WO2010098230A1 - Transdermal preparation - Google Patents

Abstract

Disclosed is an excellently safe transdermal preparation which enables excellent percutaneous absorption of citalopram, while having reduced skin irritation due to citalopram. Specifically disclosed is a transdermal preparation for reducing the skin irritation due to citalopram. The transdermal preparation contains at least one medicine selected from a group consisting of citalopram and pharmaceutically acceptable salts thereof, and at least one steroid selected from a group consisting of triamcinolone acetonide, flumethasone pivalate, alclometasone dipropionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone and prednisolone valerate acetate.

Description

Transdermal formulation

The present invention relates to a transdermal administration preparation that absorbs citalopram through the skin.

Citalopram is a drug classified as a selective serotonin reuptake inhibitor (SSRI) and is used as a drug to improve major depressive disorder, neurotic disorder, acute stress disorder, eating disorder, etc. (Patent Documents 1 to 3). As the administration method, oral administration is common. It is known that citalopram has R and S optical isomers.

On the other hand, when SSRI is orally administered to patients, side effects such as nausea, diarrhea and gastrointestinal tract are concerned, and there is also a decrease in compliance such as withdrawal of medication. Therefore, in recent years, administration methods other than oral administration have been studied. For example, Patent Document 3 discusses administration of an antidepressant such as SSRI by transdermal administration, and citalopram is mentioned as an example of an antidepressant.

However, when citalopram is administered transdermally, there is a problem that strong skin irritation occurs as a side effect. Therefore, in order to provide a citalopram-containing transdermal absorption preparation with little skin irritation that can actually be used at the treatment site, a citalopram-containing patch capable of long-term administration has been demanded.

On the other hand, Patent Document 5 discloses that skin irritation is reduced by administering an irritating drug together with a lactone compound having a hydroxyl group. However, there is room for improvement in skin irritation of a citalopram-containing preparation. There is.

Furthermore, Patent Document 6 discloses that a skin irritation reducing component (hydroquinone glycoside, pantethine, tranexamic acid, lecithin, etc.) can be blended with a patch containing fluvoxamine or fluvoxamine maleate as SSRI. However, there is no description of a transdermal preparation that actually contains citalopram.

On the other hand, for allergic dermatitis and atopic dermatitis, steroids for external use are often used as anti-inflammatory agents. Patent Document 4 discloses adding hydrocortisone to a preparation containing fluoxetine, which is an example of SSRI, in order to reduce skin irritation.

JP-T-2004-527551 JP-A-2-36177 US 2002-0192302 US Pat. No. 6,651,010 JP 2006-335714 A JP 2007-284378 A

Therefore, an object of the present invention is to provide a preparation for transdermal administration which is excellent in skin absorbability of citalopram and has excellent safety by reducing skin irritation caused by citalopram.

The present inventors formulated various skin irritation reducing components and anti-inflammatory agents in preparations showing a tendency to show primary skin irritation (Primary Skin Irritation) containing citalopram or a salt thereof, and have an effect on skin irritation. As a result of the investigation, it was found that specific anti-inflammatory steroids effectively reduce the skin irritation of citalopram.

In general, in anti-inflammatory steroids for external use, there are five levels (Class I (strongest), II (very strong), III (strong), IV (medium), Class V (weak)) depending on the strength of the anti-inflammatory action. )are categorized. The inventors of the present invention have no correlation with the suppression of skin irritation by citalopram (especially escitalopram) at all with respect to the strength of the anti-inflammatory action in the above-mentioned classification. Found that there is. In particular, by adding triamcinolone acetonide, it was found that skin irritation was remarkably reduced, and furthermore, even when triamcinolone acetonide was added, the percutaneous absorbability of citalopram or a salt thereof was not reduced, and the present invention was completed. It came to do.

That is, the present invention is a transdermal administration preparation for reducing skin irritation caused by citalopram, comprising at least one drug selected from the group consisting of citalopram and a pharmaceutically acceptable salt thereof, triamcinolone acetonide, There is provided a transdermal administration preparation containing at least one steroid selected from the group consisting of flumethasone pivalate, alcromethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone and prednisolone valerate acetate.

The steroid agent is preferably triamcinolone acetonide because of its excellent synergistic effect with the above drugs. In this case, the content of triamcinolone acetonide can be 0.005 to 0.5% by mass based on the total mass (based on the total amount of the preparation for transdermal administration).

From the viewpoint of medicinal effect, Sitalopram is preferably S-form, that is, escitalopram, among optical isomers.

Oxalate is excellent as a pharmaceutically acceptable salt of escitalopram, and a patch can be applied as a dosage form of a transdermal preparation. In this case, it is preferable to contain a styrene-isoprene-styrene block copolymer.

The present invention further provides a method of administering citalopram, particularly a method of reducing side effects caused by citalopram. The method of the present invention comprises at least one drug selected from the group consisting of citalopram and pharmaceutically acceptable salts thereof, triamcinolone acetonide, flumethasone pivalate, alcromethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone and And a step of administering to a patient a transdermal preparation containing at least one steroid selected from the group consisting of prednisolone valerate. According to the method of the present invention, it is possible to avoid side effects such as nausea, diarrhea, and digestive tract disorders caused by oral administration of citalopram, and to reduce skin irritation caused by transdermal administration of citalopram, so that the administration method of citalopram is excellent in safety. Can provide.

The transdermal administration formulation of the present invention is excellent in skin absorbability of citalopram, and is excellent in safety by reducing skin irritation caused by citalopram. Therefore, according to the preparation for transdermal administration of the present invention, skin irritation caused by citalopram is remarkably reduced and the absorption of citalopram is excellent even when the preparation is applied for a long time in anticipation of systemic pharmacological effects. .

Hereinafter, preferred embodiments of the present invention will be described in detail.

The drug used in the present invention is citalopram (1- (4-fluorophenyl) -1- [3- (dimethylamino) propyl] -1,3-dihydroisobenzofuran-5-carbonitrile) or a pharmaceutical thereof Is an acceptable salt. Citalopram has two optical isomers, R-form and S-form, but “citalopram” in this specification is any mixture of R-form and S-form, R-form, or S-form unless otherwise specified. Means. Examples of the pharmaceutically acceptable salt of citalopram include citalopram hydrobromide, citalopram hydrochloride, citalopram oxalate, etc. Among them, citalopram hydrobromide is particularly preferable.

Further, as citalopram, S-form which is an optical isomer, that is, escitalopram (Escitalopram; (S) -1- (4-fluorophenyl) -1- [3- (dimethylamino) propyl] -1,3-dihydroiso Benzofuran-5-carbonitrile) is preferably used, and pharmaceutically acceptable salts thereof include escitalopram oxalate.

The compounding amount of the above drug in the preparation is preferably 0.01 to 20% by mass, more preferably 1 to 10% by mass, based on the total mass of the transdermal preparation as citalopram. Within this range, a sufficient amount of drug for treatment can be absorbed through the skin and a preparation with less skin irritation can be obtained. As used herein, “total mass basis of transdermal administration formulation” means the total mass basis when the transdermal administration formulation is an ointment, gel, cream, liquid, etc. When the preparation is a patch, it means the total mass standard of the adhesive layer.

As the steroid agent (steroid external preparation) used in the present invention, a drug classified as medium (IV group) on the classification (IV class) indicating the strength of the external steroid agent is used. That is, at least one steroid agent selected from the group consisting of triamcinolone acetonide, flumetasone pivalate, alcromethasone propionate, clobetasone butyrate, hydrocortisone butyrate, dexamethasone and prednisolone acetate valerate is used. Such steroids also reduce side effects derived from steroids compared to strong steroids (I-III).

The blending amount of the steroid used in the present invention into the transdermal preparation varies depending on each steroid, but is blended in the range of 0.001% to 3% by mass based on the total mass of the transdermal preparation. Preferably, the content is 0.01% by mass to 0.5% by mass. Furthermore, generally it is preferable that it is the compounding quantity in an external preparation. For example, triamcinolone acetonide is 0.01 mass% to 0.2 mass%, flumethasone pivalate is 0.01 mass% to 0.05 mass%, alcromethasone propionate is 0.05 mass% to 0.2 mass%, 0.01% to 0.1% by weight of clobetasone butyrate, 0.01% to 0.2% by weight of hydrocortisone butyrate, 0.01% to 0.2% by weight of dexamethasone, and prednisolone acetate valerate Is preferably from 0.05% by mass to 0.5% by mass.

The classification of the strength of the anti-inflammatory action of the steroid can be determined according to the method (particularly ointment) described in Journal of Japanese Dermatological Association, 110 (7), 1099-1104, 2000.

Triamcinolone acetonide is particularly preferable as the steroid used in the present invention because the skin irritation suppressing effect is high even at low concentrations.

A sufficient effect can be obtained when the amount of triamcinolone acetonide is 0.005% by mass to 0.5% by mass based on the total mass of the preparation for transdermal administration. From the viewpoint of suppressing side effects derived from steroids, the blending amount of triamcinolone acetonide is more preferably 0.01% by mass to 0.1% by mass.

The preparation for transdermal administration of the present invention can further contain additives such as a basic compound, a plasticizer, an absorption accelerator, and an organic acid as necessary.

When an acid addition salt is used as a pharmaceutically acceptable salt of citalopram, it is preferable to add a basic compound. Examples of basic compounds include low molecular compounds containing basic nitrogen (triethanolamine, diisopropanolamine, diethanolamine, etc.), and high molecular compounds containing basic nitrogen (aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, Polyvinyl pyridine, etc.) and basic alkali metal salts (sodium acetate, potassium acetate, sodium borate, sodium carbonate, trisodium citrate, sodium silicate, sodium hydroxide, potassium hydroxide, etc.). Among these, sodium acetate, sodium carbonate, sodium hydroxide, and potassium hydroxide are preferable, and sodium hydroxide and potassium hydroxide are particularly preferable.

The transdermal administration preparation of the present invention can further contain a transdermal absorption enhancer as necessary. The transdermal absorption enhancer is not particularly limited as long as it can absorb the necessary amount for treatment from the skin, but 0.5 to 20% by mass based on the entire preparation is blended. Such an absorption promoter may be any compound that has been conventionally recognized as having an effect of promoting absorption into the skin, such as fatty acids, fatty alcohols, fatty acid esters or ethers having 6 to 20 carbon atoms, aromatic organic acids, Aromatic alcohols, aromatic organic acid esters, or ethers (they may be saturated or unsaturated, and may be cyclic, linear or branched), lactic acid esters, and acetic acid esters , Monoterpene compounds, azone, azone derivatives, glycerol fatty acid esters, sorbitan fatty acid esters (Span system), polysorbate (Tween system), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil system ( HCO), sugar fatty acid esters, fatty acid alkylolamide, etc. It is.

Among these compounds, from the viewpoint of less irritation to the skin of the absorption enhancer itself, caprylic acid, caproic acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, lauryl alcohol, myristyl alcohol, oleyl alcohol, Stearyl alcohol, cetyl alcohol, methyl laurate, hexyl laurate, diethanolamide laurate, isopropyl myristate, diethyl sebacate, diisopropyl adipate, propylene glycol monolaurate, N-methyl-2-pyrrolidone, pyrothiodecane, l-menthol , D-limonene. Such absorption promoters can be used alone or in admixture of two or more.

The plasticizer is not particularly limited as long as it is a compound having plasticity. For example, petroleum oil (paraffinic process oil, naphthenic process oil, aromatic process oil, etc.), squalane, squalene, plant system Oil (olive oil, camellia oil, castor oil, tall oil, peanut oil), silicon oil, dibasic acid ester (dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (polybutene, liquid isoprene rubber), liquid fatty acid esters (myristic acid) Isopropyl, hexyl laurate, diethyl sebacate, diisopropyl sebacate), diethylene glycol, polyethylene glycol, glycol salicylate, propylene glycol, dipropylene glycol, triacetin, triethyl citrate, Tamiton and the like. Such plasticizers can be used alone or in admixture of two or more.

Further, in the present invention, if necessary, an antioxidant, an ultraviolet absorber, and a crystallization inhibitor can be used. Examples of the antioxidant include tocopherol and their ester derivatives, ascorbic acid, ascorbic acid stearate, nordi. Human log ayaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like are preferable. As the ultraviolet absorber, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid compounds, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives and the like are desirable. As the crystallization inhibitor, polyvinylpyrrolidone or the like is desirable.

Furthermore, the preparation for transdermal administration of the present invention is not particularly limited as long as it is a dosage form capable of supplying a drug for a period required for treatment, and patches, ointments, gels, creams, liquids and the like can be used. Among these, as a dosage form capable of supplying an effective amount of a drug for a long time, a patch is mentioned as a dosage form suitable for the present invention.

In addition, a patch containing substantially no water is particularly preferable from the viewpoint of excellent stability of the drug in the preparation. “Contains substantially no water” means that the preparation is composed of a non-aqueous material. However, it is permissible for the preparation to contain a trace amount of water of 1% by mass or less derived from the raw material or the production environment. In general, a patch having a non-aqueous adhesive layer has a relatively strong adhesive force and therefore has good adhesion to the skin. Also, compared with a patch having an aqueous adhesive layer, the patch absorbs the skin of the drug. Can be increased.

On the other hand, when the skin absorbability of the drug increases, the skin irritation derived from the drug itself may increase, but the patch using the non-aqueous adhesive layer of the present invention has less skin irritation and excellent treatment. There is an effect.

When the dosage form is a patch, the patch preferably has a configuration having an adhesive layer on a support, and may have a release liner on the adhesive layer. Base materials used for the adhesive layer include styrene-isoprene-styrene block copolymer (SIS), isoprene rubber, polyisobutylene (PIB), styrene-butadiene-styrene block copolymer (SBS), and styrene-butadiene rubber. (SBR), copolymers such as polyacrylate copolymers (at least two copolymers of 2-ethylhexyl acrylate, vinyl acetate, methacrylate, methoxyethyl acrylate, and acrylic acid), and adhesives for drugs used It is possible to select appropriately in consideration of solubility in water. Moreover, it is also possible to mix and use these adhesives. In addition, when SIS, isoprene rubber, PIB, SBS, and SBR are used, a tackifier such as rosin, terpene, or petroleum resin may be used in combination.

The support used for the patch is not particularly limited, but a non-stretchable or stretchable material such as a polymer film, a woven fabric or a non-woven fabric can be used and provided on the support. It is preferable that the material does not adsorb or permeate the drug contained in the adhesive layer. For example, polyethylene terephthalate, polyurethane, polyethylene, polypropylene, rayon, cotton, and an aluminum sheet can be mentioned, and these may be laminated and used.

The release liner used for the patch is not particularly limited as long as it protects the adhesive surface during the period until the patch is used, but polyolefin, polyester, ethylene-vinyl acetate copolymer, paper, etc. Can be mentioned. Among these, polyethylene, polypropylene, and polyethylene terephthalate can be preferably used. In order to facilitate peeling, the surface may be subjected to a release treatment with silicone or fluorine, or may be provided with a cut such as a back crack, a half cut, or a perforation.

When using a patch, according to the desired therapeutic effect, 5 ~ 140cm ² the adhesion area of the preparation, preferably to 10 ~ 60cm ^2.

The preparation for transdermal administration of the present invention can contain a conventional base depending on the dosage form even in a dosage form other than the patch. In the case of a liquid preparation, it contains a lower alcohol, a polyhydric alcohol, water and the like. be able to. In the case of a cream, an oily base, a higher alcohol, a fatty acid ester, a polyhydric alcohol and derivatives thereof, a surfactant, a gelling agent, water and the like can be included.

Hereinafter, the present invention will be described more specifically based on examples and comparative examples, but the present invention is not limited to the following examples. In the following description, “part” means part by mass.

<Production of preparation>
A drug was added to a mixed solution of 65 parts of SIS, 35 parts of PIB, 180 parts of tackifier, 40 parts of liquid paraffin and toluene (solvent) prepared using a mixer to obtain an adhesive solution. This is spread on a release-treated film, and the solvent is dried and removed to form an adhesive layer. Then, a support is placed on the adhesive layer, and the adhesive layer is pressure-transferred to transfer the transdermal patch. An agent was obtained.

Each formulation used in the following test examples was formulated with 8.0% of escitalopram oxalate as a drug according to the above general method and a predetermined amount of the additives described in each of the examples and comparative examples. (Containing SIS, PIB, tackifier, and liquid paraffin in the composition ratio described in the above production method) were blended so that the entire preparation was 100%.

Test Example 1 Effect of additive on primary skin irritation of preparation containing escitalopram oxalate <Test method>
The back of the rabbit was depilated and various test preparations containing the additives shown in Table 1 were applied for 24 hours. The skin redness 25 hours after administration was measured using a color difference meter. The test results are shown in Table 1.

 

As is apparent from the results in Table 1, a preparation containing steroids, amino acid derivatives, vitamin derivatives, NSAIDs (non-steroidal anti-inflammatory drugs), antiallergic drugs, etc. was administered for 24 hours. As a result, in the preparation containing the steroid, the skin redness was lower than that of the other ingredients, and the skin irritation was further reduced. Of the steroids, the skin redness of prednisolone valerate belonging to class IV was particularly low.

Test Example 2 Effect of steroid agent on primary skin irritation of preparation containing escitalopram oxalate <Test method>
The back of the rat was depilated and various test preparations containing the steroids listed in Table 2 were affixed. The skin reaction 25, 48, and 72 hours after administration was evaluated according to the Draize method, and a primary irritation index (Primary Irritation Index, PII) was calculated. The test results are shown in Table 2.

 

From the results shown in Table 2, it was determined that the drug efficacy was high when a formulation containing each steroid selected from the IV categories classified according to the strength of the external steroid was applied for 24 hours. The steroids belonging to classes I to III remained high in PII, and the effect of reducing skin irritation was not recognized or very weak, whereas triamcinolone acetonide belonging to class IV markedly showed PII at a low addition concentration. It was shown to decrease. In addition, hydrocortisone, which is a steroid agent belonging to Group V, which has a lower medicinal effect than triamcinolone acetonide, had a weak skin irritation reducing effect even though a high concentration of 2.5% was added to the preparation.

Test Example 3 Skin permeability of escitalopram oxalate-containing preparation containing triamcinolone acetonide <Test method>
The dorsal skin of the hairless mouse was peeled off, and attached to a flow-through cell in which warm water of 32 ° C. was circulated around the outer periphery with the dermis side as the receptor side. Next, various test preparations are affixed to the stratum corneum side of the skin, and the receptor solution is sampled up to 24 hours every 2 hours at 5 mL / hr using a phosphate buffer (pH 7.4) as the receptor layer. In addition to the measurement, the drug concentration was measured using high performance liquid chromatography. The maximum value of the skin permeation rate of the drug per hour and the total amount of drug permeation up to 24 hours were calculated from the obtained measured values. The test results are shown in Table 3.

 

As shown in Table 3, as a result of a skin permeation test of hairless mice using preparations containing 0.025% and 0.075% triamcinolone acetonide (Examples 10 and 11), these preparations were found to be triamcinolone. The skin permeability was similar to that of the preparation containing no acetonide.

From the above, it has been shown that triamcinolone acetonide does not inhibit the skin permeability of escitalopram oxalate. From the results of Test Examples 1 to 3, the transdermally absorbable preparation of the present invention can be obtained by adding triamcinolone acetonide to escitalopram. The skin irritation of escitalopram was significantly reduced to a very low level without being disturbed.

The transdermally absorbable preparation of the present invention is useful because the skin irritation caused by citalopram is remarkably reduced by adding a specific steroid, and an amount of citalopram that can be expected to have a sufficient therapeutic effect can be transdermally administered. is there.

Claims (7)

1. A transdermal administration preparation for reducing skin irritation caused by citalopram, comprising at least one drug selected from the group consisting of citalopram and pharmaceutically acceptable salts thereof, triamcinolone acetonide, flumethasone pivalate, propionic acid A transdermal administration preparation comprising at least one steroid selected from the group consisting of alclomethasone, clobetasone butyrate, hydrocortisone butyrate, dexamethasone and prednisolone acetate valerate.
2. The transdermal administration preparation according to claim 1, wherein the steroid is triamcinolone acetonide.
3. The transdermal preparation according to claim 1 or 2, wherein the content of triamcinolone acetonide is 0.005 to 0.5 mass% based on the total mass.
4. The preparation for transdermal administration according to any one of claims 1 to 3, wherein the citalopram is escitalopram which is S-form.
5. The preparation for transdermal administration according to claim 4, wherein the pharmaceutically acceptable salt of escitalopram is oxalate.
6. The transdermal administration preparation according to any one of claims 1 to 5, which is a patch.
7. The preparation for transdermal administration according to claim 6, comprising a styrene-isoprene-styrene block copolymer.