), and the remaining three kinds are pH so as to have low pH (pH 1.2 and pH 3.9) and high pH (pH 6.94), respectively. The adjustment was made at room temperature. A 1N hydrochloric acid aqueous solution and a 1N sodium hydroxide aqueous solution were used as the pH adjuster. The amounts of pH regulators used to prepare the low and high pH solutions were 5.4 mL, 1.3 mL and 1.3 mL, respectively.
Each of these four solutions was stirred with a homogenizer (10000 rpm) at room temperature. The particles of the present invention were then prepared by freeze-drying for 2 days. 75 mg of the obtained particles were dispersed in 925 mg of isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd.) to produce the preparation of the present invention.

Manufacturing example 2
200 mg of vardenafil hydrochloride (pKa = 8.8) is dissolved in 40 g of pure water, and 3.0 g of sucrose erucate (ER-290; HLB value 2) made by Mitsubishi Chemical Foods Co., Ltd. is added to 80 g of cyclohexane. The dissolved solution was added. Prepare three types of this solution, one with unadjusted pH (pH 2.74), and adjust the pH of the remaining two types at room temperature so that the pH is low (pH 1.2) and high pH (pH 5.53), respectively. It was. A 1N hydrochloric acid aqueous solution and a 1N sodium hydroxide aqueous solution were used as the pH adjuster. The amounts of the pH regulator used when preparing the low pH solution and the high pH solution were 1.2 mLg and 4.1 mLg, respectively.
Each of these three solutions was stirred with a homogenizer (10000 rpm) at room temperature. The particles of the present invention were then prepared by freeze-drying for 2 days. 75 mg of the obtained particles were dispersed in 925 mg of isopropyl myristate (manufactured by Wako Pure Chemical Industries, Ltd.) to produce the preparation of the present invention.

Manufacturing example 3
200 mg of rivastigmine tartrate (pKa = 8.9) is dissolved in 40 g of pure water, and 3.0 g of sucrose erucic acid ester (Mitsubishi Chemical Foods Co., Ltd., ER-290; HLB value 2) is added to 80 g of cyclohexane. The dissolved solution was added. Four kinds of this solution were prepared, one was set to unadjusted pH (pH 3.53), and the remaining three kinds were adjusted to pH at room temperature so as to have low pH (pH 1 and pH 2) and high pH (pH 10), respectively. .. A 1N hydrochloric acid aqueous solution and a 1N sodium hydroxide aqueous solution were used as the pH adjuster. The amounts of pH regulators used to prepare the low and high pH solutions were 3.8 mL, 1.2 mL and 6.8 mL, respectively.
Each of these four solutions was stirred with a homogenizer (10000 rpm) at room temperature. The particles of the present invention were then prepared by freeze-drying for 2 days. The obtained particles (25 mg) were dispersed in 925 mg of isitridesyl isitridesyl isononanoate (KAK139, manufactured by Higher Alcohol Industry Co., Ltd.) to produce the preparation of the present invention.

Manufacturing example 4
200 mg of duloxetine hydrochloride (pKa = 9.7) was dissolved in 40 g of pure water. Four kinds of this solution are prepared, one is pH unadjusted (pH 3.25), and the remaining three kinds are adjusted at room temperature so as to have low pH (pH 1, pH 2) and high pH (pH 7.47), respectively. It was. A 1N hydrochloric acid aqueous solution and a 1N sodium hydroxide aqueous solution were used as the pH adjuster. The amounts of pH regulators used to prepare the low and high pH solutions were 3.8 mL, 1.2 mL and 5.4 mL, respectively.
To each of these four solutions, a solution prepared by dissolving 3.0 g of sucrose erucic acid ester (manufactured by Mitsubishi Chemical Foods, ER-290; HLB value 2) in 80 g of cyclohexane was added, and the mixture was stirred with a homogenizer (10000 rpm) at room temperature. .. The particles of the present invention were then prepared by freeze-drying for 2 days. A preparation was produced by dispersing 75 mg of the obtained particles in 925 mg of isitridesyl isitridesyl isononanoate (KAK139, manufactured by Higher Alcohol Industry Co., Ltd.).

Shape stability test A shape stability test was performed on each of the preparations obtained in Production Examples 1 to 4. Specifically, each preparation was stored at 60 ° C., and evaluation was made based on how many days after the start of storage the shape change compared with the initial stage was observed. Observation was performed with an optical microscope. The results are shown in Table 1 and FIGS. In Table 1, those in which the stability is improved as compared with the case where the pH is not adjusted are shown as examples, while those which are not improved are shown as comparative examples together with those in which the pH is not adjusted. FIGS. 1 to 3 show, in order, observation images of the preparations of Example 1, Comparative Example 1 and Comparative Example 2 at 60 ° C. after the lapse of the second day with an optical microscope. While the shape change did not occur in Example 1, the shape change occurred in Comparative Examples 1 and 2.

Claims (7)

Contains the first and second fractions,
The first fraction contains an active ingredient and a pH lowering agent.
The second fraction contains a surfactant and
The second fraction covers a part or the entire surface of the first fraction.
The active ingredient is at least one salt selected from the group consisting of hydrochloride, tartrate, hydrobromic acid, fumarate, and citrate.
The surfactant is a fatty acid ester,
Particles in which the pH lowering agent is an inorganic acid or an organic acid. The pH lowering agent is at least one selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, adipic acid, succinic acid, tartaric acid, lactic acid, fumaric acid, malic acid, benzoic acid, acetic acid and gluconic acid. The particle according to claim 1. The particles according to claim 1 or 2, wherein the pH lowering agent is hydrochloric acid. The particle according to any one of claims 1 to 3, which contains the pH lowering agent in an amount of 0.01 to 2% by weight based on the whole particle. The particle according to any one of claims 1 to 4, wherein the active ingredient is hydrophilic. A preparation containing the particles according to any one of claims 1 to 5. A method for producing particles containing an active ingredient, a surfactant, and a pH lowering agent.
The active ingredient is at least one salt selected from the group consisting of hydrochloride, tartrate, hydrobromic acid, fumarate, and citrate.
The surfactant is a fatty acid ester,
The pH lowering agent is an inorganic acid or an organic acid.
(1) A step of preparing an aqueous (W) phase containing an active ingredient and a pH lowering agent;
(2) A step of homogenizing the water (W) phase and the oil (O) phase containing a surfactant to obtain a W / O emulsion; and (3) a step of drying the W / O emulsion. ,Production method.