WO2004028515A1

WO2004028515A1 - Matrix type patch for transdermal administration of vitamin d analog and the use thereof

Info

Publication number: WO2004028515A1
Application number: PCT/KR2002/001809
Authority: WO
Inventors: Young-Kweon Choi
Original assignee: Individual
Current assignee: Individual
Priority date: 2002-09-26
Filing date: 2002-09-26
Publication date: 2004-04-08
Anticipated expiration: 2005-03-26
Also published as: AU2002368245A1

Abstract

The present invention relates to a matrix type patch for transdermal administration of vitamin D analog and the use thereof.The preparation of a matrix type patch for transdermal administration is characterized by including adhesive layer, which contains (1) 0.0001 to 10 % by weight of vitamin D analog; and (2) 90 to 99.9999 % by weight of nonpolar adhesive polymer and it maintains effective vitamin D analog concentration of the blood for long period and constant permeation of the drug with reduced skin irritation.The present invention can be used to treat diseases which need vitamin D analog, such as osteoporosis, renal failure and thyroid dysfunction.

Description

MATRIX TYPE PATCH FOR TRANSDERMAL ADMINISTRATION OF VITAMIN D ANALOG AND THE USE THEREOF

TECHNICAL FIELD

The present invention relates to a matrix type patch for transdermal administration of vitamin D analog and the use thereof.

BACKGROUND OF ART

Vitamin D plays a key role in the bone generation and mineral metabolism. Therefore, it is common to administrate vitamin D or its analog for alleviating or treating various diseases such as osteoporosis, rachitis, osteomalacia, chronic renal failure, renal osteodystrophy of patient who is treated with blood dialysis, hypoparathyroidism, hypocalcemia of chronic kidney dialysis patient, and renal osteodystrophy caused by decrease of parathyroidal hormone.

Typical vitamin D analogs are calcitriol (l,25(OH)₂D ), α-calcidol (l-α(OH)D₃) and calcifediol (25(OH)D ), and so on. These play an important role in bone and mineral metabolism and act on the growth and differentiation of tissue and also the regulation of immunal function.

Calcitriol, final active metabolite of vitamin D_3j is formed by follwing multisteps. Converted vitamin D₃ from 7-dihydrocholesterol by the action of UN in skin is carried to liver by blood flow and is metabolized to calcifediol by 25-hydroxylase enzyme, and then is converted to calcitriol by 1-hydroxylase enzyme after being transferred to kidney. In other way, calcitriol is also formed by conversion of α-calcidol, a precursor of calcitriol, by hydroxylase in liver. An amount ranging 1.0 to 1.5 zg per day of calcitriol is produced in normal kidney and the process is regulated by parathyroid hormone. Major functions of calcitriol are (1) to increase the absorption of calcium and phosphorus ion in intestine, (2) to promote reabsorption of the calcium and phosphorus ions in kidney and (3) to facilitate or to inhibit the osteogenesis by acting on the cells involved in bone metabolism directly or indirectly. The other vitamin D analogs, such as ergocalciferol, doxercalciferol, paricalcitol,

OCT (22-oxacalcitriol) and calcipotriol have been known in the art. Among those analogs, doxercalciferol and paricalcitol are used for the inhibition of enhanced thyroid function and calcipotriol is used for treatment of psoriasis.

Such vitamin D analogs show different functions according to their blood concentration; for example, it is known that calcitriol accelerates osteogenesis in appropriate physiological concentration, whereas it inhibits osteogenesis in high concentration. Through above mechanism, whole balance of bone remodeling is regulated. Therefore, adequate administration of calcitriol or other vitamin D analogs is crucial for treatment and prevention of osteoporosis and particularly, it is essential for hepatic cirrhosis or renal failure patients to supplement a proper amount of calcitriol because vitamin D₃ cannot be converted to an active form, calcitriol, in the case of deterioration of liver or kidney function.

In order to treat the diseases which need vitamin D analog, vitamin D analog has been administered with intravenous injection or oral administration and the dose of calcitriol and α calcidol to treat osteoporosis or chronic renal failure ranges from 0.25 to 0.75 tg and from 0.5 to 1.0 .g, respectively.

Since there has been known that calcitriol increases the absorption of calcium and phosphorus ion at the blood concentration in the range of 30 to 70 ρg/m£, whereas hardly increase at the concentration below 30pg/m£ or over 70pg/ . In order to maintain the calcitriol concentration in effective range continuously, conventional oral dosage form should be administered twice a day, or i.v. injection, and is recommended to be administered under the well-controlled circumstances. However, in early stage of injection or oral administration, various symptoms such as fatigue, headache, nausea, mouth dry, constipation, myalgia and the like may appear, which are involved in hypercalcemia and hypercalcinuria caused by abnonnal increase of calcitriol in blood, hi severe cases, the side effects such as hypercalcemia, hypercalcinuria, kidney dysfunction, and kidney stone, can be occurred and particularly, severe hypercalcemia whose blood calcium concentration is above 12mg/dl may lead to dementia, delirium and coma.

Side effects mentioned above are caused by a peak and valley phenomenon of drug concentration in blood, which is generally happened in intravenous injection or oral administration. To avoid abnormal increase of drug concentration in early stage and drug accumulation by repetitive administration in body, serum calcium concentration should be monitored periodically and appropriate dose thereof be adjusted.

If hypercalcemia was broken out, drug administration should be suspended in and be started to treat with small amount of drug after dropping the calcium concentration of blood to normal level. Althougli vitamin D analogs such as calcitriol and α-calcidol were frequently used for treatment of diseases such as osteoporosis, the development of controlled delivery systems has been needed for reducing their side effects and their inconvenience in administration, considering that injection or oral pathway may lead to hypercalcemia and vitamin D analog treatment is generally required for long-term period.

To solve the conventional problems concerning oral and injection administration, various controlled release systems have been designed to keep up the effective vitamin D analog concentration of the blood by regulating drug release rate continuously and consistently for a long period. Among them, transdermal drug delivery system has several advantages; administration is simple and drug efficacy lasts for a long time, and thereby it can improve patient compliance, maintain effective blood concentration for a long period in case of short half-life drug, enhance drug efficacy by detouring first pass metabolism, and be easily removed when needed.

U.S. Pat. No. 4,983,395 discloses that reservoir type of transdermal drug delivery system containing an active component such as calcitriol, can prevent active ingredients or liquid additives such as ethanol in reservoir from spreading out to adhesive layer during storage, due to use of the protective membrane between permeability-controlled membrane and adhesive layer. However, this system could lead severe skin irritation because of its excessive ethanol amount (67.5%) in reservoir and is not recommendable practically because AOβg of calcitriol content is too excessive compared with common oral dose. Moreover, the reservoir system has several disadvantages such as a complicated manufacturing process and the decrease of patient compliance due to discomfort when it is attached.

U.S. Pat. No. 6,024, 976 discloses an invention to obtain a proper transdermal permeation rate by controlling solubility parameter using acrylate and silicone polymer or the mixture of a soluble polyvinylpynolidone therewith as a base of adhesive layer. However, the drugs in the system have low transdermal permeability, and it is not suitable for the drugs such as vitamin D analogs which is treated in a small amount, because the drug content in the system ranges from 0.3 to 30 w/w %.

As shown below in Empirical formula 1, the permeation rate of drug through skin in transdermal formulation is usually in proportion to the permeation coefficient being determined by used adhesive component and the drug, and the concentration of drugs inside adhesive.

[Empirical formula 1] J_p = P_e X ΔC

Wherein the Empirical formula 1, J_p is the amount of permeated drug per the unit area and the unit time; P_e is a permeation coefficient and ΔC is the difference of drug concentration between in adhesive and skin.

Also, above permeation coefficient is in proportion to the diffusion rate and the partition coefficient of drugs as shown in following Empirical formula 2.

[Empirical formula 2]

P_e = Dp / L X K_s/p

P_e is a permeation coefficient, D_p is the diffusion coefficient in adhesive, L is the thickness of adhesive and K_s/P is the partition coefficient of drug for adhesive and skin. According to above formula, the drug permeability in transdermal administration is determined by the diffusion rate of the drugs inside adhesive and by the diffusion from the adhesive to the skin, which are governed by the interaction between drug and adhesive.

The solubility parameter (δ) is a factor for analyzing the interaction between drug and adhesive quantitatively and the parameter is defined as the sum of all intermolecular attractive forces, which is very useful to predict the compatibility of two materials and the extent of mutual solubility in the mixture of both. Solubility parameters can be determined by being calculated by known formula or experiment. The most conventional method is Hildebrand's method shown in following Empirical formula 3.

[Empirical formula 3] δ = (ΔE_V/ N)^1/2 = ((ΔH_V - RT) / N)^1/2

δ is a solubility parameter, ΔE_V is the energy of vaporization, N is the molecular weight/density, ΔH_V is the heat of vaporization, R is the gas constant and T is the absolute temperature. Therefore, the interaction between drug and adhesive can be inferred by applying solubility parameter to polymer as adhesive of preparation for transdermal administration and thereby adequate adhesive component can be selected to obtain the proper drug permeability. Consequently, the appropriate transdermal preparation to administrate vitamin D analog can be designed by controlling various factors such as dose, permeation rate and effective area.

Solubility parameters of conventional polymer determined by Empirical formula 3, are shown in Table 1.

[Table 1]

DISCLOSURE OF THE INVENTION

Accordingly, it is an object of the present invention to provide a matrix type patch for transdermal administration characterized by comprising a matrix layer which contains (1) 0.0001 to 10 % by weight of vitamin D analog; and (2) 90 to 99.9999 % by weight of nonpolar polymer selected from the group consisting of polyethylene, polyisobutylene, styrene-butadiene copolymer, styrene-isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, butyl rubber, epichlorohydrin rubber and the mixture thereof.

It is another object of the present invention to provide the use of the above matrix type patch for transdermal administration of vitamin D analog for treatment of diseases required vitamin D analog treatment, such as osteoporosis, renal failure, thyroid dysfunction and so on.

The matrix type patch preparation of the present invention is characterized by dissolving or diffusing vitamin D analog in polymer base.

In some embodiments, the vitamin D analogs is selected at least one compound among the group consisting of calcitriol, alphacalcidol, calcifediol, ergocalciferol, paricalcitol, doxercalciferol and their mixture thereof, which are effective to treat vitamin D-required diseases.

A dose of vitamin D analog per day is generally 0.5 g of calcitriol, lμg of α calcidol, Iβg of ergocalciferol, 5/tg of paricalcitol, Aβg of doxercalciferol and 50/zg of calciferdiol, respectively, whose absorption rate is close to 100%) in oral administration. When vitamin D is administered to skin, the required amount of skin permeation ranges from 0.05 to 100 g per day, considering its dose modification in accordance with the severity of symptom and administration method, preferable amount of skin permeation ranges from 0.5 to 50 g per day, most preferably from 0.1 to 50 tg per day. In some embodiments, the content of drugs ranges from 0.1 to 500 g, preferably

0.5 to 200/tg for one patch of the inventive preparation considering the amount of drug and base material, and effective permeation area and so on. When the amount of drug is less than 0.1 μg, it is difficult to maintain proposed permeation rate through skin, and when more than 500/tg, it may occur side effects, such as hypercalcemia, hypercalcinuria, renal failure, renal calculus etc. and may be uneconomical because of its high cost. Also in certain embodiments, preferable permeation rate through skin in inventive preparation ranges from 0.005 to 20/-g/cm²/day, preferably 0.01 to 10 tg /cm²/day. In other embodiments, the drug can be permeated through effective area of normal skin ranging from 1 to 50 cm², preferably 5 to 30 cm² and the administration rate of drug can be maintained for the period ranging 12 hours to 7 day effectively. According to proper combination of permeation rate and effective permeation area, in other embodiments, total amount of drug ranges from 0.05 to 100 -g/day, preferably 0.1 to 50/zg/day.

In some embodiments, the base material comprises a natural or synthetic nonpolar polymeric rubber, whose solubility paramater is ranging from 15 to 18(J/cm³)^{1 2}, for example, polyethylene, polyisobutylene, styrene-butadiene copolymer, styrene-isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, vinyl chloride- vinyl acetate copolymer, butyl rubber, epichlorohydrin rubber or the mixture thereof, desirably, elastic polymer such as silicone polymer, polyisobutylene, styrene-butadiene copolymer and styrene-isoprene copolymer, in preferred embodiment, silicone polymer.

Generally, whereas acrylate polar polymer commonly used as adhesive base material in matrix type percutaneous preparation, causes drug diffusion to slow down in adhesive base and diffusion from adhesive to skin to fall down due to the interaction between the drug and polymer in adhesive layer. In the present invention, by using the above nonpolar polymeric rubber adhesive whose solubility parameter is lower than acrylate polar polymer by 1.5 to 5.0(J/cm³)^1/2, the drug diffusion and movement rate to skin have been increased. The above adhesive layer containing vitamin D analog and nonpolar polymer base can be applied to conventional matrix type percutaneous preparation. It is further demonstrated by embodiment examples of the present invention as follows.

Fig. 1 depicts a sectional diagram showing an example of matrix type percutaneous preparation according to this invention. As seen in Fig. 1, in preferred embodiment, the matrix type patch for transdermal administration consists of drug- protecting backing layer (la); drug-containing adhesive layer (lb); and release liner (lc). Above drug-protecting backing layer (la) may provide drug-containing adhesive layer (lb) with protection and support. The backing layer should be made essentially in the same size with drug-containing adhesive layer (lb) or in larger size (lb) to support adhesive layer by expanding over the border of it (lb). Preferable materials for manufacturing backing layer (la) are high and low density polyethylene, polypropylene, polyvinyl chloride, polyvinyl acetate, polyurethane, polyester, cellulose acetate, ethylcellulose, plasticized vinylacetate-vinylchloride copolymer, plasticized polyvinylchloride, polyvmylidene chloride, metal foil, non-woven fabric, cotton cloth, paper or the laminate thereof.

Suitable thickness of backing layer (la) ranges from 5 to 500/M, desirably 5 to 200 im, to provide proposed protective and supportive function.

Above drug-containing adhesive layer (lb) comprises vitamin D analog and nonpolar polymeric adhesive. Adhesive layer (lb) can be made as a monolayer incorporated the drug to a nonpolar adhesive or multilayer laminated with non-adhesive polymer layer containing the drug and adhesive layer to attach to skin. As nonpolar adhesive polymer, polyisobutylene, styrene-butadiene copolymer, styrene-isoprene copolymer, silicone polymer and the like, can be used. As non-adhesive nonpolar polymer, polyethylene, isobutylene-isoprene copolymer, polyisobutene, ethylene- propylene copolymer, silicone rubber, neoprene rubber, butylrubber, epichlorohydrin rubber and the like, can be used. The above adhesive polymers can be used as an adhesive to be accumulated in non-adhesive nonpolar polymer layer.

Adhesive layer (lb) consists of vitamin D analog at the amount of ranging 0.0001 to 10 % by weight and nonpolar polymer ranging 90 to 99.9999% by weight.

Release liner (lc) attached to drug-containing adhesive layer (lb) blocks the drug release from the preparation during storage period before use, protects adhesive layer (lb) and is removed at use. The materials used conventionally as release liner can be applied to release liner (lc) preparation, for example, film, paper or their laminates made by silicone resin or fluoride resin-spreading polyethylene, polyester, polyvinylchloride and polyvmylidene chloride. Generally, suitable thickness of release liner (lc) ranges from 12 "to 200 mι, desirably 50 to 150 m.

Since the drug permeation rate through skin is determined by the physicochemical property and the content of a drug, component, the thickness of adhesive and the effective area of the preparation, an absorption enhancer can be comprised in drug-containing adhesive layer of the preparation to control the peraieation rate of a drug through skin. Absorption enhancer comprises various effectors having various mechanism, for example, the solvents which can increase the solubility and the diffusion of a drug in adhesive, and the components such as fatty acids, fatty acid alcohol, fatty acid ester, terpene compound, surfactant, urea and the like, which increase the lipid solubility and fluidity with acting on lipid layer of stratum corneum and thus improve the drug distribution to lipid layer of skin. While some of these effectors may have at least one mechanism, they fundamentally increase the drug permeation. Absorption enhancer can be used as alone or the mixture thereof in the amount of ranging from 1 to 50% by weight of adhesive layer (lb). Solvents as an absorption enhancer can be mainly lower alcohols, for example, ethanol, isopropanol, butanol, benzyl alcohol, propylene glycol, glycerin, low molecular weight under 1000 of polyethylene glycol, transcutol, triacetin and the like, which also act as a solubilizer or solubility aid.

Fatty acids and its derivatives as an absorption enhancer comprise fatty acid, fatty acid alcohol and fatty acid ester and the like. These can be used as alone or the mixture thereof and used with propylene glycol for enhancing effect of skin permeation. For example, fatty acids, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, oleic acid, linoleic acid, linolenic acid and the like, can be selected, which is saturated or unsaturated fatty acids having 10 to 18 carbons, desirably lauric acid or oleic acid. For exemple, fatty acid alcohol, «-octanol, H-nonanol, decanol, dodecanol, oleyl alcohol, linoleyl alcohol and the like having 10 to 18 carbons can be used. For the example of above fatty acid ester, glyceryl mono-, di-, tri-laurate, glyceryl mono-, di-, tri-oleate, glyceryl mono-, di-, tri-linoleate, glyceryl mono-, di-, tri-caprilate, propyleneglycol mono-, di-laurate, caprilic/capric triglyceride, methyl laurate, isopropyl myristate, isopropyl palmitate, ethyl oleate, oleyl oleate and the like, can be selected.

Terpene compounds as an absorption enhancer comprising 1 -menthol, 1,8-cineol, d-limonene, carbeol, camphor etc., can be mixed particularly with solvents such as alcohol to enhance skin permeation effect and accelerate the distribution of the compound to stratum corneum.

For surfactants as an absorption enhancer, non-ionic surfactants, condensed polyoxyethylene and fatty acids are commonly used, for example, polyoxyethylene cetyl-, laulyl-, oleyl-, stearyl-, o-nonylphenyl-ether and polyethyleneglycol-40 hydrogenated castor oil, polyethylene glycol-35 castor oil etc and anionic, cationic or amphoteric surfactants can be used within the concentration range not appearing skin irritation.

Also, adhesive layer (lb) of the inventive preparation can comprise additionally commercial additives with drugs and adhesives, for example, antiseptics such as sodium azide, aminoethysulfonic acid, benzoate, sodium benzoic acid, sodium edetate, cetyl pyridium chloride, benzalconium chloride, benzetonium chloride, anhydride sodium sulfate, isobutyl paraoxybenzoate, isopropyl paraoxybenzoate, ethyl paraoxybenzoate, butyl paraoxybenzoate, propyl paraoxybenzoate and methyl paraoxybenzoate etc., an antioxidant such as butylated hydroxy toluene, butylated hydroxy anisole, tocopherol, ascorbic acid, citric acid, malic acid, sodium ascorbate and sodium metabisulfate etc., aromatics, preservatives, opacifiers, surfactants, softeners, stabilizers and coloring agents.

Matrix type patch of the present invention can be prepared by conventional manufacturing process and can be made by the steps of spraying nonpolar adhesive polymer solution to release liner film, drying to make adhesive sheet, spraying or spreading ethanol solution containing vitamin D analog thereto, volatilizing the ethanol and laminating the backing film thereon.

Further, the percentages given below for solid in solid mixture, liquid in liquid, and solid in liquid are on wt/wt, vol/vol and wt/vol basis, respectively, unless specifically indicated otherwise.

BRIEF DESCRIPTION OF THE DRAWINGS

The above and other objects and features of the present invention will become apparent from the following description, when taken in conjunction with the accompanying drawings, in which:

Fig. 1 presents a sectional diagram showing one embodiment example of inventive preparation;

Fig. 2 represents the change of calcitriol permeated amount according to the solubility parameter of adhesive polymer in inventive preparation; Fig. 3 depicts the change of calcitriol permeability coefficient according to the solubility parameter of adhesive polymer in inventive preparation;

Fig. 4 shows the change of calcitriol concentration in plasma with time after administering commercially available oral dosage of calcitriol and the inventive preparation to human body.

BEST MODE FOR CARRTNG OUT THE INVENTION

The following Examples and Experimental Examples are intended to further illustrate matrix type patch formulation of the present invention without limiting its scope.

Example 1 Silicone adhesive solution (Dow Corning; Bio-PSA 7-4302) was spread on release liner film (Scotchpak 1022, 3M) coated with fluoride resin and then dried in drying oven to manufacture adhesive sheet with a thickness of 50 m. Ethanol solution containing 10.0 w/w % of calcitriol and 0.5 w/w % of butylhydroxytoluene was sprayed or spread thereon, and removed by volatilization on adhesive sheet. The sheet was made to calcitriol amount of 0.05 w/w % and then covered with polyethylene support backing film (Cotran™ 9720, 3M) and cut into pieces to a size of 5, 10 and 15 cm², respectively, to prepare matrix type patch formulation of the present invention.

Example 2 Matrix type patch formulation was prepared by the identical procedure disclosed in

Example 1, except using styrene-butadiene copolymer solution (DURO-TAK™ 87-617R, National Starch) as an adhesive.

Example 3 Styrene-isoprene copolymer adhesive solution was made by following recipe.

The mixture of styrene-isoprene-styrene block copolymer (Kraton D-1107, Shell Chemicals), acrylic petroleum resin (Akron P-100, Arakawa Chemical Industries), polyisobutylene (HV-300, Nippon Petrochemicals Co.) was made by dissolving with a ratio of 100:150:50 in solvent mixture of heptane/toluene solvent (70:30) to the solid content of 50 w/w %.

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using styrene-isoprene copolymer solution as an adhesive.

Example 4

After styrene-butadiene copolymer (DURO-TAK™ 87-3500, National Starch) was heated and melted at 130°C, the melted solution was spread on polyester release liner film (Scotchpak 1022, 3M) coated with fluoride resin with a thickness of 50 m for preparing adhesive sheet. Ethanol solution containing 10.0 w/w % of calcitriol and 0.5 w/w % of butylhydroxytoluene was sprayed or spread and removed by volatilization on above adhesive sheet. The sheet was made to the calcitriol amount of 0.05 w/w % and then covered with polyethylene support film (Cotran™ 9720, 3M) and cut into the suitable size to prepare matrix type patch formulation.

Example 5

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using polyisobutylene adhesive solution (DURO-TAK™ 87-6430, National Starch) as an adhesive.

Example 6

Polyisobutylene adhesive solution was made by following recipe. The mixture of polyisobutylene (Exxon, NistanexTM LM-HM), mineral oil and polybutene (PB-1400, Daerim) was made by dissolving with a ratio of 2:2: 1 in hexane to the solid content of 50 w/w % .

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using polyisobutylene adhesive solution as an adhesive. Example 7

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using ergocalciferol as a drug.

Example 8

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using alphacalcidol as a drug.

Example 9

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using calcifediol as a drug and using at the content of 0.5 w/w % in adhesive layer.

Example 10

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using at the calcitriol content of 0.01 w/w % in adhesive layer.

Example 11 Matrix type patch formulation was prepared by the identical procedure disclosed in

Example 1, except using at the calcitriol content of 0.5 w/w % in adhesive layer.

Example 12

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using at the calcitriol content of 2 w/w % in adhesive layer. Example 13 to 18

Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except adding absorption enhancer at the content (shown in Table 2) of 5 w/w % to the composition of adhesive layer.

[Table 2]

Example 19 to 24 Matrix type patch formulation was prepared by the identical procedure disclosed in

Example 5, except adding absorption enhancer at the content (shown in Table 3) of 5 w/w % to the composition of adhesive layer.

[Table 3]

Comparative Example 1

Matrix type patch formulation was prepared by the identical procedure disclosed in

Example 1, except using acrylate- vinylacetate adhesive solution (DURO-TAK™ 87-2051,

National Starch) as an adhesive.

Comparative Example 2

Example 1, except using acrylate- vinylacetate copolymer (DURO-TAK™ 87-4098,

National Starch) as an adhesive.

Experimental Example 1

In order to examine the drug transdermal permeability of the formulations prepared by the procedures disclosed in Example 1 to 24 and Comparative Example 1 and 2, inventive preparations were attached to human cadaver skin and then, in vitro drug permeability was measured by using Franz-diffusion cell at 32°C. The effective drug permeation area of diffusion cell was 0.64cm² and the volume of solution (phosphate buffer (pH 7.4), 40% Tween 20, 1% sodium ascorbate, 0.1 %> sodium citrate, 0.1 %> sodium azide) was 5.2m£. Samples were collected by 300 ^6 at regular intervals during 7 days and analyzed the amount of calcitriol with HPLC and calculated the drug permeation rate with time. The mixture of methanol and distilled water (80:20) was used as mobile phase and Zorbax C18 column was used. Absorbance was measured at UN 254nm. Results were shown in Table 4.

[Table 4]

As shown in Table 4, matrix type patch formulation of the present invention using nonpolar adhesive polymer, shows higher transdermal permeation rate of vitamin D analog than that of Comparative Examples using polar adhesive polymer. Additionally, the correlation with drug permeation rate of the formulations prepared by Example 1 to 6 and Comparative Example 1, 2, and solubility parameter of adhesive polymer was shown in Fig. 2. As shown in Fig. 2, while the inventive preparation using nonpolar adhesive polymer having its solubility parameter ranging 15.4 to π^J/cm³)^{1 2}, shows the skin permeation at the amount of calcitriol ranging about 29.5 to 246.8 ng/cm²/day; Comparative Examples using acrylate polymer having its solubility parameter ranging 19.9 to 20.5(J/cm³)^1/2, show much lower skin permeation at the amount of calcitriol ranging about 2.1 to 3.6 ng/cm²/day.

Drug permeation coefficient of the preparations by the procedure disclosed in Example 1 to 6 and Comparative Example 1, 2 has a correlation with solubility parameter of adhesive polymer shown in Fig. 3. As shown in Fig. 3, it is confirmed that there is a linear correlation with solubility parameter and logarithm of permeation coefficient in all cases of examples and comparative examples. These results show that the interaction between the drug and the adhesive is the most important factor in transdermal permeation of drug, and the preparation for transdermal administration can be designed considering the solubility parameter of adhesive polymer.

Experimental Example 2

To compare the blood calcitriol concentration of the matrix type patch preparation in Example 1 and conventional-oral dosage of calcitriol, both were treated to human and a phamacokinetics experiment was conducted as following procedure.

For comparative group, soft capsules containing 0.25 g of calcitriol (Bonky® Soft Cap, Yuyu Industrial Co., Ltd.) was administered twice to six healthy volunteers at 12- hour intervals and then blood samples were collected at regular intervals to determine the blood calcitriol concentration by radioimmunoassay (Gamma-B, Immunodiagnostic Systems Ltd.).

Besides, the matrix type patch prepared by Example 1 having 5cm² of its surface area, was attached to lower abdomen of each six healthy volunteers for 7 days and then blood samples were collected at regular intervals to determine the blood calcitriol concentration by the identical method with above.

As shown in Fig. 4, the inventive preparation maintained the constant blood calcitriol concentration for 7 days with one administration, while the comparative group showed steep variation of blood calcitriol concentration.

INDUSTRIAL APPLICABILITY

As mentioned above, in the matrix type patch formulation of the present invention, vitamin D analog can effectively permeate through skin by using nonpolar polymer having 15 to 18(J/cm ) of solubility parameter as an adhesive base.

A matrix type patch of the present invention can transfer 0.05 to lOO^g of vitamin D analog/day into a body and drug administration can be maintained for 12 hours to 7 days of long period.

Therefore, the present invention is useful to the patients suffering from the diseases such as osteoporosis or renal failure which need long-term constant treatment of vitamin D analog.

While the invention has been described with respect to the above specific embodiments, it should be recognized that various modification and changes might be made to the invention by those skilled in the art which also fall within the scope of the invention as defined in the appended claims.

Claims

1. A matrix type patch for transdermal administration characterized by comprising an adhesive layer which contains (1) 0.0001 to 10 w/w %> of vitamin D analog; and (2) 90 to 99.9999 w/w % of nonpolar polymer selected from the group consisting of polyethylene, polyisobutylene, styrene-butadiene copolymer, styrene- isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropylene, silicone polymer, neoprene rubber, polyvinyl chloride, vinyl chloride-vinyl acetate copolymer, butyl rubber, epichlorohydrin rubber and the mixture thereof.

2. The preparation of claim 1, wherein said vitamin D analog is selected from the group consisting of calcitriol, alphacalcidol, calcifediol, ergocalciferol, paricalcitol, doxercalciferol and the mixture thereof.

3. The preparation of claim 1, wherein said content of vitamin D analog ranges from 0.1 to 500 zg for one patch of the present invention.

4. The preparation of claim 1, wherein said nonpolar adhesive polymer is silicone polymer.

5. The preparation of claim 1, wherein said transderaial permeation rate of vitamin D analog ranges from 0.005 to 20 g/cm²/day.

6. The preparation of claim 5, wherein said transdermal permeation rate of vitamin D analog is maintained for the period ranging 12 hours to 7 days.

7. The preparation of claim 1, wherein said effective permeation area of vitamin D analog ranges from 1 to 50cm².

8. The preparation of claim 1, wherein said total amount of vitamin D analog ranges from 0.05 to 100/zg/day.

9. The preparation of any one of claim 1 to 8, wherein said matrix type patch for transdermal administration consists of drug-protecting backing layer, drug- containing adhesive layer and release liner.

10. Use of the matrix type patch for transdermal administration of vitamin D analog for the treatment of the diseases which need vitamin D analog, such as osteoporosis, renal failure and thyroid dysfunction.