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WO2004028515A1 - Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier - Google Patents

Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier Download PDF

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Publication number
WO2004028515A1
WO2004028515A1 PCT/KR2002/001809 KR0201809W WO2004028515A1 WO 2004028515 A1 WO2004028515 A1 WO 2004028515A1 KR 0201809 W KR0201809 W KR 0201809W WO 2004028515 A1 WO2004028515 A1 WO 2004028515A1
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WIPO (PCT)
Prior art keywords
vitamin
analog
preparation
drug
matrix type
Prior art date
Application number
PCT/KR2002/001809
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English (en)
Inventor
Young-Kweon Choi
Original Assignee
Young-Kweon Choi
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Filing date
Publication date
Application filed by Young-Kweon Choi filed Critical Young-Kweon Choi
Priority to AU2002368245A priority Critical patent/AU2002368245A1/en
Priority to PCT/KR2002/001809 priority patent/WO2004028515A1/fr
Publication of WO2004028515A1 publication Critical patent/WO2004028515A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7053—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained by reactions only involving carbon to carbon unsaturated bonds, e.g. polyvinyl, polyisobutylene, polystyrene
    • A61K9/7061—Polyacrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/70—Web, sheet or filament bases ; Films; Fibres of the matrix type containing drug
    • A61K9/7023—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms
    • A61K9/703—Transdermal patches and similar drug-containing composite devices, e.g. cataplasms characterised by shape or structure; Details concerning release liner or backing; Refillable patches; User-activated patches
    • A61K9/7038—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer
    • A61K9/7046—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds
    • A61K9/7069—Transdermal patches of the drug-in-adhesive type, i.e. comprising drug in the skin-adhesive layer the adhesive comprising macromolecular compounds obtained otherwise than by reactions only involving carbon to carbon unsaturated bonds, e.g. polysiloxane, polyesters, polyurethane, polyethylene oxide

Definitions

  • the present invention relates to a matrix type patch for transdermal administration of vitamin D analog and the use thereof.
  • 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.
  • 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) 2 D ), ⁇ -calcidol (l- ⁇ (OH)D 3 ) 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 D 3 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.
  • calcitriol is also formed by conversion of ⁇ -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.
  • calcitriol 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
  • calcipotriol a complex regional coherence tomography
  • doxercalciferol and paricalcitol are used for the inhibition of enhanced thyroid function
  • 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 D 3 cannot be converted to an active form, calcitriol, in the case of deterioration of liver or kidney function.
  • vitamin D analog has been administered with intravenous injection or oral administration and the dose of calcitriol and ⁇ 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.
  • 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.
  • this system could lead severe skin irritation because of its excessive ethanol amount (67.5%) in reservoir and is not recommendable practically because AO ⁇ g of calcitriol content is too excessive compared with common oral dose.
  • 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.
  • 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 %.
  • 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.
  • J p is the amount of permeated drug per the unit area and the unit time; P e is a permeation coefficient and ⁇ C is the difference of drug concentration between in adhesive and skin.
  • above permeation coefficient is in proportion to the diffusion rate and the partition coefficient of drugs as shown in following Empirical formula 2.
  • 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.
  • solubility parameter ( ⁇ ) 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.
  • ⁇ is a solubility parameter
  • ⁇ E V is the energy of vaporization
  • N is the molecular weight/density
  • ⁇ H V is the heat of vaporization
  • R is the gas constant
  • 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.
  • 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.
  • nonpolar polymer selected from the group consisting of polyethylene, polyisobutylene, styrene-butadiene copolymer, styrene-isoprene copolymer, polyisobutene, ethylene-propylene copolymer, polypropy
  • the matrix type patch preparation of the present invention is characterized by dissolving or diffusing vitamin D analog in polymer base.
  • 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, l ⁇ g of ⁇ calcidol, I ⁇ g of ergocalciferol, 5/tg of paricalcitol, A ⁇ g of doxercalciferol and 50/zg of calciferdiol, respectively, whose absorption rate is close to 100%) in oral administration.
  • 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.
  • the content of drugs ranges from 0.1 to 500 g, preferably
  • preferable permeation rate through skin in inventive preparation ranges from 0.005 to 20/-g/cm 2 /day, preferably 0.01 to 10 tg /cm 2 /day.
  • the drug can be permeated through effective area of normal skin ranging from 1 to 50 cm 2 , preferably 5 to 30 cm 2 and the administration rate of drug can be maintained for the period ranging 12 hours to 7 day effectively.
  • total amount of drug ranges from 0.05 to 100 -g/day, preferably 0.1 to 50/zg/day.
  • the base material comprises a natural or synthetic nonpolar polymeric rubber, whose solubility paramater is ranging from 15 to 18(J/cm 3 ) 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.
  • silicone polymer such as silicone polymer, polyisobutylene, styrene-butadiene copo
  • Fig. 1 depicts a sectional diagram showing an example of matrix type percutaneous preparation according to this invention.
  • 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.
  • 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.
  • nonpolar adhesive polymer polyisobutylene, styrene-butadiene copolymer, styrene-isoprene copolymer, silicone polymer and the like, can be used.
  • 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.
  • suitable thickness of release liner (lc) ranges from 12 "to 200 m ⁇ , desirably 50 to 150 m.
  • 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.
  • 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.
  • 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.
  • fatty acid alcohol «-octanol, H-nonanol, decanol, dodecanol, oleyl alcohol, linoleyl alcohol and the like having 10 to 18 carbons
  • 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.
  • 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.
  • 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.
  • antiseptics such as
  • 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.
  • 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.
  • 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 (CotranTM 9720, 3M) and cut into pieces to a size of 5, 10 and 15 cm 2 , 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-TAKTM 87-617R, National Starch) as an adhesive.
  • styrene-butadiene copolymer solution DURO-TAKTM 87-617R, National Starch
  • 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.
  • styrene-butadiene copolymer (DURO-TAKTM 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 (CotranTM 9720, 3M) and cut into the suitable size to prepare matrix type patch formulation.
  • styrene-butadiene copolymer (DURO-TAKTM 87-3500, National Starch) was heated and melted at 130°C, the melted solution was spread on polyester release liner film (Scotchpak 1022
  • Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using polyisobutylene adhesive solution (DURO-TAKTM 87-6430, National Starch) as an adhesive.
  • polyisobutylene adhesive solution DURO-TAKTM 87-6430, National Starch
  • 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.
  • Matrix type patch formulation was prepared by the identical procedure disclosed in Example 1, except using alphacalcidol as a drug.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • Matrix type patch formulation was prepared by the identical procedure disclosed in
  • Example 1 except using acrylate- vinylacetate adhesive solution (DURO-TAKTM 87-2051,
  • Matrix type patch formulation was prepared by the identical procedure disclosed in
  • Example 1 except using acrylate- vinylacetate copolymer (DURO-TAKTM 87-4098,
  • 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 0.64cm 2 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.
  • 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.
  • Example 1 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.
  • 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.).
  • the matrix type patch prepared by Example 1 having 5cm 2 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.
  • 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.
  • 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.
  • 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.

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Abstract

La présente invention se rapporte à un timbre de type matriciel pour l'administration transdermique d'un analogue de la vitamine D et à l'utilisation de ce dernier. La préparation du timbre de type matriciel pour administration transdermique de l'invention est caractérisée en ce que le timbre comprend une couche adhésive contenant (1) de 0,0001 à 10 % en poids d'un analogue de la vitamine D; et (2) de 90 à 99,9999 % en poids d'un polymère adhésif non polaire, et en ce qu'il permet de maintenir une concentration efficace en analogue de la vitamine D dans le sang pendant une longue période et une perméation constante du médicament avec une irritation cutanée réduite. L'invention peut être utilisée pour traiter des maladies nécessitant le recours à un analogue de la vitamine D, telles que l'ostéoporose, l'insuffisance rénale et les dysfonctionnements thyroïdiens.
PCT/KR2002/001809 2002-09-26 2002-09-26 Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier WO2004028515A1 (fr)

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AU2002368245A AU2002368245A1 (en) 2002-09-26 2002-09-26 Matrix type patch for transdermal administration of vitamin d analog and the use thereof
PCT/KR2002/001809 WO2004028515A1 (fr) 2002-09-26 2002-09-26 Timbre de type matriciel pour administration transdermique d'un analogue de la vitamine d et utilisation de ce dernier

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005011651A2 (fr) * 2003-07-30 2005-02-10 Abbott Laboratories Utilisation de vitamines d ou d'analogue de la vitamine d pour traiter les maladies cardio-vasculaires
WO2005011652A2 (fr) * 2003-07-29 2005-02-10 Abbott Laboratories Utilisation de vitamines d pour le traitement de maladie rénale
WO2006134272A1 (fr) * 2005-06-17 2006-12-21 Galderma Research & Development Composition pharmaceutique comprenant un elastomere organopolysiloxane et un principe actif solubilise
WO2006133828A1 (fr) * 2005-06-17 2006-12-21 Dsm Ip Assets B.V. Nouvelle utilisation du 25-hydroxycholecalciférol en combinaison avec des agents écrans d’uv-b
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. Method for treating secondary hyperparathyroidism in CKD
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
JP2014055184A (ja) * 2007-04-25 2014-03-27 Cytochroma Inc ビタミンｄ不足および欠乏症の治療方法
WO2016205245A1 (fr) * 2015-06-14 2016-12-22 Technology Recovery Systems Llc Préparation sous forme de timbre transdermique
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
CN110731952A (zh) * 2018-07-18 2020-01-31 郑州泰丰制药有限公司 一种骨化三醇贴剂及其制备工艺
WO2020132773A1 (fr) * 2018-12-27 2020-07-02 Universidad De Santiago De Chile Matière renfermant de la vitamine d pour sa libération ultérieure et procédé d'obtention de ladite matière
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease

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WO2005011652A2 (fr) * 2003-07-29 2005-02-10 Abbott Laboratories Utilisation de vitamines d pour le traitement de maladie rénale
WO2005011652A3 (fr) * 2003-07-29 2005-06-23 Abbott Lab Utilisation de vitamines d pour le traitement de maladie rénale
WO2005011651A2 (fr) * 2003-07-30 2005-02-10 Abbott Laboratories Utilisation de vitamines d ou d'analogue de la vitamine d pour traiter les maladies cardio-vasculaires
WO2005011651A3 (fr) * 2003-07-30 2005-08-11 Abbott Lab Utilisation de vitamines d ou d'analogue de la vitamine d pour traiter les maladies cardio-vasculaires
WO2006134272A1 (fr) * 2005-06-17 2006-12-21 Galderma Research & Development Composition pharmaceutique comprenant un elastomere organopolysiloxane et un principe actif solubilise
WO2006133828A1 (fr) * 2005-06-17 2006-12-21 Dsm Ip Assets B.V. Nouvelle utilisation du 25-hydroxycholecalciférol en combinaison avec des agents écrans d’uv-b
FR2887150A1 (fr) * 2005-06-17 2006-12-22 Galderma Res & Dev Composition pharmaceutique comprenant un elastomere organopolysiloxane et un principe actif solubilise
JP2008543815A (ja) * 2005-06-17 2008-12-04 ガルデルマ・リサーチ・アンド・デヴェロップメント オルガノポリシロキサンエラストマー及び可溶化した活性成分を含む医薬組成物
US11911398B2 (en) 2006-02-03 2024-02-27 Opko Renal, Llc Treating Vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US11007204B2 (en) 2006-02-03 2021-05-18 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8426391B2 (en) 2006-02-03 2013-04-23 Proventiv Therapeutics, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US10213442B2 (en) 2006-02-03 2019-02-26 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8906410B2 (en) 2006-02-03 2014-12-09 Opko Health, Inc. Oral dosage form of 25-hydroxyvitamin D
US9943530B2 (en) 2006-02-03 2018-04-17 Opko Renal, Llc Treating vitamin D insufficiency and deficiency with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3
US8329677B2 (en) 2006-06-21 2012-12-11 Cytochroma, Inc. Method of treating and preventing secondary hyperparathyroidism
US10668089B2 (en) 2006-06-21 2020-06-02 Opko Ireland Global Holdings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US20180296576A1 (en) * 2006-06-21 2018-10-18 Opko Ireland Global Holdings, Ltd. Method of Treating and Preventing Secondary Hyperparathyroidism
US9402855B2 (en) 2006-06-21 2016-08-02 Opko Renal, Llc Method of treating and preventing secondary hyperparathyroidism
US9913852B2 (en) 2006-06-21 2018-03-13 Opko Ireland Global Hodlings, Ltd. Method of treating and preventing secondary hyperparathyroidism
US9918940B2 (en) 2007-04-25 2018-03-20 Opko Renal, Llc Methods for controlled release oral dosage of a vitamin D compound
US11154509B2 (en) 2007-04-25 2021-10-26 Eirgen Pharma Ltd. Methods for controlled release oral dosage of a vitamin D compound
US8207149B2 (en) 2007-04-25 2012-06-26 Cytochroma, Inc. Method for treating secondary hyperparathyroidism in CKD
US9498486B1 (en) 2007-04-25 2016-11-22 Opko Renal, Llc Method for controlled release oral dosage of a vitamin D compound
US9925147B2 (en) 2007-04-25 2018-03-27 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US9408858B2 (en) 2007-04-25 2016-08-09 Opko Renal, Llc Method for treating secondary hyperparathyroidism in CKD
US8778373B2 (en) 2007-04-25 2014-07-15 Opko IP Holdings II, Inc. Methods for controlled release oral dosage of a vitamin D compound
JP2014055184A (ja) * 2007-04-25 2014-03-27 Cytochroma Inc ビタミンｄ不足および欠乏症の治療方法
US11801253B2 (en) 2007-04-25 2023-10-31 Opko Renal, Llc Method of safely and effectively treating and preventing secondary hyperparathyroidism in chronic kidney disease
US11752158B2 (en) 2007-04-25 2023-09-12 Eirgen Pharma Ltd. Method of treating vitamin D insufficiency and deficiency
US8361488B2 (en) 2007-04-25 2013-01-29 Cytochroma Inc. Methods and compositions for controlled release oral dosage of a vitamin D compound
US8592401B2 (en) 2007-04-25 2013-11-26 Proventiv Therapeutics, Llc Methods and compounds for vitamin D therapy
US10302660B2 (en) 2008-04-02 2019-05-28 Opko Renal, Llc Methods useful for vitamin D deficiency and related disorders
US11672809B2 (en) 2010-03-29 2023-06-13 Eirgen Pharma Ltd. Methods and compositions for reducing parathyroid levels
US11253528B2 (en) 2013-03-15 2022-02-22 Eirgen Pharma Ltd. Stabilized modified release Vitamin D formulation and method of administering same
US10350224B2 (en) 2013-03-15 2019-07-16 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US9861644B2 (en) 2013-03-15 2018-01-09 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10357502B2 (en) 2013-03-15 2019-07-23 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US10300078B2 (en) 2013-03-15 2019-05-28 Opko Ireland Global Holdings, Ltd. Stabilized modified release vitamin D formulation and method of administering same
US11007205B2 (en) 2014-08-07 2021-05-18 Eirgen Pharma Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10220047B2 (en) 2014-08-07 2019-03-05 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US10493084B2 (en) 2014-08-07 2019-12-03 Opko Ireland Global Holdings, Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US11738033B2 (en) 2014-08-07 2023-08-29 Eirgen Pharma Ltd. Adjunctive therapy with 25-hydroxyvitamin D and articles therefor
US11826478B2 (en) 2015-06-14 2023-11-28 Trs Ii, Llc Transdermal delivery formulation
WO2016205245A1 (fr) * 2015-06-14 2016-12-22 Technology Recovery Systems Llc Préparation sous forme de timbre transdermique
US11173168B2 (en) 2016-03-28 2021-11-16 Eirgen Pharma Ltd. Methods of treating vitamin D insufficiency in chronic kidney disease
CN110731952A (zh) * 2018-07-18 2020-01-31 郑州泰丰制药有限公司 一种骨化三醇贴剂及其制备工艺
WO2020132773A1 (fr) * 2018-12-27 2020-07-02 Universidad De Santiago De Chile Matière renfermant de la vitamine d pour sa libération ultérieure et procédé d'obtention de ladite matière

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