WO2016080533A1

WO2016080533A1 - Percutaneous absorption agent

Info

Publication number: WO2016080533A1
Application number: PCT/JP2015/082756
Authority: WO
Inventors: 麻実小田; 広志木下; 山根　教郎
Original assignee: 王子ホールディングス株式会社
Priority date: 2014-11-20
Filing date: 2015-11-20
Publication date: 2016-05-26
Also published as: TW201628603A

Abstract

Provided is a novel means for administrating cinacalcet or a pharmaceutically acceptable salt thereof, said means being capable of exhibiting excellent pharmacological effects while avoiding side effects which may be caused by oral administration, in the prevention or treatment of hyperparathyroidism or hypercalcemia. This percutaneous absorption agent having a support and a drug-containing layer is a percutaneous absorption agent having the drug-containing layer which contains, as an active ingredient, cinacalcet or a pharmaceutically acceptable salt thereof.

Description

Transdermal preparation

The present invention relates to a percutaneous absorption preparation containing cinacalcet or a pharmaceutically acceptable salt thereof as an active ingredient, and enhances parathyroid function by transdermal administration of cinacalcet or a pharmaceutically acceptable salt thereof. Provides a means of preventing or treating symptom or hypercalcemia.

Calcium is the main component of bone. It also regulates various in vivo functions such as muscle contraction, nerve excitation, hormone secretion, and enzyme activity via calcium receptors. Therefore, it is known as an adjustment factor that plays an essential role in the maintenance and regulation of biological functions. Since abnormalities in blood calcium levels cause various cellular functions, blood calcium levels are maintained within a certain range by calcium-regulating hormones such as parathyroid hormone (PTH) and active vitamin D. Yes.

PTH secreted from the parathyroid gland is a hormone that forms the center of the calcium metabolism regulation system. PTH acts on the kidney to suppress reabsorption of phosphorus from the urine. Moreover, by promoting vitamin D activation, calcium reabsorption in the kidney and calcium absorption from the intestinal tract are promoted. Furthermore, PTH promotes calcium elution from bone by increasing bone metabolic rate, and keeps blood calcium concentration constant. PTH is regulated through the parathyroid calcium receptor. Calcium receptors are mainly present on the membrane surface of parathyroid cells and regulate PTH secretion in response to slight changes in extracellular calcium concentration.

Therefore, in recent years, drugs that act on calcium receptors have attracted attention as therapeutic agents for hyperparathyroidism or hypercalcemia.

Cinacalcet is a calcium receptor agonist represented by the compound name N-[(1R) -1- (naphthalen-1-yl) ethyl] -3- [3- (trifluoromethyl) phenyl] propan-1-amine. It is a drug (Patent Document 1). PTH secretion is suppressed in a calcium concentration-dependent manner so that it acts allosterically on calcium receptors present on the membrane surface of parathyroid cells and enhances the blood calcium concentration. Moreover, PTH is controlled by various mechanisms such as PTH mRNA expression suppression and cell growth suppression (Non-patent Documents 1 and 2). Due to its characteristics, it is possible to suppress PTH secretion while suppressing the risk of hypocalcemia. Cinacalcet is a known compound having a chemical structure of the following formula (I).

Cinacalcet hydrochloride or placebo was orally administered once daily for 14 weeks in a phase III clinical trial conducted in patients with secondary hyperparathyroidism undergoing hemodialysis (the dose of cinacalcet was 25 mg Dosage adjustment in the range of ~ 100 mg). As a result, the effective rate of achieving serum intact PTH concentration of 250 pg / mL or less at the end of administration was 51.4% (37/72 cases) in the cinacalcet hydrochloride group, and 2.8% (2/71 cases) in the placebo group. It was significantly higher than the group (p <0.001: χ ² test). However, it has been reported that there are many cases in which continuous administration cannot be performed due to frequent gastrointestinal side effects such as nausea, vomiting, and stomach discomfort due to administration (Non-patent Documents 3 and 4).

International Publication WO96 / 12697

It is desirable to reduce the frequency of gastrointestinal side effects such as nausea, vomiting and stomach discomfort associated with cinacalcet administration. Causes of side effects on the digestive tract of cinacalcet include direct effects on the digestive tract due to low oral bioavailability (5.1-28.4% in Japan, 7.9-24.4% overseas) and blood levels after oral administration In addition to the influence of the peak, the influence of the action on the calcium receptor present in the digestive tract has been estimated (Non-patent Document 4).

An object of the present invention is to provide a novel administration means useful for the prevention or treatment of hyperparathyroidism or hypercalcemia while reducing the side effects of cinacalcet on the digestive tract.

As a result of intensive studies to achieve the above object, the present inventors are able to administer cinacalcet or a pharmaceutically acceptable salt thereof that has been orally administered as a transdermal preparation. I found. Furthermore, by appropriately controlling the skin permeation rate of cinacalcet or a pharmaceutically acceptable salt thereof, an amount of cinacalcet effective for the prevention or treatment of hyperparathyroidism or hypercalcemia can be absorbed percutaneously. It was found that the blood concentration of can be maintained above a certain level.

That is, the present invention is as follows.
[1] A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains cinacalcet, a pharmaceutically acceptable salt thereof, or a solvate thereof as an active ingredient. Skin absorption type preparation.
[2] The transdermal absorption preparation according to [1], wherein the drug-containing layer further contains an adhesive.
[3] The transdermal absorption preparation according to [1] or [2], wherein the drug-containing layer further contains a basic compound.
[4] The basic compound is at least one selected from a polymer compound containing basic nitrogen, monoethanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, and sodium bicarbonate. A transdermal absorption preparation according to [3].
[5] The transdermal absorption preparation according to any of [2] to [4], wherein the adhesive contains a rubber resin or an acrylic resin.
[6] The transdermal absorption preparation according to any of [2] to [5], wherein the pressure-sensitive adhesive contains a styrene-isoprene-styrene block copolymer.
[7] The transdermal absorption preparation according to any one of [1] to [6], wherein the drug-containing layer further contains a tackifier.
[8] The transdermal absorption preparation according to any of [1] to [7], wherein the drug-containing layer further contains an absorption enhancer.
[9] The absorption accelerator is selected from polyhydric alcohols having 3 to 8 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, and N-methyl-2-pyrrolidone. The transdermally absorbable preparation according to [8], containing at least one kind.
[10] The transdermal absorption preparation according to [9], wherein the polyoxyethylene alkyl ether having 10 to 22 carbon atoms has an HLB value of 7 to 16.
[11] The transdermal absorption preparation according to any one of [1] to [10], further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.
[A1]: A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains a pharmaceutically acceptable salt of cinacalcet, an adhesive and a basic compound as active ingredients. Transdermal preparation.
[A2]: The basic compound is at least one selected from polymer compounds containing basic nitrogen, monoethanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, and sodium hydrogen carbonate. The percutaneous absorption type preparation according to [A1].
[A3]: A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains cinacalcet and an adhesive as active ingredients.
[A4]: The percutaneous absorption preparation according to any of [A1] to [A3], wherein the pressure-sensitive adhesive comprises a rubber-based resin as a main component.
[A5]: The percutaneous absorption preparation according to [A4], wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer.
[A6]: The transdermally absorbable preparation according to any one of [A1] to [A3], wherein the pressure-sensitive adhesive comprises an acrylic resin as a main component.
[A7]: The percutaneous absorption preparation according to any of [A1] to [A6], wherein the drug-containing layer further contains a tackifier.
[A8]: The percutaneous absorption preparation according to any of [A1] to [A7], wherein the drug-containing layer further contains an absorption accelerator.
[A9]: The absorption accelerator is a polyhydric alcohol having 3 to 8 carbon atoms, polyoxyethylene alkyl ether having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, diethanolamide laurate, and N-methyl- The percutaneous absorption preparation according to [A8], which is at least one selected from 2-pyrrolidone.
[A10]: The percutaneous absorption preparation according to [A8], wherein the absorption enhancer is at least one selected from polyhydric alcohols having 3 to 8 carbon atoms.
[A11]: The transdermal preparation according to [A10], wherein the polyhydric alcohol having 3 to 8 carbon atoms is dipropylene glycol.
[A12]: The transdermal absorption preparation according to [A9], wherein the polyoxyethylene alkyl ether having 10 to 22 carbon atoms has an HLB value of 7 to 16.
[A13]: The percutaneous absorption preparation according to any of [A1] to [A12], further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.
[A14]: A method for producing a transdermally absorbable preparation described in [A1] above, comprising preparing a mixture comprising a pharmaceutically acceptable salt of cinacalcet, an adhesive and a basic compound,
Applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer;
The said manufacturing method including.
[A15]: A method for producing a transdermal absorption preparation described in [A3] above, comprising preparing a mixture containing cinacalcet and an adhesive,
Applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer;
The said manufacturing method including.
[A16]: A method for treating hyperparathyroidism or hypercalcemia,
The method comprising transdermally administering an effective amount of cinacalcet to a subject by applying the transdermal absorption preparation according to any of [A1] to [A13] to the subject's skin.
[A17]: Use of a pharmaceutically acceptable salt of cinacalcet in the manufacture of a transdermal absorption preparation for the treatment of hyperparathyroidism or hypercalcemia,
The use as described above, wherein the percutaneous absorption preparation is the percutaneous absorption preparation according to any of [A1], [A2], and [A4] to [A13].
[A18]: Use of cinacalcet in the manufacture of a transdermal preparation for the treatment of hyperparathyroidism or hypercalcemia,
The use as described above, wherein the transdermal preparation is the transdermal preparation according to any of [A3] to [A13].
[A19]: The percutaneous absorption preparation according to any of [A1] to [A13] for the treatment of hyperparathyroidism or hypercalcemia.

According to the present invention, cinacalcet or a pharmaceutically acceptable salt thereof is formulated into a transdermal absorption-type preparation, whereby cinacalcet blood concentration is effective in preventing or treating hyperparathyroidism or hypercalcemia. It becomes easy to maintain at a level that does not cause side effects. Therefore, it is possible to avoid a direct effect on the digestive organs and side effects due to blood concentration peaks. In addition, it is possible to avoid effects on the calcium receptors present in the digestive tract, thereby reducing gastrointestinal side effects such as nausea, vomiting, and stomach discomfort, while hyperparathyroidism or hypercalcemia Can be prevented or treated. If signs of side effects are observed, the administration can be stopped immediately by peeling the transdermal preparation from the skin immediately.

In addition, when dysphagia occurs and oral administration of the drug is difficult, the convenience of administration is improved by making a transdermal preparation of cinacalcet or a pharmaceutically acceptable salt thereof. In addition, since percutaneous absorption-type preparation of cinacalcet or a pharmaceutically acceptable salt thereof can be confirmed visually, an improvement in medication adherence can be expected.

It is a figure which shows transition of the cinacalcet density | concentration in plasma in an in vivo (in vivo) skin permeability test. It is a figure which shows an example of the manufacturing flow of the percutaneous absorption type formulation of this invention. It is a figure which shows the plasma concentration profile of the cinacalcet in a rat. It is a figure which shows the plasma concentration profile of the cinacalcet in a miniature pig. It is a figure which shows the result of the comparative test of percutaneous administration and oral administration about the cinacalcet density | concentration in plasma in a rat. It is a figure which shows the result of the comparative test of percutaneous administration and oral administration about the parathyroid hormone concentration in plasma in a rat. It is a figure which shows the result of the comparative test of percutaneous administration and oral administration about the calcium concentration in plasma in a rat.

In the present invention, the transdermally absorbable preparation refers to a parenteral preparation in which an active ingredient is absorbed through the skin and delivered to the bloodstream. The transdermally absorbable preparation of the present invention is a patch having a support and a drug-containing layer, and examples thereof include a tape, a poultice, and a plaster.

The transdermally absorbable preparation of the present invention may be a matrix-type patch preparation containing an adhesive in the drug-containing layer, and a controlled-release membrane and skin for adjusting the transdermal absorption of the drug on the skin-applied side of the drug-containing layer It may also be a reservoir-type patch preparation further having an adhesive layer for sticking to the skin. With such a structure, cinacalcet or a pharmaceutically acceptable salt thereof can be efficiently absorbed percutaneously.

From the viewpoint of formulation design and ease of production, a matrix-type patch preparation is preferable. Hereinafter, the matrix-type patch preparation will be described as an example, but the present invention is not limited thereto.

In this specification, “comprising” or “including” also includes the meaning of “consisting essentially of” or “consisting solely of”.

<Drug-containing layer>
1. Active ingredient In the transdermally absorbable preparation of the present invention, the drug-containing layer contains cinacalcet or a pharmaceutically acceptable salt thereof as an active ingredient. Cinacalcet is a calcium receptor agonist that allosterically activates the calcium receptor. Cinacalcet acts on the calcium receptor expressed in the parathyroid gland and has the feature of decreasing serum calcium (Ca) concentration, serum phosphorus (P) concentration and serum Ca × P concentration by suppressing PTH secretion. Yes.

"Hyperparathyroidism" means hypercalcemia, hyperphosphatemia, osteoporosis, and arteriosclerosis due to vascular calcification, urinary calculus, Or it refers to diseases that cause various symptoms such as kidney damage. Hyperparathyroidism is distinguished between primary hyperparathyroidism caused by abnormal parathyroid glands and secondary hyperparathyroidism caused by impaired calcium metabolism. Reference herein to hyperparathyroidism encompasses both primary hyperparathyroidism and secondary hyperparathyroidism.

Primary hyperparathyroidism develops due to excessive secretion of PTH caused by parathyroid adenoma, cancer, and hyperplasia. Secondary hyperparathyroidism is caused by hyperphosphatemia caused by a decrease in urinary phosphorus excretion caused by kidney disease, or hypocalcemia caused by impaired calcium reabsorption in the kidney and decreased production of activated vitamin D. It develops by promoting the synthesis and secretion of PTH and causing hyperthyroidism of parathyroid cells. Phosphorus adsorbents and vitamin D preparations are used for the treatment of secondary hyperparathyroidism, but such treatment is accompanied by an effect of increasing blood calcium and has a limited therapeutic effect. Therefore, parathyroidectomy is selected as the basic therapy for severe secondary hyperparathyroidism cases.

“Hypercalcemia” is a condition in which the blood calcium concentration deviates from the normal range and shows an abnormally high value. It is caused by calcium mobilization from bone, increased calcium reabsorption from the kidney, and increased calcium absorption from the digestive tract. It is said that it often occurs especially in primary hyperparathyroidism and malignant tumors.

In the present specification, prevention or treatment of hyperparathyroidism or hypercalcemia refers to the delay or suppression of the onset of hyperparathyroidism or hypercalcemia in human subjects, etc. Treatment of the condition, delay or suppression of recurrence after onset.

In the transdermally absorbable preparation of the present invention, the active ingredient is cinacalcet or a pharmaceutically acceptable salt thereof. Pharmaceutically acceptable salts include, for example, inorganic acid salts such as hydrochloride, hydrobromide, nitrate, sulfate, phosphate and the like; and organic acid salts such as formate, acetate, Trifluoroacetate, ascorbate, benzoate, cinnamate, citrate, fumarate, glutamate, tartrate, oxalate, glutarate, camphorate, adipate, sorbate , Lactate, maleate, linoleate, linolenate, malate, malonate, mandelate, methanesulfonate (mesylate), phthalate, salicylate, stearate, isostearate Succinate, propionate, butyrate, pamoate, p-toluenesulfonate (tosylate), benzenesulfonate (besylate), etc. Absent.

Cinacalcet or a pharmaceutically acceptable salt thereof may be used in the form of a crystal, and the crystal may be formed only from cinacalcet or a pharmaceutically acceptable salt thereof, or may be a co-crystal or solvate. (For example, a hydrate, preferably a monohydrate) may be formed. Any of cinacalcet or a pharmaceutically acceptable salt thereof may be used alone or in combination of two or more. In the present invention, it is preferable to use cinacalcet hydrochloride or its free base, cinacalcet, which has already been established for oral administration as a calcium receptor agonist.

The content of cinacalcet or a pharmaceutically acceptable salt thereof in the percutaneous absorption preparation of the present invention is an effective amount for the prevention or treatment of hyperparathyroidism or hypercalcemia. Here, the effective amount means that when the percutaneous absorption type preparation of the present invention is applied to the skin of a living body, the blood concentration of cinacalcet effective in preventing or treating hyperparathyroidism or hypercalcemia is achieved. It is a possible amount. Such content can be adjusted as appropriate based on information on the pharmacokinetics of oral administration, and may vary depending on the administration subject, disease, symptoms, and the like. For example, 1 to 60% by mass is preferable with respect to the drug-containing layer (that is, based on the total mass of the drug-containing layer; the same shall apply hereinafter), preferably 2 to 50% by mass, more preferably 2.5 to 40% by mass preferable. In the case where a rubber-based resin is used as the adhesive, 2.5 to 25% by mass is particularly preferable. When an acrylic resin is used as the pressure-sensitive adhesive, it is particularly preferably 10 to 40% by mass.

The blood concentration of cinacalcet effective for the prevention or treatment of hyperparathyroidism or hypercalcemia can be comparable to that of oral drugs of cinacalcet or a pharmaceutically acceptable salt thereof.

In the transdermal preparation of the present invention, the blood concentration effective for the prevention or treatment of hyperparathyroidism or hypercalcemia by adjusting the skin permeation rate of cinacalcet or a pharmaceutically acceptable salt thereof. Can be realized. The skin permeation rate is adjusted by any means such as adjusting the content of cinacalcet or a pharmaceutically acceptable salt thereof in the drug-containing layer, or adding an absorption enhancer described later to the drug-containing layer. It can be carried out. In addition, when the calcium receptor agonist has already been administered orally, the skin permeation rate can be appropriately adjusted based on existing information on pharmacokinetics. In the present invention, the skin permeation rate of cinacalcet or a pharmaceutically acceptable salt thereof means a value measured by an in vitro skin permeability test described in Examples described later.

The skin permeation rate of cinacalcet or a pharmaceutically acceptable salt thereof is usually 0.5 to 80 μg / cm ² / hour, preferably 1.0 to 60 μg / cm ² / hour. If the skin permeation rate is 0.5 μg / cm ² / hour or more, a sufficient blood concentration can be obtained. If the skin permeation rate is 80 μg / cm ² / hour or less, the blood concentration is not too high, which is preferable from the viewpoint of safety.

2. Basic Compound When an acid addition salt is used as a pharmaceutically acceptable salt of cinacalcet, it is preferable to contain a basic compound in the drug-containing layer. Examples of the basic compound include low molecular weight compounds containing basic nitrogen (for example, alkanolamines such as ethanolamine, isopropanolamine, diethanolamine, diisopropanolamine, triethanolamine, triisopropanolamine); Polymer compound (for example, aminoalkyl methacrylate copolymer E (copolymer of dimethylaminoethyl methacrylate, butyl methacrylate, and methyl methacrylate; preferably the molar ratio of the three components is 2: 1: 1), polyvinyl acetal Diethylaminoacetate, polyvinylpyridine, etc.); basic alkali metal salts (for example, sodium acetate, potassium acetate, sodium borate, sodium carbonate, sodium bicarbonate, trisodium citrate) , Sodium silicate); alkali metal hydroxides (e.g., sodium hydroxide, potassium hydroxide, etc.). Moreover, you may use commercially available basic acrylic resins, such as Eudragit series (Eudragit E100, Eudragit EPO: Evonik Industries company make). Of these, polymer compounds containing basic nitrogen, ethanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, and sodium bicarbonate are preferred. Aminoalkyl methacrylate copolymer E, ethanolamine, sodium hydroxide More preferred is potassium hydroxide. In order to improve the cohesiveness of the percutaneous absorption type preparation of the present invention, an organic basic compound (for example, a low molecular compound containing basic nitrogen or a high molecular compound containing basic nitrogen, preferably an aminoalkyl) is used. It is also possible to use methacrylate copolymer E, diisopropanolamine or triisopropanolamine).

Such basic compounds can be used alone or in admixture of two or more. The content of the basic compound is preferably 0.5 to 5 equivalents, preferably 0.7 to 3 equivalents, relative to the equivalent of the pharmaceutically acceptable salt of cinacalcet (particularly, acid addition salt). Is more preferable. In addition, the content of the basic compound is preferably 0.1 to 35% by mass, more preferably 0.2 to 30% by mass, and more preferably 0.25 to 20% by mass with respect to the drug-containing layer. More preferably. By containing such a basic compound, the basic compound acts on a pharmaceutically acceptable salt (especially acid addition salt) of cinacalcet, and the skin permeability of cinacalcet salt is improved. In particular, by setting the content of the basic compound within the above range, the effect of improving the skin permeability becomes more remarkable as compared with the case where the content is outside the above range.

3. Absorption Accelerator The drug-containing layer may further contain an absorption enhancer for improving skin permeability of cinacalcet or a pharmaceutically acceptable salt thereof. The absorption enhancer may be any compound that has been shown to promote skin permeation through transdermal administration, such as capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, sorbic acid, oleic acid, linol. Fatty acids or their esters such as acid, linolenic acid, isopropyl myristate, octyldodecyl myristate, glycerol oleate monoester, hexadecyl isostearate; lactic acid, acetic acid, malic acid, citric acid, tartaric acid, oxalic acid, fumaric acid, succinic acid Acids, glutaric acid, glycolic acid, adipic acid, pimelic acid, sebacic acid, benzoic acid, salicylic acid, nicotinic acid, methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, saccharin and other organic acids or salts thereof; phosphoric acid, etc. Inorganic acids or salts thereof; Alcohol such as ril alcohol, myristyl alcohol, oleyl alcohol, isostearyl alcohol, cetyl alcohol, benzyl alcohol, oleyl alcohol, propylene glycol monocaprylate, polyethylene glycol monooleate or esters thereof or ethers thereof; 3 to 8 carbon atoms Polyhydric alcohols (eg, propylene glycol, 1,3-butanediol, 1,4-butanediol, glycerin, dipropylene glycol, octanediol, etc.); sorbitan esters or ethers such as sorbitan monolaurate and sorbitan monooleate Polyoxyethylene such as polyoxyethylene sorbitan monooleate (polysorbate 80), polyoxyethylene sorbitan monopalmitate Sorbitol fatty acid esters; phenol ethers such as polyoxyethylene nonylphenyl ether and polyoxyethylene octylphenyl ether; castor oil or hydrogenated castor oil; ionic interfaces such as oleoyl sarcosine, lauryldimethylaminoacetic acid betaine, sodium lauryl sulfate Activator: C10-22 polyoxyethylene alkyl ether (eg, polyoxyethylene lauryl ether, polyoxyethylene oleyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene behenyl ether), dimethyl Nonionic surfactants such as laurylamine oxide; lauric acid diethanolamide, palmitic acid diethanolamide, stearic acid diethanolate Fatty acid amides such as luamide and oleic acid diethanolamide; alkylmethyl sulfoxides such as dimethyl sulfoxide and decylmethyl sulfoxide; 2-pyrrolidone, N-methyl-2-pyrrolidone, N-ethyl-2-pyrrolidone and the like Pyrrolidones; azacycloalkanes such as 1-dodecylazacycloheptan-2-one and 1-geranylazacycloheptan-2-one; and terpenes such as menthol, camphor and limonene. Of these, polyhydric alcohols having 3 to 8 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, diethanolamide laurate, and N-methyl-2-pyrrolidone are preferable. 3-butanediol, glycerin, dipropylene glycol, polyoxyethylene alkyl ether having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide are more preferable, isopropyl myristate, lauric acid diethanolamide, dipropylene More preferred is glycol. An absorption accelerator can be used individually by 1 type or in combination of 2 or more types. The polyhydric alcohol having 3 to 8 carbon atoms has an effect as a solubilizer that promotes dissolution of cinacalcet or a pharmaceutically acceptable salt thereof into the drug-containing layer in addition to the function as an absorption promoter. There is also an effect as a plasticizer for plasticizing the drug-containing layer (a preferable effect for imparting adhesiveness).

More preferably, the polyoxyethylene alkyl ether having 10 to 22 carbon atoms has an HLB value of 7 to 16. The HLB value is a value representing the degree of affinity of the surfactant with water and oil (an organic compound insoluble in water). The value is from 0 to 20, and the closer to 0, the higher the lipophilicity is to 20. The closer it is, the higher the hydrophilicity. When a polyoxyethylene alkyl ether having an HLB value of 7 to 16 and having 10 to 22 carbon atoms is used, the permeability to the stratum corneum is improved, and the effect of promoting the skin permeability of cinacalcet can be enhanced.

The measurement method of HLB is based on the measurement of HLB value by the emulsification method described in "Handbook-Cosmetics / Formulation raw materials-Revised edition", Nikko Chemicals Co., Ltd., revised February 1, 1977, 854-855. To do. As a specific method for obtaining the HLB value of the component (X), the component (X) is combined with sorbitan monostearate (NIKKOL SS-10, HLB4.7) as a standard substance of an emulsifier. Emulsified liquid paraffin (HLB10.1), which is to be emulsified, with the total amount of the emulsifier being constant and changing only the ratio, and after standing for a whole day and night, it is optimal with high stability in terms of creaming amount, white turbidity, lower layer water separation, etc. The proportion of the emulsifier is obtained, and the HLB value x of the component (X) is calculated by the following formula (1).
y = (x × used amount (mass%) + z × used amount (mass%)) / 100 Formula (1)

In the formula (1), “x” represents the HLB value of the component (X), “y” represents the HLB value of liquid paraffin, and “z” represents sorbitan monostearate (NIKKOL SS- 10) shows the HLB value. However, if the component (X) is lipophilic, POE sorbitan monostearate (NIKKOL TS-10, HLB 14.9) is used as a standard substance for the emulsifier.

Specifically, for example, BL-2 (polyoxyethylene lauryl ether, HLB value 9.5: manufactured by Nikko Chemicals), BL-4.2 (polyoxyethylene lauryl ether, HLB value 11.5: Nikko Chemicals) Manufactured), BL-9EX (polyoxyethylene lauryl ether, HLB value 14.5: manufactured by Nikko Chemicals), BO-2V (polyoxyethylene oleyl ether, HLB value 7.5: manufactured by Nikko Chemicals), BO-7V (Polyoxyethylene oleyl ether, HLB value 10.5: manufactured by Nikko Chemicals), BO-10V (Polyoxyethylene oleyl ether, HLB value 14.5: manufactured by Nikko Chemicals), BC-2 (Polyoxyethylene cetyl ether) , HLB value 8.0: manufactured by Nikko Chemicals Co., Ltd.), BC-5.5 (polyoxyethylene series) Luether, HLB value 10.5: manufactured by Nikko Chemicals), BC-7 (polyoxyethylene cetyl ether, HLB value 11.5: manufactured by Nikko Chemicals), BC-10 (polyoxyethylene cetyl ether, HLB value 13. 5: manufactured by Nikko Chemicals), BS-2 (polyoxyethylene stearyl ether, HLB value 8.0: manufactured by Nikko Chemicals), BS-4 (polyoxyethylene stearyl ether, HLB value 9.0: manufactured by Nikko Chemicals) Commercially available polyoxyethylene alkyl ethers such as) may be used.

The content of the absorption enhancer can be appropriately adjusted according to the kind of cinacalcet or a pharmaceutically acceptable salt thereof, but is preferably 0.1 to 40% by mass with respect to the drug-containing layer, Is more preferably 35% by mass, still more preferably 1-35% by mass, and particularly preferably 5-15% by mass.

4. Adhesive The drug-containing layer further contains an adhesive (also referred to as an adhesive base), and may contain a tackifier, a plasticizer, and the like as necessary.

Examples of the adhesive contained in the drug-containing layer include those containing a rubber resin, an acrylic resin, a silicone resin, and the like.

The pressure-sensitive adhesive is preferably composed mainly of at least one selected from the group consisting of rubber resins, acrylic resins and silicone resins, and at least one selected from the group consisting of rubber resins and acrylic resins. The main component is more preferably, and the main component is a rubber-based resin. Here, the “main component” means usually 70% by mass or more, further 80% by mass or more, further 90% by mass or more, and particularly 100% by mass with respect to the total mass of the pressure-sensitive adhesive.

Examples of rubber resins include styrene-isoprene-styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), styrene-butadiene rubber (SBR), styrene isoprene rubber, and polyisobutylene (PIB). ), Polybutene, butyl rubber, natural rubber, raw rubber, gum arabic, gum arabic powder, isoprene rubber and the like, preferably SIS. Commercially available rubber resins such as Kraton D polymer series (manufactured by Kraton Polymer Japan), JSR SIS / TR series (manufactured by JSR Life Sciences), and Quintac series (ZEON) can be used.

Examples of acrylic resins include (meth) acrylic acid esters represented by monomer units such as 2-ethylhexyl acrylate, methyl acrylate, butyl acrylate, 2-hydroxyethyl acrylate, 2-ethylhexyl methacrylate, and the like. Examples thereof include a polymer or copolymer containing at least one kind. Specifically, for example, acrylic acid / octyl acrylate copolymer, 2-ethylhexyl acrylate / vinylpyrrolidone copolymer solution, 2-ethylexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid-1 , 6-Hexane glycol copolymer, acrylic acid ester / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-hydroxyethyl acrylate / vinyl acetate copolymer, 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / methacrylic acid Examples thereof include a dodecyl copolymer solution, a methyl acrylate / 2-ethylhexyl acrylate copolymer resin emulsion, and an acrylic resin alkanolamine solution. Also, DURO-TAK (registered trademark) acrylic adhesive series (DURO TAK 87-900A, DURO TAK 87-9301, DURO TAK 87-4098, DURO TAK 387-2510, DURO TAK 87-2510, DURO TAK 387-2287, DURO TAK 87-2287, DURO TAK 87-4287, DURO TAK 387-2516, DURO TAK 87-2516, DURO TAK 87-2074, DURO TAK 387-235A, DURO TAK 387-2353, DURO TAK 87-2353, DURO TAK 87-2852, DURO TAK 387-2051, DURO TAK 87-2051, DURO TAK 387-2052, DURO TAK 87-2052, DURO TAK 387-2054, DURO TAK 87-2054, DURO TAK 87-2194, DURO TAK 87- 2196: made by Henkel), GELVA series (GELVA GMS 3083, GELVA GMS 2533, GELVA GMS 788, GELVA GMS 9073: made by Henkel), MAS-683, MAS-811, MASOS10, MAS11D1 (made by Cosmed Pharmaceutical) Commercially available acrylic resins may be used.

Examples of silicone resins include polymers having an organopolysiloxane skeleton and derivatives thereof, and specific examples include dimethylpolysiloxane, polymethylvinylsiloxane, polymethylphenylsiloxane, and diphenylsiloxane. A commercially available silicone resin such as BIO-PSA series (manufactured by Dow Corning) may also be used.

As the pressure-sensitive adhesive contained in the drug-containing layer of the transdermally absorbable preparation of the present invention, one of the rubber-based resin, acrylic resin, and silicone-based resin described above is used alone, or two or more are combined. Can be used. More preferred are acrylic or rubber resins, and even more preferred are rubber resins.

The amount of the adhesive contained in the drug-containing layer is adjusted in consideration of the formation of the drug-containing layer, sufficient skin permeability of cinacalcet or a pharmaceutically acceptable salt thereof, and the like. When the active ingredient is a pharmaceutically acceptable salt of cinacalcet, the content of the pressure-sensitive adhesive is usually 5 to 98.9% by mass, preferably 10 to 97.8%, based on the drug-containing layer. When the adhesive is a rubber-based resin, the content of the adhesive is preferably 5 to 98.9% by mass, more preferably 10 to 97.8% by mass, and 12 to 97% by mass with respect to the drug-containing layer. Further preferred. In the case of an acrylic resin, it is preferably 40 to 98.9% by mass, more preferably 45 to 97.8% by mass, and further preferably 50 to 97% by mass with respect to the drug-containing layer. In the case of a silicone-based resin, it is preferably 40 to 98.9% by mass, more preferably 50 to 97.8% by mass, and further preferably 60 to 97% by mass with respect to the drug-containing layer.

When the active ingredient is cinacalcet, the content of the adhesive is usually 5 to 99% by mass, preferably 10 to 98%, based on the drug-containing layer. When the adhesive is a rubber-based resin, the content of the adhesive is preferably 5 to 99% by mass, more preferably 10 to 98% by mass, and further preferably 12 to 97.5% by mass with respect to the drug-containing layer. . In the case of an acrylic resin, it is preferably 40 to 99% by mass, more preferably 45 to 98% by mass, and further preferably 50 to 97.5% by mass with respect to the drug-containing layer. In the case of a silicone-based resin, the content is preferably 40 to 99% by mass, more preferably 50 to 98% by mass, and still more preferably 60 to 97.5% by mass with respect to the drug-containing layer.

5. Plasticizer The drug-containing layer may further contain a plasticizer. Plasticizers include petroleum oils (eg, paraffinic process oil, naphthenic process oil, aromatic process oil, liquid paraffin, etc.), squalane, squalene, vegetable oils (eg, olive oil, camellia oil, castor oil, tall Oil, peanut oil, etc.), silicone oil, dibasic acid ester (eg, dibutyl phthalate, dioctyl phthalate, etc.), liquid rubber (eg, polybutene, liquid isoprene rubber, etc.), liquid fatty acid esters (eg, isopropyl myristate, laurin) Acid hexyl, diethyl sebacate, diisopropyl sebacate), glycol salicylate, triacetin, triethyl citrate, crotamiton and the like. Moreover, as a plasticizer, you may use suitably what is marketed, such as the Moresco white series (made by Moresco), the high call M series (made by Kaneda). In particular, when the rubber-based resin is used as an adhesive, liquid paraffin is preferably used as a plasticizer. A plasticizer can be used individually by 1 type or in combination of 2 or more types.

The content of the plasticizer is adjusted in consideration of sufficient permeability of cinacalcet or a pharmaceutically acceptable salt thereof and maintenance of sufficient cohesive strength as a patch. When a rubber-based resin is used as the adhesive, the total amount is preferably 1 to 70% by mass, more preferably 5 to 60% by mass, and still more preferably 10 to 50% by mass with respect to the drug-containing layer. When an acrylic resin is used as the adhesive, the total amount is preferably 0.1 to 50% by mass, more preferably 0.1 to 40% by mass, and further preferably 0.1 to 30% by mass with respect to the drug-containing layer. . When a silicone resin is used as the pressure-sensitive adhesive, the total amount is preferably 0.1 to 40% by mass, more preferably 0.1 to 30% by mass, and further preferably 0.1 to 20% by mass with respect to the drug-containing layer. .

6. Tackifier The drug-containing layer may further contain a tackifier to improve the adhesive strength. Examples of the tackifier include rosin derivatives such as rosin, glycerin ester of rosin, hydrogenated rosin, glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, alicyclic hydrocarbon resin, terpene resin, aliphatic Saturated hydrocarbon resin, aliphatic hydrocarbon resin, maleic resin, carnauba wax, carmellose sodium, xanthan gum, chitosan, glycerin, magnesium aluminum silicate, light anhydrous silicic acid, benzyl acetate, talc, hydroxyethylcellulose, hydroxypropylcellulose, hypromellose , Polyacrylic acid, sodium polyacrylate, partially neutralized polyacrylic acid, polyvinyl alcohol and the like. In addition, as the tackifier, commercially available products such as Alcon series (Arakawa Chemical Co., Ltd.), Pine Crystal series (Arakawa Chemical Co., Ltd.), Clearon series (Yasuhara Chemical Co., Ltd.), YS Resin Series (Yasuhara Chemical Co., Ltd.), etc. You may use suitably. In particular, when the rubber-based resin is used as an adhesive, it is preferable to use a glycerin ester of hydrogenated rosin, an alicyclic saturated hydrocarbon resin, a terpene resin, or an aliphatic saturated hydrocarbon resin as a tackifier. A tackifier can be used individually by 1 type or in combination of 2 or more types.

The content of the tackifier is preferably 5 to 70% by mass, preferably 10 to 60% by mass with respect to the drug-containing layer when a rubber-based resin is used as the adhesive in consideration of sufficient adhesive strength as a patch. % Is more preferable, and 20 to 50% by mass is further preferable. When an acrylic resin is used as the adhesive, it is preferably 0.1 to 40% by mass, more preferably 0.1 to 30% by mass, and further preferably 0.1 to 20% by mass with respect to the drug-containing layer. When a silicone resin is used as the pressure-sensitive adhesive, it is preferably 0.1 to 30% by mass, more preferably 0.1 to 20% by mass, and still more preferably 0.1 to 10% by mass with respect to the drug-containing layer.

7. Other optional components The drug-containing layer further contains a known additive such as a pH adjuster, a crosslinking agent, an antioxidant, a coloring agent, an ultraviolet absorber, a filler, or an antiseptic, as necessary. May be.

The pH regulator is a drug-containing layer for the purpose of improving the solubility, stability and skin permeability of cinacalcet, its pharmaceutically acceptable salt, or a solvate thereof, and improving the safety to the skin. Can be used to adjust the pH. The pH adjuster may be any compound as long as it is an acid or base or a salt thereof that is usually used for pH adjustment in the pharmaceutical field. For example, hydrochloric acid, sulfuric acid, phosphoric acid, citric acid, gluconic acid, succinate Acid, acetic acid, lactic acid, methanesulfonic acid, edetic acid, aqueous ammonia, monoethanolamine, diethanolamine, triethanolamine, diisopropanolamine, triisopropanolamine, meglumine, trometamol, glycine, potassium hydroxide, calcium hydroxide, hydroxylated Sodium, magnesium hydroxide, sodium citrate, sodium acetate, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and the like can be mentioned.

Examples of crosslinking agents include thermosetting resins such as amino resins, phenol resins, epoxy resins, alkyd resins, and unsaturated polyesters, isocyanate compounds, blocked isocyanate compounds, organic crosslinking agents, and inorganic crosslinking agents such as metals or metal compounds. Is mentioned. Among these, an isocyanate compound or a blocked isocyanate compound is preferable.

Examples of the antioxidant include tocopherol and ester derivatives thereof, ascorbic acid, ascorbic acid stearate, nordihydroguaiaretic acid, dibutylhydroxytoluene (BHT), butylhydroxyanisole and the like.

Examples of colorants include indigo carmine, yellow iron oxide, yellow iron sesquioxide, carbon black, caramel, photosensitive element 201, Kumazasa extract, black iron oxide, ketket, zinc oxide, titanium oxide, iron sesquioxide, amaranth, water Examples thereof include sodium oxide, talc, copper chlorophyllin sodium, green leaf extract powder, d-borneol, octyldodecyl myristate, methylene blue, ammonium manganese phosphate, and rose oil.

Examples of ultraviolet absorbers include amino acid compounds, benzophenone compounds, cinnamic acid derivatives, cyanoacrylate derivatives, p-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, and the like. Can be mentioned.

Fillers include calcium carbonate, magnesium carbonate, sodium carbonate, ammonium carbonate, potassium carbonate, potassium bicarbonate, silicate (eg, aluminum silicate, magnesium silicate, calcium silicate, magnesium aluminum silicate, magnesium silicate Sodium), magnesium hydroxide, silicic acid, barium sulfate, calcium sulfate, calcium zincate, zinc oxide, titanium oxide and the like.

Examples of preservatives include ethyl paraoxybenzoate, propyl paraoxybenzoate, and butyl paraoxybenzoate.

The total content of other optional components is preferably 0 to 10% by mass, more preferably 0 to 5% by mass with respect to the drug-containing layer.

The area of the drug-containing layer in the transdermally absorbable preparation of the present invention should be appropriately adjusted according to the content and / or skin permeation rate of cinacalcet, a pharmaceutically acceptable salt thereof, or a solvate thereof. Can do. Typically, it is in the range of 2 to 140 cm ² , preferably 2 to 100 cm ² , more preferably 4 to 50 cm ² . The shape is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.

The thickness of the drug-containing layer in the transdermal preparation of the present invention can be appropriately adjusted according to the type of adhesive, the content of cinacalcet or a pharmaceutically acceptable salt thereof, and / or the skin permeation rate. Yes, it is not particularly limited. Typically, it is in the range of 20 to 300 μm, preferably 30 to 200 μm, more preferably 30 μm to 150 μm.

One embodiment of the drug-containing layer in the transdermally absorbable preparation of the present invention includes one containing a pharmaceutically acceptable salt of cinacalcet, a basic compound and an adhesive (see the above [A1]).

As the pharmaceutically acceptable salt of cinacalcet, cinacalcet acid addition salt (particularly hydrochloride) is preferable.

The basic compound is preferably at least one selected from the group consisting of alkanolamines, aminoalkyl methacrylate copolymers E, polyvinyl acetal diethylaminoacetate, polyvinyl pyridine, basic alkali metal salts, and alkali metal hydroxides. Sodium, potassium hydroxide or aminoalkyl methacrylate copolymer E is more preferred.

The pressure-sensitive adhesive preferably contains a rubber-based resin as a main component. As the rubber resin, a styrene-isoprene-styrene block copolymer is preferable.

As other adhesives, those containing an acrylic resin as a main component are also preferred. As the acrylic resin, a polymer or copolymer containing at least one (meth) acrylic acid ester is preferable.

The content of the pharmaceutically acceptable salt of cinacalcet is 1 to 60% by mass, the content of the adhesive is 5 to 98.9% by mass, and the content of the basic compound is 0.1 to It is preferably 35% by mass.

As a more preferable embodiment of the drug-containing layer in the transdermally absorbable preparation of the present invention, a pharmaceutically acceptable salt of cinacalcet, a basic compound, a pressure-sensitive adhesive mainly comprising a rubber-based resin, a tackifier, and an absorption accelerator The thing containing is mentioned.

The rubber resin is preferably a styrene-isoprene-styrene block copolymer.

The tackifier is preferably at least one selected from the group consisting of glycerin ester of hydrogenated rosin, alicyclic saturated hydrocarbon resin, terpene resin, and aliphatic saturated hydrocarbon resin.

Absorption accelerators include polyhydric alcohols having 3 to 8 carbon atoms, polyoxyethylene alkyl ethers having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, and N-methyl-2-pyrrolidone. At least one selected from the group consisting of isopropyl myristate, lauric acid diethanolamide, and dipropylene glycol is more preferable.

The content of pharmaceutically acceptable salt of cinacalcet is 1 to 60% by mass, the content of adhesive is 5 to 93.8% by mass, and the content of tackifier is 5 to 70% by mass with respect to the drug-containing layer. %, The content of the basic compound is preferably 0.1 to 35% by mass, and the content of the absorption accelerator is preferably 0.1 to 40% by mass.

The content of the pharmaceutically acceptable salt of cinacalcet is 2 to 50% by mass, the content of the adhesive is 10 to 87.3% by mass, and the content of the tackifier is 10 to 60% by mass with respect to the drug-containing layer. %, The content of the basic compound is 0.2 to 30% by mass, and the content of the absorption accelerator is further preferably 0.5 to 35% by mass.

The area of the drug-containing layer is typically in the range of 2 to 140 cm ² , preferably 2 to 100 cm ² , more preferably 4 to 50 cm ² . The shape is not particularly limited, and may be a square, a rectangle, a circle, an ellipse, or the like.

The thickness of the drug-containing layer is typically in the range of 20 to 300 μm, preferably 30 to 200 μm, more preferably 30 μm to 150 μm.

Other modes of the drug-containing layer in the transdermal preparation of the present invention include those containing cinacalcet and an adhesive (see [A3] above).

It is preferable that the content of cinacalcet is 1 to 60% by mass and the content of the adhesive is 5 to 99% by mass with respect to the drug-containing layer.

Other preferred embodiments of the drug-containing layer in the transdermal preparation of the present invention include those containing cinacalcet, a pressure-sensitive adhesive containing a rubber-based resin as a main component, a tackifier, and an absorption accelerator.

The rubber resin is preferably a styrene-isoprene-styrene block copolymer.

For the drug-containing layer, the content of cinacalcet is 1 to 60% by mass, the content of the adhesive is 5 to 93.9% by mass, the content of the tackifier is 5 to 70% by mass, the content of the absorption accelerator Is preferably 0.1 to 40% by mass.

For the drug-containing layer, the content of cinacalcet is 2 to 50% by mass, the content of the adhesive is 10 to 87.5% by mass, the content of the tackifier is 10 to 60% by mass, the content of the absorption accelerator Is more preferably 0.5 to 35% by mass.

<Support>
As the support in the transdermal preparation of the present invention, a drug-impermeable, stretchable or non-stretchable support can be used. Such a support is not particularly limited as long as it is usually used in the field of pharmaceuticals. For example, polyethylene, polypropylene, polybutadiene, ethylene vinyl acetate copolymer, polyvinyl chloride, polyester (polyethylene terephthalate, etc.), Examples thereof include synthetic resin films or sheets such as nylon and polyurethane, laminates thereof, porous bodies, foams, films obtained by vapor-depositing aluminum, paper, woven fabrics, and nonwoven fabrics.

<Release liner>
The transdermally absorbable preparation of the present invention may further have a release liner. In this case, the release liner is laminated on the surface of the drug-containing layer laminated on the support opposite to the surface in contact with the support, and protects the drug-containing layer until the transdermal preparation is applied to the skin. can do. The release liner is not particularly limited as long as it is impermeable to at least cinacalcet, a pharmaceutically acceptable salt thereof, or a solvate thereof in the drug-containing layer. For example, polyethylene, polypropylene, polyester, polyethylene terephthalate, etc. Films made of the above polymer materials, films in which aluminum is vapor-deposited, and those in which silicone oil or the like is coated on paper can be mentioned.

The transdermal preparation of the present invention can be produced according to a known method. (A) A mixture containing a pharmaceutically acceptable salt of cinacalcet, a pressure-sensitive adhesive, and a basic compound, and if necessary, an absorption enhancer, a tackifier, and other optional components is prepared, and this mixture is used as a release liner. By applying (spreading) on it to form a drug-containing layer and attaching a support to this drug-containing layer, or (b) cinacalcet and an adhesive, and if necessary an absorption promoter, an adhesive Produced by preparing a mixture containing an imparting agent and other optional components, applying (spreading) the mixture onto a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer be able to.

Specifically, the pharmaceutically acceptable salt of the cinacalcet, the pressure-sensitive adhesive, and the basic compound, and if necessary, an absorption accelerator, a plasticizer, a tackifier, and other optional components, The coating solution is prepared by adding and stirring to an organic solvent.

As the organic solvent, ethyl acetate, hexane, pentane, toluene, cyclohexane, chloroform, methylene chloride, methanol, ethanol, isopropyl alcohol, methyl ethyl ketone, cyclohexanone, acetone, a mixed solvent thereof or the like can be used. The content of the organic solvent in the coating solution is not particularly limited, and is, for example, 30 to 90% by mass, preferably 40 to 80% by mass with respect to the entire coating solution.

Next, this coating solution is spread on a release liner, the solvent in the coating solution is evaporated to form a drug-containing layer, and then a transdermal absorption preparation can be obtained by laminating a support. . Alternatively, the percutaneous absorption preparation can be obtained by spreading the coating solution on a support, evaporating the solvent in the coating solution to form a drug-containing layer, and then attaching a release liner. From the viewpoint of ease of production, a method of spreading a coating solution on a release liner, evaporating the solvent in the coating solution to form a drug-containing layer, and then laminating the support is preferable. The coating solution can be applied using a knife coater, comma coater, reverse coater, or die coater. An example of the manufacturing flow is shown in FIG. 2, but is not limited to this.

The percutaneous absorption type preparation of the present invention heats and melts the pharmaceutically acceptable salt of cinacalcet, a pressure-sensitive adhesive, and a basic compound, and if necessary, an absorption accelerator, a tackifier, and other optional components, The melt can be applied (spread) onto a release liner to form a drug-containing layer, and then a transdermal preparation can be produced by laminating a support. Or after cinacalcet and adhesive, and if necessary, absorption accelerator, tackifier, and other optional ingredients are heated and melted and this melt is applied (spread) onto a release liner to form a drug-containing layer A percutaneous absorption type preparation can also be produced by laminating a support. After the melt is spread on a support to form a drug-containing layer, a transdermal preparation may be produced by laminating a release liner.

<Method of administration>
The prevention or treatment of hyperparathyroidism or hypercalcemia with the percutaneous absorption type preparation of the present invention is carried out by directly applying the percutaneous absorption type preparation of the present invention to the skin of the subject, and cinacalcet or a pharmaceutically acceptable product thereof. Can be performed by transdermal administration of the salt. The subject in the present invention is a mammal such as a human, preferably a human.

When transdermal administration of cinacalcet or a pharmaceutically acceptable salt thereof by the transdermal absorption preparation of the present invention, a blood concentration effective for the prevention or treatment of hyperparathyroidism or hypercalcemia should be realized. In addition, the percutaneously absorbable preparation of the present invention is prepared by appropriately adjusting the content and / or skin permeation rate of cinacalcet in the drug-containing layer and the area of the drug-containing layer and / or the thickness of the drug-containing layer. Apply to skin.

The percutaneous absorption-type preparation of the present invention may be applied to the skin of any part of the body as long as it can be applied. Can be pasted.

The transdermal administration of the transdermal preparation of the present invention to a subject may be combined with the administration of a pharmaceutical composition containing a pharmaceutical ingredient other than cinacalcet or a pharmaceutically acceptable salt thereof, if necessary. In this case, the administration form may be simultaneous administration or administration with a time difference, and the pharmaceutical composition may be intravenous, intraperitoneal, subcutaneous and intramuscular, oral, topical or transmucosal. It can be administered by various routes including: In addition, a pharmaceutical composition containing a pharmaceutical ingredient other than cinacalcet or a pharmaceutically acceptable salt thereof is administered to a subject by an administration route usually used for the pharmaceutical ingredient. Examples of pharmaceutical ingredients other than cinacalcet or a pharmaceutically acceptable salt thereof include, but are not limited to, an active vitamin D preparation and a bone resorption inhibitor.

Hereinafter, the present invention will be described more specifically based on examples, but the present invention is not limited to the following examples. Moreover, in each Example,% is mass% unless there is particular notice.

(Manufacture of transdermal preparations containing cinacalcet hydrochloride)
Comparative Example 1
After cinacalcet hydrochloride is dissolved in methanol so that the solid content after coating and drying is the following blending ratio, MAS-683 (pyrrolidone ring-containing acrylic resin, manufactured by Kosmedy Pharmaceutical Co., Ltd.) is added as an adhesive base, Further, an appropriate amount of ethyl acetate was added and mixed and stirred, and then a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
MAS-683 (Cosmedy Pharmaceutical) 95%

After coating the coating liquid on a release film (75 μm single-sided silicon-treated PET film, film binder 75E-0010 No. 23: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent is about 50 μm, and after drying Then, a support (25 μm PET film, Lumirror T-60: manufactured by Toray Industries, Inc.) was bonded to produce a transdermal preparation.

Comparative Examples 2 and 3
Except that the adhesive base was changed to the adhesive base shown in Table 1, the percutaneously absorbable preparations of Comparative Examples 2 to 3 were produced in the same manner as Comparative Example 1.

Comparative Example 4
After cinacalcet hydrochloride is dissolved in chloroform so that the solid content after coating and drying is the following blending ratio, SIS5002 (styrene-isoprene-styrene block copolymer: manufactured by JSR, styrene / rubber ratio = 22/78). , Diblock content = 15%), Moresco White P-350P (liquid paraffin: manufactured by MORESCO), and Alcon P-100 (rosin resin: manufactured by Arakawa Chemical Co.) were mixed and stirred to obtain a coating solution. A percutaneously absorbable preparation of Comparative Example 4 was produced in the same manner as in Comparative Example 1 except that.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
SIS5002 (manufactured by JSR) 33%
Moresco White P-350P
(MORESCO) 38%
Alcon P-100 (Arakawa Chemical Co., Ltd.) 24%

Example 5
After cinacalcet hydrochloride is dissolved in methanol so that the solid content after coating and drying is as follows, Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) as a basic compound and MAS as an adhesive base -683 (Pyrrolidone ring-containing acrylic resin, manufactured by Cosmed), percutaneously absorbable in the same manner as in Comparative Example 1, except that an appropriate amount of ethyl acetate was added, mixed and stirred, and then a coating solution was obtained. The formulation was manufactured.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
MAS-683 (Cosmedy Pharmaceutical) 85%
Eudragit EPO
(Evonik Industries) 10%

Examples 6-7
Except for the adhesive base shown in Table 1, the transdermal preparations of Examples 6 to 7 were produced in the same manner as in Example 5.

Example 8
After cinacalcet hydrochloride is dissolved in chloroform so that the solid content after coating and drying is as follows, Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by EVONIK) as a basic compound, SIS5002 (styrene-isoprene- Styrene block copolymer: manufactured by JSR, styrene / rubber ratio = 22/78, diblock content = 15%, Moresco White P-350P (liquid paraffin: manufactured by MORESCO), and Alcon P-100 (Rosin) A percutaneous absorption type preparation of Example 8 was produced in the same manner as in Comparative Example 1 except that a base resin (manufactured by Arakawa Chemical Co., Ltd.) was added and mixed and stirred to obtain a coating solution.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
SIS5002 (manufactured by JSR) 30%
Moresco White P-350P
(MORESCO) 34%
Alcon P-100 (Arakawa Chemical Co., Ltd.) 21%
Eudragit EPO
(Evonik Industries) 10%

Example 9
After cinacalcet hydrochloride is dissolved in methanol so that the solid content after coating and drying is as follows, Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) as a basic compound and BL as an absorption accelerator -2 (polyoxyethylene lauryl ether HLB value 9.5: manufactured by Nikko Chemicals) and MAS-683 (pyrrolidone ring-containing acrylic adhesive, manufactured by Cosmed) as an adhesive base, and an appropriate amount of ethyl acetate In addition, after mixing and stirring, the percutaneously absorbable preparation of Example 9 was produced in the same manner as in Comparative Example 1 except that a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
MAS-683 (Cosmedy Pharma) 75%
Eudragit EPO
(Evonik Industries) 10%
BL-2 (Nikko Chemicals) 10%

Examples 10 to 19
Transdermal absorption preparations of Examples 10 to 19 were produced in the same manner as in Example 9, except that the absorption accelerators shown in Table 2 were used.

Example 20
After cinacalcet hydrochloride is dissolved in methanol so that the solid content after coating and drying is as follows, Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) as a basic compound and BL as an absorption accelerator -2 (polyoxyethylene lauryl ether HLB value 9.5: manufactured by Nikko Chemicals), SIS 5002 (styrene-isoprene-styrene block copolymer: manufactured by JSR, styrene / rubber ratio = 22/78, diblock content = 15%), Moresco White P-350P (liquid paraffin: manufactured by MORESCO), and Alcon P-100 (rosin resin: manufactured by Arakawa Chemical Co.) were mixed and stirred in toluene to obtain a coating solution. In the same manner as in Example 1, the percutaneous absorption preparation of Example 20 was produced.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
SIS5002 (manufactured by JSR) 26%
Moresco White P-350P
(MORESCO) 30%
Alcon P-100 (Arakawa Chemical Co., Ltd.) 19%
Eudragit EPO
(Evonik Industries) 10%
BL-2 (Nikko Chemicals) 10%

Examples 21-30
Transdermal absorption preparations of Examples 21 to 30 were produced in the same manner as in Example 20, except that the absorption accelerators shown in Table 3 were used.

Example 31
After cinacalcet hydrochloride is dissolved in chloroform so that the solid content after coating and drying is as follows, Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) as a basic compound, and 1 as an absorption accelerator. , 3-butanediol (manufactured by Wako Pure Chemical Industries, Ltd.), SIS 5002 (styrene-isoprene-styrene block copolymer: manufactured by JSR, styrene / rubber ratio = 22/78, diblock content = 15%), Moresco White P-350P (liquid paraffin: manufactured by MORESCO) and Alcon P-100 (rosin resin: manufactured by Arakawa Chemical Co., Ltd.) were added and mixed and stirred. The percutaneous absorption type preparation of Example 31 was produced.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
SIS5002 (manufactured by JSR) 26%
Moresco White P-350P
(MORESCO) 30%
Alcon P-100 (Arakawa Chemical Co., Ltd.) 19%
Eudragit EPO
(Evonik Industries) 10%
1,3-butanediol (Wako Pure Chemical Industries, Ltd.) 10%

Examples 32-34
The percutaneous absorption type preparations of Examples 32-34 were produced in the same manner as in Example 31 except that the absorption enhancer shown in Table 3 was used as the absorption enhancer.

Examples 35-40
Example 20 except that the basic compound was changed to the basic compound shown in Table 4 and the absorption accelerator was changed to BL-9EX (polyoxyethylene lauryl ether, HLB value 14.5: manufactured by Nikko Chemicals). In the same manner as described above, transdermal absorption preparations of Examples 35 to 40 were produced. However, sodium hydroxide and potassium hydroxide were added after dissolving in ethanol.

Examples 41-44
Example 9 except that the adhesive base was changed to the adhesive base shown in Table 5 and the absorption accelerator was changed to BL-9EX (polyoxyethylene lauryl ether, HLB value 14.5: manufactured by Nikko Chemicals). In the same manner, transdermal absorption types of Examples 41 to 44 were produced. However, acrylic A represents acrylic acid / octyl acrylate ester copolymer, acrylic B represents acrylic 2-ethylhexyl / acrylic acid 2-hydroxyethyl / vinyl acetate copolymer (weight ratio 17: 2: 1), Acrylic C is 2-ethylhexyl acrylate / N-vinyl-2-pyrrolidone / dimethacrylic acid 1,6-hexane glycol copolymer, and acrylic D is 2-ethylhexyl acrylate / 2-ethylhexyl methacrylate / dodecyl methacrylate. A polymer (molar ratio 1: 8: 1) is shown.

Test Example 1 In Vitro Skin Permeability Test 7-week-old male Hos: HR-1 hairless mouse isolated skin (lab skin, manufactured by Hoshino Experimental Animal Breeding Co., Ltd.) After the transdermal preparation was applied, it was attached to a vertical diffusion cell (palm cell vertical TP-6: manufactured by Beadrex) so that the skin basement membrane was on the receiver side. The receiver cell was filled with an aqueous solution prepared by mixing 60/40 (volume ratio) of diluted McIlvaine buffer pH 4.0 (manufactured by Kanto Chemical Co., Ltd.) and polyethylene glycol 400, and the amount of cinacalcet transferred into the receiver solution was measured. Cinacalcet was quantified by HPLC. From the measurement results, the cumulative amount of cinacalcet permeated 24 hours after the start of the test was calculated. The results are shown in Tables 1-5.

As is clear from Tables 1 to 5, the percutaneous absorption preparation of the present invention was able to release cinacalcet and permeate the skin. Further, in Examples 5 to 8 to which the basic compound was added, the skin permeability of cinacalcet was improved as compared with Comparative Examples 1 to 4 in which the basic compound was not used. Further, in Examples 9 to 44, the skin permeability of cinacalcet was improved by the accelerator. Further, from the data of Examples 9 to 13 and 20 to 25, when polyoxyethylene alkyl ether having 10 to 22 carbon atoms is used as the absorption accelerator, the permeability is further increased when the HLB value is in the range of 7 to 16. Was observed to improve.

Test Example 2 Release Test Percutaneously absorbable preparations of Examples and Comparative Examples were fixed in a vertical diffusion cell (palm cell vertical TP-6: manufactured by Beadrex) so that the drug-containing layer was exposed to the test solution. did. The test solution was added so that the percutaneous absorption preparation of each Example was immersed, and the amount of cinacalcet transferred into the test solution was measured. As the test solution, an aqueous solution obtained by mixing diluted McIlvaine buffer pH 4.0 (manufactured by Kanto Chemical Co., Ltd.) and polyethylene glycol 400 at a volume ratio of 60 to 40 (volume ratio) was used. Cinacalcet was quantified by HPLC. The release rate was calculated from the amount of cinacalcet released 16 hours after the start of the test obtained from the measurement results. There is no problem if the release rate is 30% or more. The results are shown in Tables 1-5.

From Tables 1 to 5, the percutaneous absorption preparation of the present invention was able to release cinacalcet. In addition, in Examples 5 to 8 to which the basic compound was added, the release property of cinacalcet was improved as compared with Comparative Examples 1 to 4 in which the basic compound was not used. Further, in Examples 9 to 44, improvement of cinacalcet release by the accelerator was observed.

Test Example 3 Formulation Adhesive Test The release film of the percutaneous absorption preparation of each Example was removed, and the drug-containing layer surface was touched to evaluate the adhesive strength. It was confirmed that all examples had sufficient adhesive strength as a transdermally absorbable preparation.

Test Example 4 In vivo skin permeability test The back skin of 8-week-old male SD rats (Charles River, n = 6) was shaved with an electric clipper. The transdermal preparations prepared in Examples 8, 11, 22 and 30 were affixed to the back and wrapped with a member (white cross), tegaderm (3M), and non-woven adhesive bandage (Nichiban) 24 Blocked for hours. The formulation was removed after 24 hours. At 4, 6, 8, 12, 20 and 24 hours after application, blood was collected (approximately 0.4 mL) using a heparinized tube from the portion of the tail vein that had been stabbed with anesthesia under no anesthesia. Transferred to a container. The obtained blood was separated into plasma and blood cells with a centrifuge (4 ° C., 1000 g). Thereafter, cinacalcet blood concentration (ng / mL) at each time was measured using plasma, and the average value of 6 samples was calculated. Cinacalcet was quantified by LC / MS method. The result is shown in FIG.

As is clear from FIG. 1, it was confirmed that cinacalcet was continuously absorbed into the blood during the pasting 24 hours and maintained at a certain level or higher.

Reference Examples 1 and 2
A patch was produced in the same manner as in Example 22 except that cinacalcet hydrochloride was not added according to the mixing ratio of Table 6.

Test Example 5 Rabbit Skin Primary Irritation Test An 8-week old JW female rabbit was used. The patches (1.5 cm × 1.5 cm square) of Example 8, Example 22, Reference Example 1 and Reference Example 2 were applied to the back of the smooth skin part from which the hair had been removed, and the member (manufactured by White Cross) , Tegaderm (manufactured by 3M), and adhesive bandage (manufactured by Nichiban) were layered in order and patched for 24 hours. Skin irritation was evaluated according to the Draize method shown in Table 7 24, 48, and 72 hours after the patch. The PII value was calculated by adding the score of “erythema and crust formation” and the score of “formation of edema” to the value at each time point, adding the value at each time point and dividing by the number of time points. .

The results are shown in Table 8. As shown in Table 9, the irritation category was defined as weak irritation when the skin primary irritation index was 0 to less than 2, and 2 or more as strong irritation.

As apparent from Table 8, the skin irritation of the percutaneous absorption preparations of Examples 8 and 22 has no practical problem.

(Manufacture of transdermal preparations containing cinacalcet)
Example A1
-Preparation of rubber-based resin composition (1) SIS5002 (styrene-isoprene-styrene block copolymer, manufactured by JSR), Alcon P100 (alicyclic saturated hydrocarbon resin) so that the solid content has the following blending ratio Arakawa Chemical Industries, Ltd.) and Moresco White P-350P (liquid paraffin, manufactured by MORESCO) were dissolved in toluene to obtain a rubber-based resin composition (1).
Ingredient name Mixing ratio SIS5002 (manufactured by JSR) 35%
Alcon P100 (Arakawa Chemical Industries) 25%
Moresco White P-350P (MORESCO) 40%

・ Manufacture of transdermal preparations Potassium hydroxide dissolved in cinacalcet hydrochloride as an active ingredient and an appropriate amount of ethanol as a basic compound (made by Wako Pure Chemical Industries, Ltd.) so that the solid content after coating and drying has the following blending ratio The rubber-based resin composition (1) as an adhesive was mixed and stirred in an appropriate amount of toluene, and then a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
Potassium hydroxide (Wako Pure Chemical Industries) 0.7%
Rubber resin composition (1) 94.3%

The coating solution was applied onto a release film (75 μm single-sided silicon-treated PET film, film binder 75E-0010 BD: manufactured by Fujimori Kogyo Co., Ltd.) so that the thickness after evaporation of the solvent was about 50 μm, and dried. A support (25 μm PET film, Lumirror T-60: manufactured by Toray Industries, Inc.) was bonded to produce a transdermal preparation.

Example A2
In Example A1, the blending ratio of cinacalcet hydrochloride was changed to 20% instead of 5%, the blending ratio of potassium hydroxide was changed to 2.8% instead of 0.7%, and the rubber-based resin composition (1) A percutaneous absorption type preparation was produced in the same manner as in Example 1 except that the blending ratio was changed to 97.2% instead of 94.3%.

Example A3
Cinacalcet as an active ingredient and rubber-based resin composition (1) as an adhesive were mixed and stirred in an appropriate amount of toluene so that the solid content after coating and drying would be the following blending ratio, and then a coating solution was obtained Produced a transdermally absorbable preparation in the same manner as in Example A1.
Ingredient name Composition ratio Cinacalcet 5%
Rubber-based resin composition (1) 95%

Example A4
In Example A3, except that the blending ratio of cinacalcet hydrochloride was 20% instead of 5% and the blending ratio of rubber-based resin composition (1) was 80% instead of 95%, Example A1 and Similarly, a transdermal preparation was produced.

Example A5
Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) dissolved in cinacalcet hydrochloride as an active ingredient and an appropriate amount of ethyl acetate as a basic compound so that the solid content after coating and drying has the following blending ratio, adhesive A percutaneously absorbable preparation was produced in the same manner as in Example A1, except that the rubber-based resin composition (1) was mixed and stirred as an agent in an appropriate amount of toluene and then a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
Eudragit EPO (Evonik Industries) 10%
Rubber resin composition (1) 85%

Example A6
Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) dissolved in cinacalcet hydrochloride as an active ingredient and an appropriate amount of ethyl acetate as a basic compound so that the solid content after coating and drying is the following blending ratio, absorption Dipropylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) as an accelerator and rubber-based resin composition (1) as an adhesive were mixed and stirred in an appropriate amount of toluene, and then the same as in Example A1, except that a coating solution was obtained. Thus, a percutaneous absorption type preparation was produced.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
Eudragit EPO (Evonik Industries) 10%
Dipropylene glycol (Tokyo Chemical Industry Co., Ltd.) 10%
Rubber resin composition (1) 75%

Examples A7 to A16
A percutaneous absorption type preparation was produced in the same manner as in Example A6, except that the absorption enhancer shown in Tables 11 and 12 was used.

Examples A17 to A22
Except for changing the basic compound to the basic compounds shown in Table 13, the transdermal preparations of Examples A17 to A22 were produced in the same manner as in Example A5. However, sodium hydroxide and potassium hydroxide were added after dissolving in an appropriate amount of ethanol.

Example A23
-Preparation of rubber-based resin composition (2) Quintac 3570C (styrene-isoprene-styrene block copolymer, manufactured by Nippon Zeon Co., Ltd.), YS resin PX1150N (terpene resin, Yashara Chemical Co., Ltd.) so that the solid content is as follows. And High Coal M-352 (liquid paraffin, manufactured by Kaneda Corporation) were dissolved in toluene to obtain a rubber-based resin composition (2).
Ingredient name Mixing ratio Quintac 3570C (made by Nippon Zeon) 35%
YS resin PX1150N (manufactured by Yasuhara Chemical) 50%
High call M-352 (Kaneda) 15%

・ Manufacture of transdermal preparations Potassium hydroxide dissolved in cinacalcet hydrochloride as an active ingredient and an appropriate amount of ethanol as a basic compound (made by Wako Pure Chemical Industries, Ltd.) so that the solid content after coating and drying has the following blending ratio ), Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries) dissolved in an appropriate amount of ethyl acetate, dipropylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) as an absorption accelerator, and rubber-based resin composition (2) as an adhesive Was mixed and stirred in an appropriate amount of toluene, and then a percutaneously absorbable preparation was produced in the same manner as in Example A1, except that a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 5%
Potassium hydroxide (Wako Pure Chemical Industries) 0.71%
Eudragit EPO (Evonik Industries) 0.71%
Dipropylene glycol (Tokyo Chemical Industry Co., Ltd.) 10%
Rubber-based resin composition (2) 83.58%

Example A24
A percutaneously absorbable preparation was produced in the same manner as in Example A23, except that the blending ratio of cinacalcet hydrochloride, potassium hydroxide, Eudragit EPO and the rubber-based resin composition (2) was changed to the blending ratio shown in Table 14. .

Example A25
A percutaneous absorption type preparation was produced in the same manner as in Example A24, except that the thickness after evaporation of the solvent was about 30 μm and the coating was dried.

Example A26
A percutaneous absorption type preparation was produced in the same manner as in Example A24, except that the thickness after evaporation of the solvent was about 100 μm and the coating was dried.

Examples A27 to A29
A percutaneously absorbable preparation was produced in the same manner as in Example A23, except that the blending ratio of cinacalcet hydrochloride, potassium hydroxide, Eudragit EPO and the rubber-based resin composition (2) was changed to the blending ratio shown in Table 14. .

Examples A30 to A31
A transdermal absorption preparation was produced in the same manner as in Example A28, except that the blending ratio of the rubber-based resin composition (2) and dipropylene glycol was changed to the blending ratio shown in Table 15.

Example A32
-Preparation of rubber-based resin composition (3) SIS5002 (styrene-isoprene-styrene block copolymer, manufactured by JSR), Quintac 3520 (styrene-isoprene-styrene block co-polymer) so that the solid content has the following blending ratio Combined, high diblock-containing type, manufactured by Nippon Zeon Co., Ltd., Alcon P100 (alicyclic saturated hydrocarbon resin, manufactured by Arakawa Chemical Industries), Moresco White P-350P (liquid paraffin, manufactured by MORESCO) dissolved in toluene As a result, a rubber-based resin composition (3) was obtained.
Ingredient name Mixing ratio SIS5002 (manufactured by JSR) 23%
Quintac 3520 (made by Nippon Zeon) 12%
Alcon P100 (Arakawa Chemical Industries) 25%
Moresco White P-350P (MORESCO) 40%

-Production of transdermal absorbable preparation A transdermal absorbable preparation was produced in the same manner as in Example A24 except that the rubber-based resin composition (3) was used instead of the rubber-based resin composition (2).

Example A33
A transdermal preparation was produced in the same manner as in Example A28, except that the rubber resin composition (3) was used instead of the rubber resin composition (2).

Example A34
Dissolve in cinacalcet hydrochloride as an active ingredient, potassium hydroxide dissolved in an appropriate amount of ethanol as a basic compound (manufactured by Wako Pure Chemical Industries, Ltd.), and an appropriate amount of ethyl acetate so that the solid content after coating and drying is as follows. Eudragit EPO (aminoalkyl methacrylate copolymer E: manufactured by Evonik Industries Co., Ltd.), dipropylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) as an absorption accelerator, BO-10V (polyoxyethylene oleyl ether, manufactured by Nikko Chemicals Co., Ltd.), and adhesive A percutaneously absorbable preparation was produced in the same manner as in Example A1, except that the rubber-based resin composition (1) was mixed and stirred in an appropriate amount of toluene and then a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 20%
Potassium hydroxide (Wako Pure Chemical Industries) 2.85%
Eudragit EPO (Evonik Industries) 2.82%
Dipropylene glycol (Tokyo Chemical Industry Co., Ltd.) 5%
BO-10V (Nikko Chemicals) 5%
Rubber resin composition (1) 64.33%

Example A35
Cinacalcet hydrochloride as an active ingredient, sodium hydroxide dissolved in an appropriate amount of ethanol as a basic compound (made by Wako Pure Chemical Industries, Ltd.), and BL- 2 (polyoxyethylene lauryl ether, manufactured by Nikko Chemicals), MAS-683 as adhesive (pyrrolidone ring-containing acrylic resin, manufactured by Kosmedy Pharmaceutical Co., Ltd.), mixed and stirred in an appropriate amount of ethyl acetate, and then a coating solution was obtained. A percutaneously absorbable preparation was produced in the same manner as in Example A1, except that.
Ingredient name Composition ratio Cinacalcet hydrochloride 20%
Sodium hydroxide (Wako Pure Chemical Industries) 2%
BL-2 (Nikko Chemicals) 10%
MAS-683 (Cosmedy Pharmaceutical) 68%

Examples A36 to A37
A transdermal absorption preparation was produced in the same manner as in Example A35, except that the combination ratio of cinacalcet hydrochloride, sodium hydroxide and MAS-683 was changed to the combination ratio shown in Table 16.

Examples A38 to A39
A percutaneous absorption type preparation was produced in the same manner as in Example A35 except that the absorption enhancer was changed to the absorption enhancer shown in Table 16.

Example A40
A transdermal absorption preparation was produced in the same manner as in Example A39, except that DURO TAK87-4098 (non-functional acrylic resin, manufactured by Henkel) was used instead of MAS-683.

Example A41
A transdermal preparation was produced in the same manner as in Example A39, except that DURO TAK87-2516 (hydroxyl group-containing acrylic resin, manufactured by Henkel) was used instead of MAS-683.

Example A42
Appropriate amounts of cinacalcet as an active ingredient, rubber resin composition (1) as an adhesive, and dipropylene glycol (manufactured by Tokyo Chemical Industry Co., Ltd.) as an absorption accelerator so that the solid content after coating and drying is as follows. A percutaneously absorbable preparation was produced in the same manner as in Example A1, except that a coating solution was obtained after mixing and stirring in toluene.
Ingredient name Composition ratio Cinacalcet 5%
Rubber resin composition (1) 85%
Dipropylene glycol (Tokyo Chemical Industry Co., Ltd.) 10%

Example A43
Transdermal absorption type preparation similar to Example A42 except that the combination ratio of cinacalcet was changed to 5% to 20% and the ratio of the rubber-based resin composition (1) was changed to 85% instead of 70%. Manufactured.

Example A44
Cinacalcet hydrochloride as an active ingredient, potassium hydroxide dissolved in an appropriate amount of ethanol (manufactured by Wako Pure Chemical Industries, Ltd.), Eudragit EPO (Evonik Industries) so that the solid content after coating and drying has the following blending ratio IPM-EX (isopropyl myristate, manufactured by Nikko Chemicals), lauric acid diethanolamide (polyoxyethylene oleyl ether, manufactured by Nikko Chemicals), and rubber-based resin composition (2) as an adhesive Was mixed and stirred in an appropriate amount of toluene, and then a percutaneously absorbable preparation was produced in the same manner as in Example A1, except that a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 20%
Potassium hydroxide (Wako Pure Chemical Industries) 2.85%
Eudragit EPO (Evonik Industries) 1.76%
IPM-EX (Nikko Chemicals) 15%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 3%
Rubber resin composition (2) 57.39%

Example A45
Cinacalcet hydrochloride as an active ingredient, diisopropanolamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.), Eudragit EPO (manufactured by Evonik Industries Co., Ltd.), absorption accelerator so that the solid content after coating and drying has the following blending ratio IPM-EX (isopropyl myristate, manufactured by Nikko Chemicals), lauric acid diethanolamide (polyoxyethylene oleyl ether, manufactured by Nikko Chemicals), and rubber-based resin composition (2) as an adhesive in an appropriate amount of toluene After mixing and stirring, a transdermal absorption preparation was produced in the same manner as in Example A1, except that a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 20%
Diisopropanolamine (Tokyo Chemical Industry Co., Ltd.) 6.8%
Eudragit EPO (Evonik Industries) 1.76%
IPM-EX (Nikko Chemicals) 15%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 3%
Rubber resin composition (2) 53.44%

Example A46
A percutaneous absorption type preparation was produced in the same manner as in Example A45, except that Eudragit EPO was not used and the blending ratio of the rubber-based resin composition was changed from 53.44% to 55.2%.

Example A47
Cinacalcet hydrochloride as an active ingredient, triisopropanolamine (manufactured by Tokyo Kasei Kogyo Co., Ltd.), Eudragit EPO (manufactured by Evonik Industries Co., Ltd.), absorption accelerator so that the solid content after coating and drying is as follows: IPM-EX (isopropyl myristate, manufactured by Nikko Chemicals), lauric acid diethanolamide (polyoxyethylene oleyl ether, manufactured by Nikko Chemicals), and rubber-based resin composition (2) as an adhesive in an appropriate amount of toluene After mixing and stirring, a transdermal absorption preparation was produced in the same manner as in Example A1, except that a coating solution was obtained.
Ingredient name Composition ratio Cinacalcet hydrochloride 20%
Triisopropanolamine (Tokyo Chemical Industry Co., Ltd.) 9.7%
Eudragit EPO (Evonik Industries) 1.76%
IPM-EX (Nikko Chemicals) 15%
Lauric acid diethanolamide (Wako Pure Chemical Industries, Ltd.) 3%
Rubber-based resin composition (2) 50.54%

Example A48
A percutaneous absorption type preparation was produced in the same manner as in Example A47 except that Eudragit EPO was not used and the blending ratio of the rubber-based resin composition was changed from 50.54% to 52.3%.

Comparative Example A1
A percutaneous absorption type preparation was prepared in the same manner as in Example A2, except that potassium hydroxide was not used and the blending ratio of the rubber-based resin composition (1) was changed to 80% instead of 77.15%.

Test Example A1 In Vitro Skin Permeability Test 7-week-old male Hos: HR-1 hairless mouse isolated skin (lab skin, manufactured by Hoshino Experimental Animal Breeding Co., Ltd.) percutaneous absorption of each example After applying the type preparation, in the vertical diffusion cell (trade name: Palm Cell Vertical Type TP-6: manufactured by Beadrex) in which hot water of 32 ° C was circulated around the outer periphery, the skin basement membrane was on the receiver side Installed. Fill the receiver cell with an aqueous solution prepared by mixing 60/40 (volume ratio) of diluted McIlvaine buffer pH 4.0 (manufactured by Kanto Chemical Co., Ltd.) and polyethylene glycol 400, and sample the receiver solution over time. The amount of cinacalcet was measured. From the measurement results, the cumulative permeation amount of cinacalcet (converted to cinacalcet) in 24 hours after the start of the test was calculated, and the skin permeation rate was calculated (average value of n = 3). The results obtained are shown in Tables 10-17.

<HPLC measurement conditions>
Apparatus: High performance liquid chromatography NexeraX2 system (manufactured by Shimadzu Corporation)
Column: Inertsil ODS3, 5μm, 4.6 X 150mm (manufactured by GL Sciences)
Column temperature: 40 ° C
Flow rate: 1 mL / min Detector: PDA UV-visible detector SPD-M20A (manufactured by Shimadzu)
Detection wavelength 223nm
Mobile phase: 0.1% phosphoric acid aqueous solution and acetonitrile mixture Sample injection volume: 10 μL

As is apparent from Tables 10 to 17, the percutaneous absorption preparation of the present invention released cinacalcet and was able to penetrate the skin. Moreover, when the absorption enhancer was used, the skin permeability of cinacalcet was improved. When a styrene-isoprene-styrene block copolymer was used as an adhesive and dipropylene glycol was used as an absorption accelerator, particularly high skin permeability was exhibited.
Test Example A2 In vivo skin permeability test (rat)

The back skin of 8-week-old male SD rats (Charles River, n = 6) was shaved with an electric clipper. The percutaneous absorption preparations produced in Example A32, Example A33 and Example A34 were affixed to the back, Member (White Cross Co., Ltd.), Tagaderm Roll (manufactured by 3M Healthcare Co., Ltd.), non-woven adhesive bandage (Silky Tech, ALCARE) was wound and pasted for 24 hours. The transdermal preparations of Example A32 and Example A34 were cut to a size of 10 cm ² (3.16 cm × 3.16 cm) (cinacalcet hydrochloride content per preparation: Example A32 about 3.75 mg / Sheet, Example A34, about 10 mg / sheet). The percutaneous absorption type preparation of Example A33 was cut into a size of 4 cm ² (2 cm × 2 cm) and used (about 4 mg / sheet). The formulation was removed after 24 hours. For Example A34, at 1, 2, 4, 6, 8, 12, 20 and 24 hours after application, blood was collected from the tail vein (approximately 0.3 mL) without anesthesia, and the blood was transferred to a polypropylene container. did. For Examples A32 and A33, blood was collected in the same manner at 1, 3, 6, 12, 20 and 24 hours. Plasma was separated from the obtained blood by a centrifuge (4 ° C., 1000 g). The plasma obtained using Oasis was subjected to solid-phase extraction, and the plasma concentration (ng / mL) of cinacalcet at each time was measured using LC / MS / MS, and the average value of 6 samples was calculated (cinacalcet Converted as concentration). Cinacalcet was quantified by LC / MS method. The result is shown in FIG.

<LC / MS / MS measurement conditions>
Equipment: ACQUITY UPLC H-Class system (Waters)
Column: Acquity UPLC BEH C18 1.7μm 2.1 x 50mm (Waters)
Column temperature: 40 ° C
Flow rate: 0.4mL / min Detector: Xevo G2-S Q-Tof (manufactured by Waters)
Detection condition: Resolution / Positive, m / z = 358.18
Mobile phase: 0.1% formic acid aqueous solution and 0.1% formic acid-methanol solution mixed sample injection volume: 1μL

As is apparent from FIG. 3, when the transdermally absorbable preparation of the present invention is applied to a rat, cinacalcet is continuously absorbed through the skin, and a plasma concentration of a certain level or more is maintained for 24 hours. It was confirmed that Moreover, from the comparison between Example A32 and Example A33, even when the content of cinacalcet hydrochloride in the preparation is changed, the same plasma profile is shown as long as the active ingredient content per preparation is equivalent. It has been suggested.

Test Example A3 In vivo skin permeability test (mini pig)
Three male pigs (Goettingen Minipig, manufactured by Oriental Yeast Co., Ltd.) weighing about 18 kg were used. The day before applying the percutaneous absorption preparation, the entire hair was shaved from the back part including the vertebra part to the buttocks with an electric clipper, and the entire shaved area excluding the spine part was shaved with an electric razor. The percutaneous absorption type preparation manufactured in Example A34 was cut into a size of 4 cm ² × 6 cm ² and 24 sheets (576 cm ² ) were pasted in the shaved area. After the application, in order to protect the application site, a mesh pore (manufactured by Nichiban Co., Ltd.) was applied so as to cover the application part, and a jacket was attached. At 1, 4, 8, 12 and 24 hours after administration, about 3 mL of blood was collected from the jugular vein. Plasma was separated from the obtained blood by centrifugation (about 1600 g, 4 ° C., 10 minutes). In the same manner as in Test Example A2, the cinacalcet blood concentration was measured by LC / MS method, and the average value of 6 samples was calculated. The result is shown in FIG.

As is apparent from FIG. 4, when the transdermal absorption preparation of the present invention is applied to minipigs, cinacalcet is continuously absorbed through the skin and the plasma concentration is maintained above a certain level for 24 hours. It was confirmed that

Reference Examples A1 and A2
A patch was produced in the same manner as in Example A5 and Example A14 except that cinacalcet hydrochloride was not added according to the blending ratio in Table 18.

Test Example A4 Rabbit skin primary irritation test A 19-week-old JW female rabbit was used. The percutaneously absorbable preparation (1.5 cm × 1.5 cm square) produced in Example A5 and Example A14, Reference Example A1 and Reference Example A2 was applied to the back of the smooth skin part from which the hair had been removed, and Tegaderm Roll After fixing with (3M Healthcare), cover the back with a foam pad with adhesive (3M Healthcare), and then a self-adhesive elastic bandage (3M Coban Self-Adherent Wrap, manufactured by 3M Healthcare) ) Was wound around the body and further fixed with a polyethylene film tape (Keeppore A, manufactured by Nichiban Co., Ltd.). 24 hours after administration, the percutaneous absorption preparation was peeled off, and the application site was wiped with absorbent cotton moistened with acetone. The skin reaction was observed 24, 48, and 72 hours after administration, and a skin irritation index (PI) was calculated with reference to the Draize criteria (1959) shown in Table 19, Skin irritation was evaluated. However, 24 hours after administration, observation was performed about 1 hour after wiping. For each test substance, a score by individual at 24, 48 and 72 hours after administration was calculated and divided by the number of observations (three times). I. I. (Individual PI) was calculated. Individual P.M. I. I. Values were summed, and the average value was calculated as P.I. I. I. It was.

The results are shown in Table 20. The evaluation of irritation is based on P.I. I. When I was 0, it was designated as “non-irritant”, when it was greater than 0 and less than 2, “mildly irritating”, when 2 or more and less than 5, “moderately irritating”, and when 5 or more, “strongly irritating” Statistical processing was not performed during the evaluation.

As is clear from Table 20, the skin irritation of the transdermal absorption preparation of Example A5 was non-irritating, and the skin irritation of the transdermal absorption preparation of Example A14 was mild.

Test Example A5 Percutaneous and Oral Administration Comparison Test 5-1 Rat Plasma Cinacalcet Concentration 5-2 Rat Plasma Intact PTH (Parathyroid Hormone: hereinafter referred to as iPTH) Concentration and Rat Plasma Calcium (Ca) Reduction Capability Comparison Test 7 weeks Age-old male SD rats (Nippon Charles River, Inc., body weight of about 300 g, 6 animals / group) were used. Rats were divided into a group for oral administration and a group for transdermal administration so that each group had the same body weight. The transdermal administration group was obtained by cutting the percutaneously absorbable preparation produced in Example A32 at 1 cm ² / animal (amount of cinacalcet hydrochloride in the preparation relative to the rat body weight: about 1.25 mg / kg), 3 cm ² / Rats (approx. 3.75 mg / kg) and 10 cm ² / animal (approx. 12.5 mg / kg) were applied to the rats in the same manner as in Test Example A2 (n = 6). The oral administration group was divided into a control group and a cinacalcet oral administration group. In the control group, a placebo transdermal preparation was affixed, and only the administration solvent (0.5% methylcellulose 400 solution, manufactured by Wako Pure Chemical Industries, Ltd.) was administered. The cinacalcet oral administration group was also applied with a placebo transdermal preparation and a suspension of cinacalcet hydrochloride in the administration solvent. The cinacalcet solution was adjusted so that the dose was 3 mg / kg, 10 mg / kg, and 30 mg / kg with respect to the body weight of the rat, and the dose was 5 ml / kg. In both the transdermal administration group and the oral administration group, blood was collected from the tail vein without anesthesia before administration (0 hour) and 0.5, 1, 3, 6, 12, 20 and 24 hours after administration. (0.3 mL) and the blood was transferred to a polypropylene container. Plasma was separated from the obtained blood by centrifugation (4 ° C., 2000 g, 15 minutes).
5-1: Cinacalcet concentration in rat plasma was measured by the same method as in Test Example A2. The result is shown in FIG.
5-2: Plasma concentrations of iPTH and Ca were measured using ELISA and MXB methods, respectively. The results are shown in FIGS.

<IPTH and Ca concentration measurement conditions>
Fluorescence plate reader: infinite200Pro-FL (manufactured by Tacan)
ELISA kit: Rat intact PTH ELISA Kit (manufactured by Immunopics)
Ca measurement kit: Calcium E-Test Wako (Wako Pure Chemical Industries, Ltd.)

As is clear from FIG. 5, the percutaneously absorbable preparation of Example A32 can stably maintain the cinacalcet concentration in plasma as compared with oral administration. As is clear from FIGS. 6 and 7, the percutaneous absorption preparation of Example A32 can lower the iPTH concentration in plasma for a longer time than oral administration. In addition, since the Ca concentration in plasma is also continuously reduced over a long period of time, it has a higher medicinal effect and lower risk of side effects compared to oral administration (calcium receptors in the digestive tract). Presumably due to stimulation avoidance and reduced maximum plasma concentration.

According to the present invention, there is provided a transdermal preparation containing cinacalcet or a pharmaceutically acceptable salt thereof, which can reduce side effects that may occur with oral administration. The transdermally absorbable preparation of the present invention can more effectively prevent or treat hyperparathyroidism or hypercalcemia.

Claims

A transdermally absorbable preparation having a support and a drug-containing layer, wherein the drug-containing layer contains pharmaceutically acceptable salt of cinacalcet, an adhesive and a basic compound as active ingredients Formulation.
The basic compound is at least one selected from a polymer compound containing basic nitrogen, monoethanolamine, diisopropanolamine, triisopropanolamine, sodium hydroxide, potassium hydroxide, and sodium bicarbonate. Item 4. A transdermal absorption preparation according to Item 1.
A transdermal preparation having a support and a drug-containing layer, wherein the drug-containing layer contains cinacalcet and an adhesive as active ingredients.
The percutaneous absorption preparation according to any one of claims 1 to 3, wherein the adhesive is composed mainly of a rubber-based resin.
The transdermal preparation according to claim 4, wherein the rubber-based resin is a styrene-isoprene-styrene block copolymer.
The transdermally absorbable preparation according to any one of claims 1 to 3, wherein the adhesive comprises an acrylic resin as a main component.
The transdermal preparation according to any one of claims 1 to 6, wherein the drug-containing layer further contains a tackifier.
The percutaneous absorption preparation according to any one of claims 1 to 7, wherein the drug-containing layer further contains an absorption enhancer.
The absorption accelerator is a polyhydric alcohol having 3 to 8 carbon atoms, polyoxyethylene alkyl ether having 10 to 22 carbon atoms, isopropyl myristate, isopropyl palmitate, lauric acid diethanolamide, and N-methyl-2-pyrrolidone. The percutaneously absorbable preparation according to claim 8, which is at least one selected.
The percutaneous absorption preparation according to claim 8, wherein the absorption accelerator is at least one selected from polyhydric alcohols having 3 to 8 carbon atoms.
The transdermal preparation according to claim 10, wherein the polyhydric alcohol having 3 to 8 carbon atoms is dipropylene glycol.
10. The transdermal preparation according to claim 9, wherein the polyoxyethylene alkyl ether having 10 to 22 carbon atoms has an HLB value of 7 to 16.
The percutaneous absorption preparation according to any one of claims 1 to 12, further comprising a release liner, wherein the support, the drug-containing layer, and the release liner are laminated in this order.
A method for producing a transdermally absorbable preparation according to claim 1, wherein a mixture comprising a pharmaceutically acceptable salt of cinacalcet, an adhesive and a basic compound is prepared.
Applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer;
The said manufacturing method including.
A method for producing a transdermally absorbable preparation according to claim 3, wherein a mixture containing cinacalcet and an adhesive is prepared.
Applying or spreading the mixture on a release liner to form a drug-containing layer, and bonding a support to the drug-containing layer;
The said manufacturing method including.