JP4832806B2 - Transdermal formulation - Google Patents

Description

  The present invention relates to a preparation for transdermal administration that absorbs drugs required for treatment of various diseases through the skin. More specifically, the present invention relates to a preparation for transdermal administration which is excellent in skin absorbability of a drug and has excellent safety by reducing skin irritation based on the drug.

In recent years, various attempts have been made to develop transdermal preparations for administering drugs through the skin. Since the skin functions as a barrier against foreign substances from the outside world, it is usually difficult for the drug to permeate the skin, but a device has been devised to increase the skin permeability of the drug by using chemical or physical absorption promotion methods. Yes.
On the other hand, drugs may contact the skin and cause primary irritation or allergic contact sensitization, the degree of which is thought to depend on the drug concentration and the contact time with the skin. Attempts have been made to add additives to reduce irritation or the like.
For example, fluoxetine, a serotonin reuptake inhibitor, has skin irritation, but it has been disclosed that fluoxetine is converted to acetate and administered together with a steroid that has a strong anti-inflammatory effect to reduce skin irritation. (Patent Document 1). Further, in cosmetic compositions, it is disclosed that skin irritation and / or tingling sensation caused by cosmetic ingredients such as hydroxy acid and retinol are suppressed by gluconolactone and / or glucarolactone. (Patent Document 2)

US Patent 6,512,010 Special Table 2002-504504

In the prior art, minor skin irritation on the skin surface based on cosmetic compositions has been improved to prevent it by blending certain additives. However, in the case of a transdermal preparation that is expected to have a medicinal effect by administering the drug from the skin, the drug must be in contact with the skin during the period required for treatment, and the drug must be absorbed to the living epidermis layer. In spite of having sex, if the benefits of transdermal treatment can be enjoyed, it was unavoidable to add an anti-inflammatory agent such as steroid. When the steroid is added in this way, the skin irritation itself can be suppressed, but there is a problem that there is a concern about the occurrence of side effects caused by the steroid.
The present invention has been made in view of such problems, and in a transdermal administration formulation in which a drug is blended for the purpose of transdermal absorption, a base and an additive can be used without using an irritation reducing agent such as an anti-inflammatory agent. By devising the combination of these, a transdermal administration preparation capable of suppressing skin irritation based on a drug even when applied to the skin for a long time is provided.

  In order to solve the above-mentioned problems, the present inventors have conducted intensive studies, and even if the drug has a tendency to exhibit primary skin irritation at a relatively low concentration, such as citalopram, the specific amount having a hydroxyl group The formulation for transdermal administration in which these lactone compounds coexist has been found to significantly reduce the irritation to the skin, leading to the completion of the invention.

That is, the present invention relates to a preparation for transdermal administration containing a drug and a lactone compound having a hydroxyl group.
The present invention also relates to the above-mentioned preparation for transdermal administration, wherein the lactone compound having a hydroxyl group is a δ-lactone compound.
Furthermore, the present invention relates to the above-mentioned preparation for transdermal administration, wherein the δ-lactone compound is glucono-δ-lactone.
Furthermore, the present invention relates to the above-mentioned preparation for transdermal administration, wherein the content of the lactone compound having a hydroxyl group is 0.01 to 10% by mass with respect to the whole preparation.

The present invention relates to the preparation for transdermal administration, wherein the drug is a basic compound or a pharmaceutically acceptable salt thereof.
The present invention also relates to the above-mentioned preparation for transdermal administration, wherein the drug is citalopram, fluoxetine, sertraline, fluvoxamine, paroxetine or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to the above-mentioned preparation for transdermal administration, wherein the drug is citalopram or a pharmaceutically acceptable salt thereof.
Furthermore, the present invention relates to the preparation for transdermal administration, wherein the drug content is 0.01 to 20% by mass relative to the whole preparation.

The present invention relates to the preparation for transdermal administration, wherein the preparation further contains a transdermal absorption enhancer.
The present invention also relates to the transdermal administration preparation whose dosage form is a patch.
The present invention further relates to the patch, which is substantially free of water.

  According to the preparation of the present invention, even when a long-term preparation is applied in anticipation of a systemic pharmacological effect, a preparation for transdermal administration excellent in absorbability that can remarkably reduce skin irritation based on a drug is provided. It is possible.

Hereinafter, preferred embodiments of the present invention will be described in detail.
The present invention is a preparation for transdermal administration containing a drug and a lactone compound having a hydroxyl group.
The drug used in the preparation for transdermal administration of the present invention is not particularly limited as long as it is a compound that can be absorbed through the skin and used for the treatment of various diseases described below. For example, non-steroidal anti-inflammatory analgesics (diclofenac, indomethacin) , Ketoprofen, felbinac, loxoprofen, ibuprofen, flurbiprofen, thiaprofen, acemetacin, sulindac, etodolac, tolmethine, piroxicam, meloxicam, ampiroxicam, naproxen, azapropazone, methyl salicylate, glycolicoxib, valdecoxib, celdecoxib, celdecoxib, celdecob (Diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril), antiparkinsonian (pergolide, bromocriptine, ropinirole, Phosphorus), bronchodilators (tulobuterol, isopretenolol, salbutamol), narcotic analgesics (fentanyl, morphine), urinary agents (oxybutynin), neuropsychiatric agents (promazine, chlorpromazine), antidepressants (sertraline, Fluoxetine, paroxetine, citalopram, fluvoxamine), anti-dementia drugs (donepezil, risperidone, rivastigmine, galantamine, idebenone), expectorant (ambroxol), anxiolytic (tandospirone), antipsychotic (olanzapine), central nervous system stimulant (Methylphenidate), osteoporosis treatment drugs (raloxifene, alendronate), breast cancer prevention drugs (tamoxifen), anti-obesity drugs (mazindol, sibutramine), insomnia improvement drugs (melatonin), etc. Pharmaceutically acceptable salts and derivatives may be used Among these, basic drugs tend to cause damage to cell membranes such as negatively charged epidermal cells, and use as a transdermal preparation is often accompanied by skin irritation, but basic drugs are used as the agents of the present invention. When used, it is preferably used because of its excellent stimulus suppression effect.

  In addition, the primary skin irritation of a drug depends on the concentration of the drug in contact with the skin and the amount of skin permeation. Antibiotics (diltiazem, nicardipine, nilvadipine, metoprolol, bisoprolol, trandolapril), antiparkinsonian agents (pergolide, bromocriptine, ropinirole, selegiline), osteoporosis treatment (raloxifene) , Alendronate), antidepressants (sertraline, fluoxetine, paroxetine, citalopram, fluvoxamine), or a pharmaceutically acceptable salt thereof is preferably used. Particularly preferred are citalopram and citalopram hydrobromide.

  The drug used in the present invention is not particularly limited as long as the amount necessary for treatment can be supplied from the skin, but it is preferable to blend 0.01 to 20% by mass with respect to the whole preparation, and more preferably. Moreover, you may mix | blend 0.01-10 mass% with respect to the whole formulation.

Next, the lactone compound having a hydroxyl group used in the transdermal administration preparation of the present invention is not particularly limited as long as it can suppress the skin irritation of the drug, and examples thereof include δ-lactone and γ-lactone compounds, and the like. Is glucono-δ-lactone, D-manninoic-δ-lactone, D-xylocic-δ-lactone, stearoyl-δ-lactone, arabinoic-δ-lactone, γ-D-galactonolactone, α-D-glucoheptano Ic-γ-lactone, L-glucono-1,5-lactone, D-glucurono-6,3-lactone and the like.
Among them, since δ-lactone having a hydroxyl group has many hydroxyl groups in one molecule, it contributes to hydrogen bonding with the cell surface constituting the skin, and has an effect of protecting the cell membrane. It is suitable because it is expected to have an antioxidative action and is excellent in the effect of suppressing the irritating action of the target drug of the present invention on the skin. In particular, glucono-δ-lactone, which is a δ-lactone having a hydroxyl group at the 2,3,4,6 position, can be mentioned as a particularly preferable one.

  The lactone compound having a hydroxyl group used in the transdermal administration preparation of the present invention is not particularly limited as long as it has a concentration that can reduce the skin irritation of the drug, but 0.01 to 10% by mass based on the entire preparation is incorporated. It is preferred that If it is 0.01% by mass or less, the effect of reducing skin irritation is insufficient, and if it is 10% by mass or more, the drug content stability may be lowered, which is not preferable. The amount of the lactone compound to be blended is preferably 0.5 to 5% by mass in consideration of the skin absorbability of the drug by the preparation for transdermal administration. Particularly when the preparation for transdermal administration is a patch, it is applied to the skin. It has excellent adhesion.

  The percutaneous administration preparation of the present invention can further contain a percutaneous absorption enhancer as necessary. The percutaneous absorption enhancer is not particularly limited as long as it can absorb the necessary amount for treatment from the skin, but is contained in an amount of 0.5 to 20% by mass based on the whole preparation. 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), polysorbate (Tween), polyethylene glycol fatty acid esters, polyoxyethylene hydrogenated castor oil ( HCO type), sugar fatty acid esters, fatty acid alkylolamide and the like.

  Among these compounds, from the viewpoint that the absorption accelerator itself is less irritating to the skin, 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- Mentor, d-limonene.

  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. As a dosage form capable of supplying an effective amount of a drug for a long time, a patch is mentioned. 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. Although it can be increased, increased skin absorption of the drug may increase the associated skin irritation. However, in the present invention, a patch using a non-aqueous pressure-sensitive adhesive layer is particularly preferable because it is safe for the skin because it is excellent in the effect of reducing skin irritation and can exhibit an excellent therapeutic effect.

  As the adhesive layer used for the base when the dosage form is a patch, styrene-isoprene-styrene block copolymer (hereinafter abbreviated as SIS), isoprene rubber, polyisobutylene (hereinafter abbreviated as PIB). ), Styrene-butadiene-styrene block copolymer (hereinafter abbreviated as SBS), styrene-butadiene rubber (hereinafter abbreviated as SBR), polyacrylate copolymer (2-ethylhexyl acrylate, vinyl acetate, And a copolymer such as at least two copolymers of methacrylate, methoxyethyl acrylate, and acrylic acid), which can be appropriately selected in consideration of the solubility of the drug used in the adhesive. Moreover, it is also possible to mix and use these adhesives.

  The support used in the patch of the present invention 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. A material that does not cause adsorption or penetration of the drug contained in the pressure-sensitive adhesive layer provided above is preferable. For example, polyethylene terephthalate, polyurethane, polyethylene, polypropylene, rayon, cotton, and an aluminum sheet can be mentioned, and these may be laminated and used.

  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 ayaretinic 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. Such antioxidants, UV absorbers and anti-crystallization agents are combined in a total amount of preferably 15% by mass or less, more preferably 10% by mass or less, based on the total mass of the adhesive layer composition of the patch preparation. Can be done.

The release liner used in the patch of the present invention 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, For example, paper. 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 the adhesive patch of the present invention, depending on the desired therapeutic effect, 5～140Cm ² the adhesion area of the preparation can preferably be a 10~60cm ^2.

The transdermal administration preparation of the present invention can contain a conventional base depending on the dosage form, and in the case of a liquid preparation, it can contain a lower alcohol, a polyhydric alcohol, water and the like.
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.

Examples of the lower alcohol used in the above dosage form include methanol, ethanol, denatured ethanol, and isopropanol.
Examples of the oily base include liquid paraffin, petrolatum, paraffin wax, and the higher alcohol is an alcohol having 10 to 20 carbon atoms, preferably cetyl alcohol, stearyl alcohol, cetostearyl alcohol, and oleyl alcohol. .
Examples of the polyhydric alcohol and derivatives thereof include glycerin, ethylene glycol, propylene glycol, 1,3-butylene glycol, dipropylene glycol, polyethylene glycol, polypropylene glycol, and esters or ethers thereof.
The fatty acid ester is an ester of a higher fatty acid, and examples thereof include esters of a higher fatty acid such as myristic acid, palmitic acid, stearic acid, and oleic acid with a lower alcohol (having 1 to 6 carbon atoms).

Surfactants include polyoxyethylene alkyl phosphate esters, anionic surfactants such as sodium alkyl sulfate, sorbitan sesquioleate, sorbitan trioleate, sorbitan monostearate, sorbitan monolaurate, polyoxyethylene stearic acid sorbitan, etc. Sorbitan fatty acid esters, or nonionic surfactants such as polyoxyethylene ethers such as polyoxyethylene nonyl ether, monooxyethylene cetyl ether, monooxyethylene lauryl ether, and other cationic properties such as benzethonium chloride and benzalkonium chloride It may be a surfactant or an amphoteric surfactant.
Examples of the gelling agent include carboxyvinyl polymer, hydroxyethyl cellulose, hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, carboxymethyl cellulose and the like.

  Further, the features of the present invention will be described in detail with reference to examples.

Example 1
Effect of additives on induced cytotoxicity reaction using citalopram (antidepressant) as a model drug

<Test method>
In this experiment, human-derived normal epidermal keratinocytes (keratinocytes) were used. Cytotoxicity was determined using the amount of lactose dehydrogenase (LDH) released from the cell as an index. First, keratinocytes were seeded on a 96-well culture plate (5 × 10 ³ cell / 80 μL / well) and allowed to stand for 24 hours in a CO ₂ incubator (37 ° C., 5% CO ₂ ). Thereafter, citalopram and each additive were treated in predetermined wells and incubated for 2 hours 30 minutes. After completion of the incubation, centrifugation was performed (250 xg, 5 min), and 50 μL of each culture supernatant was collected and used as a test sample (measurement of released LDH amount). At the same time, the cells remaining in each well were completely lysed with lysis buffer, and this lysate was diluted 10-fold with the culture solution to prepare a test sample (total amount of 50 μL of intracellular residual LDH). Next, a tetrazolium salt solution (lactate, 50 μL) serving as a reaction substrate was added to each test sample, and after incubation for 20 minutes, absorbance at 490 nm was measured with a microplate reader. The test result was calculated according to the following formula as% of total LDH.
;% Of total LDH = released LDH amount / (released LDH amount + intracellular residual LDH amount) × 100
Details of each group are as follows. The keratinocyte culture medium was used for the preparation of each reagent, and the amount added to each well was 10 μL (the final volume of each well was 100 μL).

<Group structure>
(1) Keratinocytes + Medium + Lysis buffer (positive control group)
(2) Keratinocytes + Medium + Citalopram (600 μM)
(3) Keratinocytes + Glucono-δ-lactone (100 μM) + Citalopram (600 μM)
(4) Keratinocytes + Glucono-δ-lactone (300 μM) + Citalopram (600 μM)
(5) Keratinocytes + Glucono-δ-lactone (600 μM) + Citalopram (600 μM)
(6) Keratinocytes + L-tartaric acid (600 μM) + Citalopram (600 μM)
(7) Keratinocytes + D-tartaric acid (600 μM) + Citalopram (600 μM)
(8) Latinocyte + L-sodium tartrate (600 μM) + Citalopram (600 μM)
(9) Keratinocytes + Dibutylhydroxytoluene (10 μM) + Citalopram (600 μM)
(10) Keratinocytes + Sodium pyrosulfite (300 μM) + Citalopram (600 μM)

The test results are shown in Table 1.
First, almost 100% LDH release was observed in the positive control group in which the cells were completely lysed by adding lysis buffer, while mild to moderate cell damage was observed in the citalopram (600 μM) addition group. Sex was recognized. That is, it is understood that citalopram can be a factor that directly destroys the cell membrane of keratinocytes and expresses skin irritation. This suggests that the skin irritation of citalopram is also dependent on a mechanism different from the inflammatory expression that produces various prostaglandins and leukotrienes based on the so-called arachidonic acid cascade.
Under these conditions, the effect of each additive on the cytotoxicity of citalopram was examined. Glucono-δ-lactone, L-tartaric acid, D-tartaric acid, L-sodium tartrate, dibutylhydroxytoluene and sodium pyrosulfite The cytotoxic response of citalopram was prominently suppressed by the addition of. Moreover, glucono-δ-lactone has a tendency to suppress irritation in a dose-dependent manner.

  Under the same conditions as this test, L-tartaric acid (600 μM), D-tartaric acid (600 μM), L-sodium tartrate (600 μM), dibutylhydroxytoluene (10 μM) and sodium pyrosulfite (300 μM) When added alone, no cytotoxicity was observed.

Example 2
Effect of glucono-δ-lactone on primary anti-depressant drug citalopram-induced skin irritation

<Outline of test method>
The back of the guinea pig was depilated, and various test solutions dissolved in physiological saline were administered intradermally (100 mL / site). The skin reaction 24, 48, and 72 hours after administration was evaluated according to the Draize method ¹⁾ , and a primary irritation index (Primary Irritation Index; PII) was calculated.

<Group structure>
(1) Saline
(2) 0.5% glucono-δ-lactone physiological saline
(3) 0.3% citalopram physiological saline
(4) 0.3% citalopram / 0.1% glucono-δ-lactone physiological saline
(5) 0.3% citalopram / 0.3% glucono-δ-lactone physiological saline
(6) 0.3% citalopram / 0.5% glucono-δ-lactone physiological saline
(7) 0.3% citalopram / 0.5% L-tartaric acid saline
(8) 0.3% citalopram / 0.1% dibutylhydroxytoluene physiological saline
(9) 0.3% citalopram / 0.5% sodium pyrosulfite physiological saline

1)Draize,J.H. J.Pharmacol.Exp.Ther., 82, 377-390(1944)

1) Draize, JHJ Pharmacol. Exp. Ther., 82, 377-390 (1944)

  Skin irritation test using guinea pigs showed that citalopram primary irritation score (PII) 2.6-3.0 (moderate irritation) could be reduced to 2 or less (mild irritation) by adding glucono-δ-lactone. It has become possible. Other additives that were found to be effective in in vitro tests did not show a stimulating reduction effect in the in vivo system.

Claims (9)

A transdermal administration preparation comprising a drug and a lactone compound having a hydroxyl group , wherein the drug is citalopram or a pharmaceutically acceptable salt thereof . Percutaneous preparation of claim 1 lactone compound is a δ- lactone compound having a hydroxyl group. The transdermal administration preparation according to claim 2 , wherein the δ-lactone compound is glucono-δ-lactone. The transdermal administration preparation according to any one of claims 1 to 3, wherein the content of the lactone compound having a hydroxyl group is 0.01 to 10% by mass relative to the whole preparation. The transdermal administration preparation according to any one of claims 1 to 4, wherein the drug is a basic compound or a pharmaceutically acceptable salt thereof. The transdermal administration preparation according to any one of claims 1 to 5 , wherein the content of the drug is 0.01 to 20 mass% with respect to the whole preparation. The transdermal administration preparation according to any one of claims 1 to 6 , further comprising a percutaneous absorption enhancer in the preparation. The preparation for transdermal administration according to any one of claims 1 to 7 , wherein the dosage form is a patch. The preparation for transdermal administration according to claim 8 , which is substantially free of water.