KR100438254B1 - Matrix form of preparation for transdermal administration of vitamin d analog - Google Patents

Abstract

The present invention relates to a matrix transdermal absorption preparation of Vitamin D analog (Vitamin D analog), specifically (1) 0.0001 to 10% by weight of the vitamin D analog; And (2) a matrix layer containing 90 to 99.9999% by weight of a non-polar polymer, wherein the matrix type transdermal absorption agent is administered at a constant rate without skin irritation so that the vitamin D analog is maintained at an effective blood concentration for a period of time.

Description

Matrix transdermal absorption agent containing vitamin D analogues {MATRIX FORM OF PREPARATION FOR TRANSDERMAL ADMINISTRATION OF VITAMIN D ANALOG}

The present invention relates to a matrix transdermal absorption preparation of vitamin D analogue (Vitamin Danalog) such as calcitriol, alpha calcidol and the like.

Vitamin D plays an important role in bone and mineral metabolism in the body, and its deficiency is caused by osteoporosis, rickets, osteomalacia, chronic kidney failure, especially hypocalcemia in hemodialysis patients, hypothyroidism, and chronic renal dialysis. It has been known to lead to diseases such as dichotomous dystrophy due to the reduction of parathyroid hormone. It is common to administer suitable vitamin D or analogs thereof in order to alleviate or treat such diseases.

Representative vitamin D analogues include calcitriol (1,25 (OH) ₂ D ₃ ), alphacalcidol (alfacalcidol; 1α (OH) D ₃ ), calcididi (calcifediol; 25 (OH) D ₃ ), and the like. They play an important role in bone and mineral metabolism, as well as in the growth and differentiation of tissues and in the regulation of immune function.

Of the calcitriol is the final active form of vitamin D _3, receives ultraviolet rays from the skin 7-dihydro vitamin D ₃ in a conversion from cholesterol is carried to the liver via the blood stream 25 by calcineurin hydroxide enzyme (25-hydroxylase) Fe After being metabolized to diol, it is transported to the kidney and converted into calcitriol by 1-hydroxylase, and alpha calcidol, a precursor of calcitriol, is also converted into calcitriol by hydroxylase in the liver. In normal human kidneys, 1.0-1.5 μg of calcitriol is produced daily, which is regulated by parathyroid hormone. The main action of calcitriol is to increase the absorption of calcium and phosphorus in the intestine, to promote resorption of calcium and phosphorus in the kidney and to act directly or indirectly on cells involved in bone metabolism, promoting or inhibiting bone tissue formation.

Other vitamin D analogues include ergocalciferol, doxercalciferol, paricalcitol, OCT (22-oxacalcitriol) and calcipotriol. Reading calciferol and paricalcitol are used for the purpose of suppressing hyperthyroidism, and calcipotriol is used for the treatment of psoriasis.

These vitamin D derivatives may have different functions depending on blood concentrations. For example, calcitriol promotes bone formation at moderate physiological concentrations, while inhibiting bone formation at high concentrations. By promoting or inhibiting bone formation, the overall balance of bone remodeling is regulated. Therefore, it is most important to take calcitriol or other vitamin D analogs in an appropriate amount for the treatment or prevention of osteoporosis, especially in patients with cirrhosis or renal failure, because the function of the liver or kidney is reduced and vitamin D ₃ is not converted into active form. It is more essential to replenish the appropriate amount of calcitriol.

In order to treat diseases caused by vitamin D deficiency, vitamin D analogs were generally administered intravenously or orally, and the oral dose of calcitriol was 0.25 to 0.75 μg and alpha calcidol was 0.5 to 1.0 μg. Calcitriol increases calcium and phosphorus absorption at blood concentrations of 30 to 70 pg / ml, but calcium absorption is less likely to occur at blood concentrations below 30 pg / ml or above 70 pg / ml. In order to maintain oral administration, conventional oral products should be administered twice daily or by intravenous administration under a well-controlled environment. However, symptoms such as fatigue, headache, nausea, tenderness, constipation, and muscle pain may occur at the initial stage of injection or oral administration, most of which are associated with hypercalcemia and hypercalciuria caused by excessively high blood levels of calcitriol. In case of side effects such as hypercalcemia, hypercalciuria, renal insufficiency, nephrolithiasis, and the like, especially in severe hypercalcemia with a calcium concentration of 12 mg / ㎗ or more, confusion, delirium, and lethargy may occur.

These side effects are usually the ridges of drug concentrations that are common during intravenous injection or oral administration. (Excess drug is absorbed in the early stage after administration, so blood concentration is excessively increased. After a certain time, blood concentration is increased through metabolism and excretion. Decreases below the effective concentration). In order to prevent such an increase in the initial drug concentration or the possibility of drug accumulation in the body due to repeated administration, the calcium concentration in the urine and serum should be frequently measured after the administration of the drug, and an appropriate dose should be set for each individual. You should stop and wait for the calcium levels to return to normal before starting treatment again in small amounts. Therefore, although vitamin D analogues such as calcitriol and alpha calcidol are frequently used for the treatment of osteoporosis, the conventional injection or oral route of administration has the biggest disadvantage of hypercalcemia and the treatment of diseases caused by vitamin D deficiency. Considering that in many cases vitamin D analogs, such as calcitriol, should be administered for a long time, it has been desirable to develop new release modulating agents that can ameliorate these side effects and discomfort.

In order to solve the problems of conventional oral administration and intravenous administration, various controlled release systems have been devised to maintain effective blood concentration by continuously and constantly controlling the release rate of drugs over a long period of time. Among these, transdermal drug delivery system can improve the compliance of patients' medications because of simple method of administration and long-term continuous expression, and can reduce the severe concentration variation caused by absorption and metabolism during oral administration. In the case of a drug with a short half-life, the effective blood concentration can be maintained for a long time, the effectiveness can be improved by bypassing the first pass of the liver, and it can be easily removed when the administration should be stopped.

As a prior art for transdermal formulations, U.S. Patent No. 4,983,395 discloses a reservoir-type transdermal administration system containing an active ingredient such as calcitriol, in particular in the reservoir by using a protective membrane between the permeation control membrane and the adhesive layer. The active ingredient or liquid additives such as ethanol may have an effect of preventing spreading to the adhesive layer during storage. However, this system may cause serious skin irritation due to the excessive amount of ethanol contained in the reservoir of 67.5%, and the calcitriol content of the formulation is also 40 ㎍, which is too far beyond the usual calcitriol dosage range, so that the actual amount of calcitriol Not suitable as a system for transdermal administration. In addition, the reservoir type system disclosed in this patent has a disadvantage in that the manufacturing method is complicated and the comfort is inconvenient to attach, resulting in poor drug compliance.

U. S. Patent No. 6,024, 976 discloses a technique for obtaining proper skin permeability by adjusting solubility parameters using an acrylate and a silicone-based polymer or a mixture of these and a soluble polyvinylpyrrolidone as a base of the adhesive layer. The low skin permeability of the drug and the drug content of 0.3 to 30% by weight are not suitable for drugs that need to be administered in trace amounts, such as vitamin D analogs.

In general, in the transdermal absorbent formulation, the rate of penetration of the drug through the skin is proportional to the permeation coefficient (Pe) and the concentration of the drug inside the adhesive determined by the adhesive component and the drug used as shown in Equation 1 below. do.

In the above formula, J _p is the amount of drug permeated per unit time, unit area, P _e is the permeability coefficient, and ΔC is the drug concentration difference (approximate value and drug concentration inside the adhesive) in the adhesive and skin.

In addition, the transmission coefficient is proportional to the diffusion rate and the distribution coefficient of the drug as shown in Equation 2 below.

Where P _e is the transmission coefficient, D _p is the diffusion coefficient of the drug inside the pressure-sensitive adhesive, L is the thickness of the pressure-sensitive adhesive, K _{s / p} is the distribution coefficient of the drug to the pressure-sensitive adhesive and the skin.

According to the above formula, it can be seen that the permeability of the drug in the transdermal dosage form is determined by the speed of the drug movement inside the adhesive and the degree of transition from the adhesive layer to the skin, which is governed by the degree of interaction between the drug and the adhesive. .

One factor that can quantify the interaction between the drug and the adhesive is the solubility parameter (δ). The solubility parameter is defined as the sum of all the interaction forces between the molecules that make up the substance. In mixtures of substances it is useful to predict the compatibility or dissolution of two substances. The solubility parameter may be calculated by a theoretically known formula or determined by experiment. Most commonly, the solubility parameter is calculated using a Hildebrand equation (Hildebrand Equation) represented by Equation 3 below.

Where δ is the solubility parameter, ΔE _v is the vaporization energy, V is the molar volume, ΔHv is the heat of vaporization, R is the gas constant, and T is the absolute temperature.

Therefore, by applying the solubility parameter to the polymer used as a pressure-sensitive adhesive in the transdermal absorbent, it is possible to predict the interaction between the drug and the pressure-sensitive adhesive inside the pressure-sensitive adhesive, and based on this, it is necessary to select a suitable pressure-sensitive adhesive component that can obtain the appropriate drug permeability. In this way, factors such as the dosage, penetration rate, effective area, etc. of the drug can be appropriately adjusted to allow the design of a transdermal formulation suitable for administration of the vitamin D analog.

The solubility parameter values of the general purpose polymers determined according to Equation 3 are shown in Table 1 below.

Polymer Solubility Parameters (J / cm 3) ^1/2 Polydimethylsiloxane (Silicon Rubber) 15.6 Polyisobutylene 15.8 Polyethylene 16.2 Polyisoprene 16.6 Polybutadiene 17.2 Butadiene-Styrene Copolymer 17.4 Styrene-isoprene copolymer 17.9 Polyethyl acrylate 18.8 Polymethyl methacrylate 19.0 Polymethylacrylate 19.8 Ethylene-Vinyl Acetate Copolymer 20.9

Accordingly, it is an object of the present invention to provide a transdermal absorption preparation that maintains vitamin D analogs such as calcitriol or alpha calcidol in effective blood levels for a period of time without skin irritation or side effects.

1 is a cross-sectional structural view showing an embodiment of a transdermal absorption preparation according to the present invention,

2 is a graph showing the change in the permeation rate of calcitriol according to the solubility parameter value of the polymer in the transdermal absorption preparation according to the present invention,

3 is a graph showing the change in the coefficient of permeation of calcitriol according to the solubility parameter value of the polymer in the transdermal absorption preparation according to the present invention,

Figure 4 is a graph showing the change in the concentration of calstriol in blood over time after administration of a commercial oral formulation of calstriol and a transdermal absorption preparation according to the present invention.

According to the above object, in the present invention

(1) 0.0001 to 10 weight percent of a vitamin D analog; And

(2) styrene-butadiene copolymer, styrene-isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, butyl rubber, epichlorohydrin rubber and mixtures thereof 70 to 99.9999% by weight of nonpolar polymer selected from the group consisting of

It provides a matrix transdermal absorption agent, characterized in that it comprises a matrix layer containing.

Hereinafter, the present invention will be described in detail.

The transdermal absorption preparation according to the present invention is characterized in that the vitamin D analog is dissolved or dispersed in the non-polar polymer base in the matrix layer.

Examples of vitamin D analogues include calcitriol, alpha calcidol, calcididiol, ergocalciferol, paricalcitol, and reading calciferol, and can be used in one or a mixture of two or more thereof. These drugs are effective in the treatment of diseases caused by vitamin D deficiency, such as osteoporosis, kidney failure, and thyroid dysfunction.

The daily dosage of vitamin D analogues is about 0.5 μg of calcitriol, about 1 μg of alpha calcidol, about 7 μg of ergocalciferol, about 5 μg of paricalcitol, about 4 μg of reading calciferol, and calcife Diol is about 50 μg, their absorption rate is known to be close to 100% when orally administered. Therefore, in case of transdermal administration of vitamin D analogues, the required skin dosage ranges from 0.5 to 50 µg / day, but considering the extent of symptoms and whether or not the dosage is added or not, the appropriate range of skin dosage is 0.05 to 100 µg. / Day, preferably in the range from 0.1 to 50 μg / day.

In order to satisfy the range of the dosage, a combination of the base, drug content, effective penetration area, and the like has been studied. As a result, the drug content is 0.1 to 500 ㎍ per one percutaneous absorbent preparation, preferably 0.5 to In the range of 200 μg. If the drug content is less than 0.1 ㎍, it is difficult to maintain the desired skin permeation rate. If the drug content exceeds 500 ㎍, the excessive supply of the drug may cause side effects such as hypercalcemia, hypercalciuria, kidney failure, kidney stones, and expensive stones. Excessive use of drugs is uneconomical. In addition, the skin permeation rate of the vitamin D analog in the transdermal absorption preparation is 0.005 to 20 µg / cm 2 / day, and preferably in the range of 0.01 to 10 µg / cm 2 / day. The drug may be transdermally administered through an effective area of 1 to 50 cm 2, preferably 5 to 30 cm 2, of normal skin, and maintain an effective rate of drug administration for a period of 12 hours to 7 days. According to such a suitable combination of permeation rate and effective penetration area, the total amount of drug is in the range of 0.05 to 100 μg / day, preferably 0.1 to 50 μg / day.

As the polymer base, natural or synthetic rubber-based nonpolar polymers having a solubility parameter value ranging from 15 to 18 (J / cm 3) ^1/2 may be used. For example, styrene-butadiene copolymer, styrene-isoprene copolymer, poly Isobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, butyl rubber, epichlorohydrin rubber or mixtures thereof, preferably silicone polymer, styrene-butadiene copolymer, styrene It is an elastic polymer, such as an isoprene copolymer, More preferably, it is a silicone type polymer.

In general, when the acrylate-based polar polymer is commonly used as a polymer base for transdermal administration, the diffusion of the drug in the base is slowed due to the interaction between the drug and the polymer in the adhesive layer, but the transition of the drug from the base to the skin is also reduced. In the present invention, by using a natural or synthetic rubber-based nonpolar polymer adhesive having a solubility parameter of about 1.5 to 5.0 (J / cm 3) ^1/2 lower than that of an acrylate-based polar polymer, the diffusion of drugs and the speed of transition to the skin are increased.

The matrix layer including the vitamin D analog and the non-polar polymer base may be applied to a conventional matrix type transdermal absorbent, which will be described in more detail with reference to embodiments of the transdermal absorbent according to the present invention.

1 is a cross-sectional view showing an embodiment of a matrix transdermal absorption preparation according to the present invention. As shown in Figure 1, the matrix transdermal absorption agent is a drug protective layer (1a); Drug-containing matrix layer 1b; And a release layer 1c.

The drug protective layer 1a acts as a protective film on the drug containing matrix layer 1b and also provides a supporting function. The drug protection layer may be prepared to have essentially the same size as the drug-containing matrix layer 1b, or may extend beyond the edge of the drug-containing matrix layer 1b and contain such drugs so that this extended area can be a support layer of adhesive material to the skin. It can be manufactured in a larger size than the matrix layer 1b. Suitable materials for the preparation of the drug protective layer 1a include high density and low density polyethylene, polypropylene, polyvinyl chloride, polyvinyl acetate, polyurethane, polyester, cellulose acetate, ethyl cellulose, plasticized vinyl acetate-vinyl chloride air Coalesce, plasticized polyvinyl chloride, polyvinylidene chloride, metal foil, nonwoven fabric, cotton cloth, paper or a laminate thereof. In addition, the drug protective layer 1a is suitably 5 to 500 mu m, preferably 5 to 200 mu m, as a thickness suitable for providing a desired protective function and a supporting function.

The drug containing matrix layer 1b comprises a vitamin D analog and a nonpolar polymer. The drug-containing matrix layer may be composed of a single layer in which a drug is contained in a tacky non-polar polymer layer, or may be formed in a multilayer form in which a non-tacky drug-containing polymer layer and an adhesive layer for adhering to the skin are laminated. Examples of non-polar polymers having tackiness include styrene-butadiene copolymers, styrene-isoprene copolymers, and silicone-based polymers. Non-adhesive nonpolar polymers include polyisobutene, ethylene-propylene copolymers, silicone rubbers, neoprene rubbers, butyl rubbers, epichlorohydrin rubbers, and the like. In this case, the pressure-sensitive adhesive polymer may be used as the pressure-sensitive adhesive that may be laminated on the non-tacky non-polar polymer layer.

The composition of the drug-containing matrix layer 1b is composed of 0.0001 to 10% by weight of the vitamin D analog and 90 to 99.9999% by weight of the nonpolar polymer.

The release layer 1c is attached to the drug-containing matrix layer 1b to prevent the release of the drug from the formulation during the storage period before use and to protect the drug-containing adhesive layer 1b and is removed during use. The release layer 1c may be applied in a material or a form commonly used in transdermal agents, for example, a film such as polyethylene, polyester, polyvinyl chloride, polyvinylidene chloride or the like coated with silicone resin or fluorine resin, Paper or laminates thereof can be used. Generally the thickness of a peeling layer is 12-200 micrometers, Preferably it is 50-150 micrometers.

In the transdermal absorbent preparation of the present invention, the skin permeation amount of the drug is determined according to the type and content of the drug, the component and thickness of the base, and the effective area of the preparation. Thus, the drug-containing matrix layer (1b) of the transdermal absorbent preparation of the present invention contains the drug. It may further contain a skin permeation enhancer commonly used for the purpose of controlling the rate of skin penetration. The skin permeation enhancer includes those having various mechanisms of action as agents for the skin used to enhance skin permeation of the drug, for example, solvents, skin having the action of increasing the solubility and diffusion of the drug to the base. Fatty acids, fatty alcohols, fatty acid esters, terpene compounds, surfactants, ureas, etc., which act on the lipid portion of the stratum corneum to increase lipid solubility and fluidity and increase the distribution of the drug to the lipid portion. Some of these agents may have one or more mechanisms of action, but essentially act to increase the permeation of the drug. Skin permeation enhancers may be used alone or in combination and may be used in an amount ranging from 1 to 50% by weight based on the total amount of vitamin D analogs and nonpolar polymers included in the drug-containing matrix layer 1b.

Low molecular weight alcohols may be used as the solvent, and representative examples thereof include ethanol, isopropanol, butanol, benzyl alcohol, propylene glycol, glycerin, low molecular weight polyethylene glycol having a molecular weight of 1000 or less, transcutol and triacetin. It promotes skin penetration of the drug and at the same time acts as a solubilizer or dissolution aid.

Fatty acids and derivatives thereof include fatty acids, fatty alcohols and fatty acid esters, which may be used alone or in combination, and may be used in combination with solvents such as propylene glycol for synergistic effects of skin permeation promotion. Examples of the fatty acid include saturated or unsaturated fatty acids having 10 to 18 carbon atoms such as capuric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid, and preferably laurin Acid or oleic acid. Examples of fatty acid alcohols include alcohols having 10 to 18 carbon atoms, such as n-octanol, n-nonanol, decanol, dodecanol, oleyl alcohol, and linoleyl alcohol. Examples of the fatty acid esters are glycerol mono-, di-, tri-laurate, glycerol mono-, di-, tri-oleate, glycerol mono-, di-, tri-linoleate, glycerol mono-, di-, tri Caprylate, propylene glycol mono-, di-laurate, caprylic / capric triglyceride, methyl laurate, isopropyl myristate, isopropyl palmitate, ethyl oleate, oleyl oleate and the like. have.

Examples of the terpene compound include l-menthol, 1.8-cineol, d-limonene, carveol, and camphor. In particular, when used in combination with solvents such as alcohols, the terpene compound promotes distribution to the stratum corneum to increase skin permeation promoting effect. do.

As surfactants, nonionic surfactants, which are generally condensation compounds of polyoxyethylene and fatty acids, are commonly used. Examples thereof include polyoxyethylene cetyl-, lauryl-, oleyl-, stearyl-, and 9-nonylphenyl-ether. And polyethylene glycol-40 hydrogenated castor oil, polyethylene glycol-35 castor oil, and the like. In addition, anionic, cationic or amphoteric surfactants may be used within a concentration range in which skin irritation is not expressed.

In addition, the drug-containing matrix layer 1b of the transdermal agent of the present invention may further include a conventionally known additive in addition to the drug and the nonpolar polymer base, for example, sodium azide, aminoethylsulfonic acid, benzoic acid, sodium benzoate. , Sodium edetate, cetyl pyridinium chloride, benzalkonium chloride, benzetonium chloride, anhydrous sodium sulfate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl para Preservatives such as oxybenzoate and methyl paraoxybenzoate and the like; Antioxidants such as butylated hydroxytoluene, butylated hydroxyanisole, tocopherol, ascorbic acid, citric acid, dried acid, sodium ascorbate, sodium metabisulfite, and the like; air freshener; Preservatives; Bleach; Surfactants; Softeners; Stabilizer; Pigments and the like.

Transdermal absorption preparations of the present invention can be prepared according to conventional manufacturing methods. Alternatively, the non-polar polymer solution is applied onto a release film and dried to prepare a pressure-sensitive adhesive layer sheet, followed by spraying or applying an ethanol solution containing a vitamin D analog thereon, volatilizing ethanol, and laminating a support layer film thereon. Percutaneous absorption preparations may also be prepared.

Hereinafter, the present invention will be described in more detail with reference to Examples and Test Examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

A silicone pressure sensitive adhesive solution (Dow Corning; Bio-PSA 7-4302) was applied onto a polyester release film (Scotchpak 1022, 3M) coated with a fluororesin-based release agent and dried in a hot air dryer to obtain an adhesive layer sheet having a thickness of 50 μm. Prepared. An ethanol solution containing 10.0% by weight of calcitriol and 0.5% by weight of butylhydroxytoluene (BHT) was sprayed or applied onto the pressure-sensitive adhesive layer sheet, and then prepared so that the calcitriol content in the pressure-sensitive adhesive layer was 0.05% by weight. A polyethylene support film (Cotran ^™ 9720, 3M) was laminated thereon and cut into appropriate sizes to prepare a transdermal absorbent.

Example 2

A percutaneous absorbent preparation was prepared in the same manner as in Example 1 except that a styrene-butadiene copolymer solution (National Starch, DURO-TAK ^™ 87-617R) was used as the adhesive.

Example 3

Styrene-isoprene copolymer pressure-sensitive adhesive solution (styrene-isoprene-styrene block copolymer (Kraton D-1107, Shell Chemicals), acrylic petroleum resin (akron P-100, Arakawa Chemical Industries), polyisobutyl as an adhesive Except that HV-300 (Nippon Petrochemicals Co.) was dissolved in a heptane / toluene solvent (70:30) at a ratio of 100: 150: 50 to 50% by weight of solids. In the same manner as in Example 1 to prepare a transdermal absorption preparation.

Example 4

As an adhesive, the styrene-butadiene copolymer (National Starch, DURO-TAK ^TM 87-3500) was melted by heating to 130 ° C., and the melt was coated on a polyester release film (Scotchpak 10223M) coated with a fluororesin-releasing agent. It applied to 50 micrometers and manufactured the adhesive layer sheet. An ethanol solution containing 10.0% by weight of calcitriol and 0.5% by weight of butylhydroxytoluene was sprayed or applied onto the pressure-sensitive adhesive layer sheet, and then prepared so that the calcitriol content in the pressure-sensitive adhesive layer was 0.05% by weight after the ethanol was removed by volatilization. A film (Cotran ^™ 9720, 3M) was laminated and cut into appropriate sizes to prepare a transdermal absorbent.

Example 5

A transdermal absorbent preparation was prepared in the same manner as in Example 1 except that a polyisobutylene pressure-sensitive adhesive solution (National Starch, DURO-TAK ^™ 87-6430) was used as the pressure-sensitive adhesive.

Example 6

Polyisobutylene pressure-sensitive adhesive solution (polyisobutylene (Exon, Vistanex ^TM LM-HM), mineral oil and polybutene (Daelim, PB-1400) as a pressure-sensitive adhesive in the hexane at a ratio of 2: 2: 1 by weight of 50% by weight Percutaneous absorption preparation was prepared in the same manner as in Example 1 except for dissolving to be prepared.

Example 7

A transdermal absorption preparation was prepared in the same manner as in Example 1 except that ergocalciferol was used as the drug.

Example 8

A transdermal absorption preparation was prepared in the same manner as in Example 1 except that alphacalcidol was used as a drug.

Example 9

A transdermal absorption preparation was prepared in the same manner as in Example 1 except that calcididiol (calcipediol) was used and the calcifediol content in the adhesive layer was 0.5% by weight.

Example 10

A percutaneous absorption preparation was prepared in the same manner as in Example 1 except that the calcitriol content in the adhesive layer was 0.01% by weight.

Example 11

A transdermal absorbent preparation was prepared in the same manner as in Example 1 except that the calcitriol content in the adhesive layer was 0.5% by weight.

Example 12

A transdermal absorption preparation was prepared in the same manner as in Example 1 except that the calcitriol content in the adhesive layer was 2% by weight.

Examples 13-18

A percutaneous absorption preparation was prepared in the same manner as in Example 3 except that the skin permeation enhancer shown in Table 2 was added to the composition of the adhesive layer in an amount of 5% by weight.

Example Skin Permeation Enhancer Example 13 Glycerol Monooleate and Methyllaurate (3: 2) Example 14 Glycerol Monolaurate Example 15 Propylene Glycol and Oleic Acid (1: 1) Example 16 Isopropyl myristate Example 17 Isopropyl Alcohol Example 18 Transcutol

Examples 19 to 24

A transdermal absorption preparation was prepared in the same manner as in Example 5 except that the skin permeation enhancer shown in Table 3 was added to the composition of the adhesive layer in an amount of 5% by weight.

Example Skin Permeation Enhancer Example 19 Sorbitan monolaurate Example 20 Triacetin Example 21 Propylene glycol and lauric acid (1: 1) Example 22 Limonene Example 23 1-methylpyrrolidone Example 24 Lauraamide diethylamine

Comparative Example 1

A percutaneous absorbent preparation was prepared in the same manner as in Example 1 except that an acrylate-vinylacetate adhesive solution (National Starch, DURO-TAK ^™ 87-2051) was used as the adhesive.

Comparative Example 2

A percutaneous absorption preparation was prepared in the same manner as in Example 1 except that an acrylate-vinylacetate copolymer (National Starch, DURO-TAK ^™ 87-4098) was used as the adhesive.

Test Example 1

In order to investigate the drug skin permeability of the transdermal absorption preparations prepared in Examples 1 to 24 and Comparative Examples 1 and 2, the transdermal absorption preparation was attached to human cadaver skin and then a Franz-diffusion cell. In vitro drug permeation testing was performed at 32 ° C. The effective drug penetration area of the diffuser was 0.64 cm 2, and the volume of aqueous solution (phosphate buffer, pH = 7.4, Tween20 0.4%, Sodium ascorbate 1%, Sodium citrate 0.1%, Sodium Azide 0.1%) was 5.2 ml. Samples were collected at 300 μl at regular time intervals for 7 days, and then calcitriol was quantified using high performance liquid chromatography (HPLC), and drug permeation rate was calculated over time. In this case, a mixed solution of methanol and water (80/20) was used as a mobile phase of HPLC, and the column was Zorbax C18, and the absorbance at 254 nm was measured. The results are shown in Table 4.

Example Skin penetration rate (ng / ㎠ / day) Example 1 246.8 Example 2 33.7 Example 3 29.6 Example 4 35.4 Example 5 192.8 Example 6 148.6 Example 7 101.3 Example 8 82.7 Example 9 165.3 Example 10 152.7 Example 11 333.9 Example 12 372.0 Example 13 55.1 Example 14 44.6 Example 15 38.7 Example 16 35.8 Example 17 48.2 Example 18 51.6 Example 19 221.2 Example 20 243.7 Example 21 235.6 Example 22 195.4 Example 23 211.0 Example 24 248.6 Comparative Example 1 2.1 Comparative Example 2 3.6

As shown in Table 2, the transdermal absorption agent of the present invention using the non-polar polymer showed a higher skin permeation rate of the vitamin D analogue than the transdermal absorption agent of the comparative example using the polar polymer.

In addition, the correlation between the permeation rate of the drug and the solubility parameter of the polymer base from the transdermal absorbents prepared in Examples 1 to 6 and Comparative Examples 1 and 2 of the present invention is shown in FIG. As shown in FIG. 2, in the transdermal absorbent preparation of the present invention using a nonpolar polymer having a solubility parameter ranging from 15.4 to 17.9 (J / cm 3) ^1/2 , the skin permeation amount of calcitriol as a drug is 29.5 to 246.8 ng / cm 2 / day. On the other hand, in the comparative example using an acrylate polymer having a solubility parameter in the range of 19.9 to 20.5 (J / cm 3) ^1/2 , the skin permeation amount of calcitriol was markedly low as 2.1 to 3.6 ng / cm 2 / day.

The relationship between the permeation coefficient of the drug and the solubility parameter value of the polymer base from the transdermal absorption preparations prepared in Examples 1 to 6 and Comparative Examples 1 and 2 of the present invention is shown in FIG. 3. As shown in FIG. 3, it can be seen that in all cases of Examples and Comparative Examples, a linear relationship is established between the solubility parameter value and the logarithmic value of the transmission coefficient. These results indicate that the interaction of drug and base in transdermal absorbents is a very important factor in skin permeation of drugs and that the design of suitable transdermal absorbents is possible in consideration of the solubility parameter of the polymer base.

Test Example 2

In order to compare blood concentrations of the transdermal absorption preparation prepared in Example 1 and the oral preparation of calcitriol, pharmacokinetic experiments in humans were performed as follows.

In the comparative group, soft capsules containing 0.25 mg of calcitriol (boil milk industry and Bonkey capsule) were administered twice to 12 healthy volunteers every 12 hours, and then blood was collected at regular intervals to radiate the concentration of calcitriol in the blood. Determined according to immunoassay (Radioimmunoassay, Gamma-B, Immunodiagnostic Systems Ltd.).

In addition, one percutaneous absorbent preparation (area 5 cm 2) prepared in Example 1 was attached to the lower abdomen of six healthy volunteers for 7 days and blood was collected at predetermined time intervals to determine blood calcitriol concentration in the same manner.

The results are shown in FIG. As shown in FIG. 4, in the case of commercial oral preparations, the blood concentration of calcitriol was severely changed, whereas the transdermal absorption preparation of the present invention maintained a constant blood concentration for 7 days by only one administration.

The transdermal absorption preparation according to the present invention effectively administers the active vitamin D analog through the skin by using a nonpolar polymer having a solubility parameter ranging from 15 to 18 (J / cm 3) ^1/2 as a base of the adhesive layer. From one transdermal absorption agent of the present invention, 0.05-100 μg of vitamin D analogs are delivered to the body per day, and the administration of the drug is maintained for a long period of 12 hours to 7 days. Accordingly, the transdermal absorption preparations of the present invention are very useful in patients with osteoporosis and renal failure who have to continuously administer vitamin D analogues for a long time.

Claims (9)

(1) 0.0001 to 10% by weight of a vitamin D analogue selected from the group consisting of calcitriol, alpha calcidol, calcididiol, ergocalciferol, paricalcitol, sucalcalciferol and mixtures thereof; And (2) styrene-butadiene copolymer, styrene-isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, butyl rubber, epichlorohydrin rubber and mixtures thereof 90 to 99.9999% by weight of nonpolar polymer selected from the group consisting of A matrix-type transdermal absorbent, characterized in that it comprises a matrix layer containing. delete The method of claim 1, The percutaneous absorption preparation of the vitamin D analog is 0.1 to 500 μg per transdermal administration. The method of claim 1, Transdermal absorption agent wherein the non-polar polymer is a silicone-based polymer. The method of claim 1, A transdermal absorption preparation having a steady skin penetration rate of 0.005 to 20 µg / cm 2 / day for the vitamin D analog. The method of claim 5, wherein A transdermal absorption preparation for maintaining the skin penetration rate of the vitamin D analog for 12 hours to 7 days. The method of claim 1, A transdermal absorption preparation having an effective penetration area of the vitamin D analogue of 1 to 50 cm 2. The method of claim 1, A transdermal absorbent preparation having a skin permeation amount of the vitamin D analogue of 0.05 to 100 µg / day. The method according to any one of claims 1 to 8, A transdermal absorbent agent having a protective layer attached to one side of the matrix layer and a release layer attached to the other side.