JPS6335521A - Drug preparation - Google Patents

Abstract

PURPOSE:A drug preparation having a drug existing in a fine crystallite state, showing improved releasability to the skin, consisting of a drug supply layer containing diltiazem hydrochloride having >=saturated solubility in a specific high polymer and a carrier layer having no permeability to drug. CONSTITUTION:A drug supply layer containing (preferably 5-50wt%) diltiazem hydrochloride having >=saturated solubility in a polymer selected from (A) a polymer of a (meth)acrylic alkyl ester monomer (preferably 2-ethylhexyl acrylate), (B) a polymer of a monomer (e.g. acrylate or acrylamide containing ethylene oxide unit in the side chain) containing nonelectrolytic and/or cationic electrolytic group in the side chain and (C) a copolymer of both the monomers A and B is formed in a lamellar state in 5-1,000mum thickness on a carrier layer having nonpermeability to drug. The drug supply layer preferably contains 5-15wt% absorption promoter (e.g. polyoxyethylene lauryl ether).

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a pharmaceutical formulation containing diltiazem hydrochloride which is applied directly to the skin or by means of an auxiliary means during use.

[Conventional technology]

Diltiazem hydrochloride, d-3-acetoxy-cis-2,3-dihydro-5-(2-(dimethylamino)ethyl)-2-(p-methoxyphenyl)-1,5-benzodiazepine-4 (51() -one hydrochloride (hereinafter referred to as D
ZH) has a selective and strong coronary vasodilator effect based on its calcium antagonistic action, and also exhibits excellent pharmacological effects in improving exertional angina pectoris and angina in old myocardial infarction. It is. Furthermore, DZH has a blood pressure lowering effect through peripheral vasodilation, and its usefulness is highly evaluated in the treatment of mild to moderate essential hypertension.

Currently, DZ1 is exclusively administered orally in the form of tablets, but in addition to problems with its dosage form, such as low bioavailability and large individual differences in blood concentration, it also causes digestive problems such as back discomfort. There is a problem in that side effects occur on the organ system, and improvements are desired.

Recently, as a method to eliminate or reduce the side effects caused by oral administration, a nitro compound such as isosorbite cinitrate or nitroglycerin is blended with a high molecular weight polymer and then applied onto a carrier. Formed tape-like preparations have been proposed and put into practical use. In this type of preparation, the nitro compound, which is a drug, is blended into the polymer in an amount that is less than its saturation solubility, and therefore the nitro compound exists in the polymer in a dissolved state.

However, according to repeated experiments conducted by the inventors, D Z H is hardly dissolved in high molecular weight polymers;
Even if it is forcibly dissolved, the concentration is around 5% at most, which is much higher than that of nitro compounds.DZH
However, with the above-mentioned content, it was not possible to obtain a tape-like preparation that could sufficiently exhibit the desired pharmacological effect.

On the other hand, a percutaneously absorbable drug with a saturation solubility or higher in the polymer is contained in the polymer, and the drug with a saturation solubility or higher is dispersed in the polymer in the form of recrystallized fine particles of approximately uniform size. Japanese Patent Application Laid-Open No. 185713/1983 has proposed a formulation that allows the drug to be absorbed transdermally even if the drug is not completely dissolved.

Although this proposal does not disclose that DZH can be applied as a transdermal drug, considering that DZH has low solubility in high molecular weight polymers as mentioned above, The above method is considered to be a very effective means for expressing the pharmacological effects of DZI.

[Problem that the invention seeks to solve]

However, since the effective blood concentration of DZ If the polymer is not in good condition, the expected pharmacological effect cannot be expected.According to the inventors' experimental studies, in many cases sufficient pharmacological effects cannot be obtained due to the characteristics of the polymer. Admitted.

Therefore, the present invention provides D containing in a high molecular weight polymer at a high content that is higher than the saturation solubility of the polymer.
The purpose of the present invention is to obtain a pharmaceutical preparation with a large pharmacological effect that allows Z II to be effectively and sustainably absorbed through the skin.

[Means for solving problems]

As a result of intensive studies to achieve the above object, the inventors have found that by using a specific polymer containing DZH, it is possible to thicken (improve) the skin absorbency of DZl. This invention was completed based on the knowledge that this transdermal absorption can be further enhanced by the combined use of an absorption enhancer, and very satisfactory results can be obtained in terms of pharmacological effects.

That is, the first aspect of the present invention is composed of at least a drug-impermeable carrier layer and a drug supplying layer containing a drug in a high molecular weight polymer at a saturation solubility or higher for the polymer; The present invention relates to a pharmaceutical preparation characterized in that the polymer is at least one selected from the following groups a) to c), and the drug is DZH.

b) (meth)acrylic acid alkyl ester monomer (
a) polymerization or copolymer of monomer (b) having a non-electrolytic group and/or cationic electrolytic group in the side chain c) copolymer of the monomers (a) and (b); The second aspect of this invention is the drug supply layer in the first invention,
In other words, DZH as a drug is added to the drug supply layer made of a specific polymer selected from the group of (a) to (c) above.
This invention relates to a pharmaceutical preparation characterized in that it also contains an absorption enhancer.

[Structure and operation of the invention]

The high molecular weight polymer used in this invention has viscoelasticity at room temperature, contains DZH in a dissolved or dispersed state in the presence of a solvent, and moreover, DZH does not grow as large crystals in the polymer. D Z H can exist in a microcrystalline state without any oxidation, and is highly effective in releasing D Z H into the skin.
As materials having such characteristics, those shown in (a) to (c) above are used.

First, the polymer of the (meth)acrylic acid alkyl ester monomer (a) in (a) is a (meth)acrylic acid alkyl ester having an alkyl group having 4 to 12 carbon atoms, such as n-butyl (meth)acrylate, Isoamyl (meth)acrylate, 2-ethylbutyl (meth)acrylate, n-hexyl (meth)acrylate, isooctyl (meth)acrylate, 2-ethylhexyl (meth)acrylate
It is formed by polymerizing acrylate, isononyl (meth)acrylate, decyl (meth)acrylate, dodecyl (meth)acrylate, etc. by a conventional method. This a)
A particularly preferred polymer is poly-2-ethylhexyl acrylate.

In addition, as the polymerization or copolymer of the monomer (b) having a non-electrolytic group and/or a cationic electrolytic group in the side chain of A product obtained by polymerizing or copolymerizing by a conventional method, a product obtained by polymerizing or copolymerizing at least one of the monomers (b) with a cationic electrolytic group, or a product obtained by polymerizing or copolymerizing by a conventional method with at least one of the monomers (b) and Any of those obtained by copolymerizing at least one of the above monomers (b)'' by a conventional method can be used.

A monomer (b)° having a non-electrolytic group is a monomer that does not have an electrolytic group such as a carboxyl group or a phosphoric acid group in its molecule, and the most typical example thereof is, for example, tetrahydrofurfuryl (meth). Acrylate, carpitol (meth)acrylate, methoxyethyl (meth)acrylate, ethquinethyl (meth)acrylate, butquinethyl (meth)7acrylate, and 3-ethoxypropyl(tsuku)acrylate, which have an ether bond in the side chain (meth)acrylate. )7 acrylates, polyethylene glycol (meth)acrylate, methoxypolyethylene glycol (meth)acrylate, ethoxypolyethylene glycol (meth)acrylate, ethoxydiethylene glycol (meth)acrylate, butoxydiethylene glycol (meth)acrylate, butylene glycol (meth)acrylate Examples include acrylates having an ethylene oxide unit in the side chain.

Other examples of the above monomers (b)' include (meth)acrylates having a hydroxyl group in the side chain such as 2-hydroxyethyl (meth)acrylate and hydroxypropyl (meth)acrylate, vinyl acetate, Examples include vinyl esters such as vinyl pionate, vinyl ethers such as vinyl methyl ether, vinyl butyl ether, and vinyl 2-ethylhexyl ether, and other monomers such as acrylonitrile, acrolene, and vinyl chloride.

On the other hand, examples of the monomer (b)'' having a cationic electrolytic group include (meth)acrylamide, dimethylaminoethyl (meth)acrylate, diethylaminoethyl (meth)acrylate, 1-butylaminoethyl (meth)acrylate, vinylimidazole, Examples include monomers such as vinylpyridine and vinylpyrrolidone.

Particularly preferable polymers or copolymers of the above item) are polymers or copolymers of (meth)acrylates having an ether bond or ethylene oxide unit in the side chain, or the same polymers or copolymers of (meth)acrylates and vinyl as mentioned above. Examples include copolymers with esters or vinylpyrrolidone, the copolymerization ratio of the former being in the range of 1:0.5 to 2 (weight ratio).

As for the copolymer of (meth)acrylic acid argyl ester monomer (a) and the monomer (b) having a non-electrolytic group and/or cationic electrolytic group in the side chain, monomer (a) On the other hand, the monomer (b) was 0.25 to 1.
5 (weight ratio) is preferably used.

Among the above copolymers c), particularly preferred from the viewpoint of DZH release properties are copolymers containing a (meth)acrylic acid alkyl ester having an alkyl group having 6 to 9 carbon atoms and an ether bond or ethylene oxide unit in the side chain. have (meta)
A copolymer obtained by copolymerizing acrylates or vinyl esters in a ratio of the former to the latter = 11.3 to 1.2 (weight ratio), or an ester similar to the above and a (meth)acrylate similar to the above. and further vinyl esters or vinylpyrrolidone in a weight ratio of 1:0.3 in the above order.
-1: A terpolymer formed by copolymerizing in a range of 0.2 to 1.

In this invention, any one of the polymers or copolymers shown in the above groups a) to c) may be used,
A mixture of two or three of these may be used. In each embodiment, preferably the monomer (b) having a non-electrolytic group in the side chain among all the monomers constituting the polymer has at least 10 liffi in one monomer unit.
It is desirable that the content is adjusted to %. In addition,
The molecular weight of each polymer or copolymer shown in the above group is not particularly defined, but generally the number average molecular weight is s
It is desirable that the number be in the range of o,ooo to 450,000.

In this invention, such a high molecular weight polymer includes DZH.
is blended so that it has a saturation solubility or higher in the above polymer, and about 5 to 1,000
The drug supply layer is formed into a layer with a thickness of 0 μm.

The amount of DZH in this supply layer is preferably set in the range of 5 to 50% by weight, and practically 15 to 40% by weight.

If it is less than 5% by weight, it will not be possible to obtain the desired pharmacological effect.
If it exceeds % by weight, the crystals of D Z H in the polymer will grow and the transdermal absorbability of D Z H will decrease, so neither is preferable.

In this invention, the above-mentioned D Z
By including an absorption enhancer together with H, the transdermal absorbability of DZH, which exists in a dissolved and microcrystalline state, can be further improved.

This accelerator increases D from the polymer to the applied skin surface.
Increasing the initial absorption of ZH, stabilizing DZH in the polymer, that is, DZH stably exists in a microcrystalline state in the polymer and grows into larger crystals. , to release DZH from the high molecular weight polymer to the skin surface to which it is applied, and to facilitate transdermal absorption of DZH supplied to the skin surface by loosening the stratum corneum. Any material having at least one of the functions may be used.

Such absorption enhancers include, for example, -hydric or polyhydric alcohols, adipates, sebacates, laurates, but especially polyoxyethylene lauryl ether, sodium polyoxyethylene lauryl ether sulfate, polyoxyethylene lauryl ether phosphorus, etc. At least one selected from the group of sodium acids is most preferred.

The absorption enhancer is preferably contained in the drug supply layer in an amount of 1 to 20% by weight, practically 5 to 15% by weight. If it is less than 1% by weight, the above effect will be poor, and if it exceeds 20% by weight, there is a risk of bruising on the surface of the supply layer, and the absorption enhancer may plasticize the polymer too much, leaving a residue when it is removed from the applied skin surface. Both are undesirable as they may leave some residue behind.

In the present invention, the drug supplying layer composed of a high molecular weight polymer and DZH and further containing an absorption enhancer is a polyolefin film, a polyester film, a polyurethane film, a polyacrylic film, an ethylene film, etc. As described above, about 5 to 1,000 μm is applied directly or via an undercoat layer onto a carrier layer made of a flexible and drug-impermeable plastic film such as a copolymer film. It is formed with a thickness of

The undercoat layer is not particularly limited as long as it improves the adhesion between the carrier layer and the drug supply layer.
Examples include vinyl acetate copolymers and acrylic or rubber pressure sensitive adhesives.

By using a pressure-sensitive adhesive as described above as an undercoat layer and forming a drug supply layer partially in the form of stripes, spots, etc. on the surface of this layer, pharmaceutical preparations can be easily applied to the skin without the aid of auxiliary means. Can be pasted on the surface. On the other hand, in order to obtain the same effect, a pressure-sensitive adhesive with or without DZH3 permeability may be formed on the surface of the drug supply layer, either entirely or partially, such as in the shape of a window frame.

However, if the preparation itself has the function of directly adhering to the skin surface, the above-mentioned application and formation of the adhesive can be omitted.

In this invention, the above-mentioned drug supply layer can be formed by solution polymerizing the above-mentioned high molecular weight polymer in the presence of a solvent or by emulsion polymerization in the presence of water. Alternatively, mix DZH or an absorption enhancer with an aqueous dispersion, apply this onto a carrier and dry it, or apply the above formulation onto a release liner and dry it in the same manner as above. What is necessary is just to transfer it onto a carrier. In the latter case, the release liner can serve to protect the drug delivery layer until just before the formulation is used.

The pharmaceutical preparation of the present invention constructed in this way can be applied to the skin surface to which it is applied, either by utilizing the adhesive properties of the preparation itself or by using an auxiliary means such as an adhesive film that is more impermeable than the preparation. Ru.

〔Effect of the invention〕

In the pharmaceutical preparation of the present invention, the drug supply layer is composed of a combination of DZH and a specific high molecular weight polymer, so that the DZH having a saturation solubility or higher becomes a microcrystalline state in the polymer, and the DZH that exceeds the saturation solubility becomes microcrystalline in the polymer. DZH does not grow into large crystals, therefore the effective concentration of DZH per unit area is high, and effective and sustained transdermal absorption of DZH is possible, so the effective blood concentration is low. DZ is expensive
Despite the characteristics of H, it has the characteristic of being able to fully express its pharmacological effects.

Furthermore, by using an absorption enhancer in combination, the growth of DZH crystals can be more reliably prevented, and moisture from the skin can be absorbed into DZH.
It further promotes the absorption of DZH into II-containing bases, increases the release and initial absorption of DZH from the base, and further increases transdermal absorption due to its ability to loosen the stratum corneum. , thereby making it possible to further develop the pharmacological effect.

〔Example〕

Examples of this invention are shown below. In addition, the following parts shall mean parts by weight.

Example 1 Four blends consisting of 70 parts of 2-ethylhexyl acrylate (hereinafter referred to as 2EHA), 30 parts of ethyl acetate, and 0.21 parts of azobisisobutyronitrile (hereinafter referred to as AIBN) were charged into a Lof flask. Under an inert gas atmosphere, 60 parts were stirred at a heating temperature of 1°C, and 70 parts of ethyl acetate was added dropwise while maintaining a reaction temperature of 58 to 62°C to react for 12 hours, and further heated to 75 to 80°C. The reaction was carried out under these conditions for 6 hours to obtain a polymer solution with a polymerization rate of 98.8% and a solution viscosity of 350 voids.

Next, 30 parts of D Z H was added to this polymer solution based on 70 parts of the solid content while being dispersed and dissolved in methanol. The solution was applied onto a separator that had undergone release treatment on paper so that the thickness after drying would be 60 μm, and the solution was heated at 120°C.
was dried for 4 minutes to form a drug supply layer. Next, the above-mentioned drug was supplied to the EVA surface of a carrier made of a laminate film of polyethylene terephthalate (hereinafter referred to as PET) and an ethylene-vinyl acetate copolymer (hereinafter referred to as EVA) having a vinyl acetate content of 28% by weight. A pharmaceutical formulation of the invention was obtained by laminating the layers together and pressing with a hot roll.

Example 2 Sodium polyoxyethylene lauryl ether phosphate (DZH) was added to the polymer solution obtained in Example 1.
(hereinafter referred to as AP-2) was blended so that the concentration of DZH in the total solid content was 30% by weight and the concentration of AP-2 was 10% by weight. A pharmaceutical formulation was obtained.

Example 3 100 parts of ethoxyethyl methacrylate (hereinafter referred to as EEMA), 200 parts of ethanol, and A I B N
A fourth flask was charged with 0.25 parts of the formulation, stirred under an inert gas atmosphere at a heating temperature of 60 ± 1'C, and 60 parts of ethyl acetate was added dropwise.
The reaction temperature was maintained at 0 to 64°C for 36 hours to obtain a polymer solution with a polymerization rate of 99.3% and a solution viscosity of 78 voids.

Next, 30 parts of DZH was added to the solid content of 70 parts of this polymer solution while dispersing and dissolving it in methanol. This solution was applied onto a separator made of a polyester film subjected to a release treatment so that the thickness after drying would be 60 μrn, and dried at 80° C. for 6 minutes to form a drug supply layer. Next, 5 μm of acrylic adhesive (butyl acrylate: acrylic acid-95=5 copolymer) was applied as an undercoat layer.
A thickly coated EVA film was used as a carrier, and the above drug supply layer was transferred onto the adhesive surface of the carrier to obtain a pharmaceutical preparation of the present invention.

Example 4 The polymer solution obtained in Example 3 was added with DZH and sodium polyoxyethylene lauryl ether sulfate (hereinafter referred to as
(referred to as AP-1), the concentration of DZH in the total solid content is 3
The pharmaceutical formulation of the present invention was obtained in the same manner as in Example 3.

Example 5 As monomers, 60 parts of methoxyethyl acrylate (hereinafter referred to as MEA) and vinylpyrrolidone (hereinafter referred to as v
A polymer solution was obtained in the same manner as in Example 1, using 40 parts of 40 parts of P. A pharmaceutical preparation of the present invention was obtained by the following procedure.

Example 6 Polyoxyethylene lauryl ether (hereinafter referred to as AP-3) was added to the polymer solution obtained in Example 5 together with DZH, and the concentration of DZH in the total solid content was 30% by weight.
AP-3 was blended so that the concentration was 10% by weight, and the same procedure as in Example 1 was carried out to obtain a 1-preparation drug of the present invention.

Example 7 Isononyl 7 acrylate (hereinafter referred to as i
A polymer solution was obtained in the same manner as in Example 1 using 70 parts of s o N A) and 30 parts of MEA, and to this was added D.
ZH was blended so that its concentration was 30% by weight based on the total solid content, and the same procedure as in Example 1 was carried out to obtain a pharmaceutical formulation of the present invention.

Example 8 AP- was added to the polymer solution obtained in Example 7 together with DZH.
1, the concentration of DZH in the total solid content is 30% by weight, 5f%, AP-
A pharmaceutical formulation of the present invention was obtained by the same procedure as in Example 1.

Example 9 50 parts of 2EHA, 30 parts of MEA, vinyl acetate (hereinafter referred to as V
A mixture consisting of 20 parts of AIB No., 2 parts of ethyl acetate, and 25 parts of ethyl acetate was charged into a fourth flask and stirred at a heating temperature of 60 ± 1 °C under an inert gas atmosphere.
While adding 08.3 parts of ethyl acetate dropwise, the reaction temperature was maintained at 58-62°C for 6 hours, and further at 75-80°C.
The polymerization rate was 90.8% after 4 hours of reaction under heating conditions at ℃.
A polymer solution having a liquid viscosity of 130 poise was obtained.

Next, 30 parts of DZH based on 70 parts of the solid content was added to this polymer solution while being dispersed in methanol. This solution was applied onto a separator made of a polyester film subjected to a release treatment so that the thickness after drying would be 60 μm, and dried at 120° C. for 4 minutes to form a drug supply layer.

Next, 5μ of an acrylic adhesive (butyl acrylate: acrylic acid-95=5 copolymer) was applied as an undercoat layer.
A 30 μm polyethylene film coated to m thickness is used as a carrier, and the above drug supply layer is transferred to the adhesive surface of the carrier.
A pharmaceutical formulation of this invention was obtained.

Example 1O A was added to the polymer solution obtained in Example 9 together with D Z H.
P-3, the concentration of DZH in the total solid content is 30% by weight, AP
-3 was blended so that the concentration was 5% by weight, and the same procedure as in Example 9 was carried out to obtain a pharmaceutical formulation of the present invention.

Example 11 DZ II and AI)-,3 were added to the polymer solution obtained in Example 9 so that the concentration of DZH in the total solid content was 30% by weight and the concentration of AP-3 was 10% by weight. The following procedure was carried out in the same manner as in Example 9 to obtain a pharmaceutical formulation of the present invention.

Example 12 A polymer solution was obtained in the same manner as in Example 9 using 60 parts of 2E HA, 30 parts of MEA, and 10 parts of VAc as monomers, and DZH and AP-3 were added to this to give DZH in the total solid content. The concentration of is 30%, and the concentration of AP-3 is 1%.
A pharmaceutical formulation of the present invention was obtained by the same procedure as in Example 9.

Example 13 DZH and AP- were added to the polymer solution obtained in Example 12.
3, the concentration of D Z H in the total solid content is 40% by weight, A
P-3 was blended so that the concentration was 10% by weight, and the same procedure as in Example 9 was carried out to obtain a pharmaceutical formulation of the present invention.

Example 14 D Z H and AP- were added to the polymer solution obtained in Example 12.
3, the concentration of D Z H in the total solid content is 15% by weight, A
P-3 was blended so that the concentration was 10% by weight, and the same procedure as in Example 9 was carried out to obtain a pharmaceutical formulation of the present invention.

Comparative Example 1 Using 93 parts of 2E[IA and 7 parts of acrylic acid (hereinafter referred to as AA) as monomers, 7 volumes of polymer were obtained in the same manner as in Example 1, and D Z l+ was added to it in a completely solid state. The ingredients were blended at a concentration of 30% by weight per minute, and a pharmaceutical preparation was obtained in the same manner as in Example 1.

Comparative Example 2 D Z f (and AP-
2, the concentration of DZH in the total solid content is 30%, AP-
A pharmaceutical preparation was obtained in the same manner as in Example 1.

Comparative Example 3 Using 35 parts of styrene-isoprene-styrene block copolymer (hereinafter referred to as SIS) and 65 parts of liquid paraffin as a base, D Z H and AI''-3 were added to the solution in the total solid content. They were blended so that the concentration of D Z II was 30% by weight and the concentration of AP-3 was 10% by weight, and a pharmaceutical preparation was obtained according to the procedure of Example 1.

Comparative Example 4 0.3 parts of 1-liglycidyl isocyanurate was added to 15 parts of sodium polyacrylate and 85 parts of water, and D Z II and AP-1 were further added to D Z [
The concentration of AP-1 was 30% by weight, and the concentration of AP-1 was 10% by weight. This mixed solution was applied to the same separator as in Example 3, and a nonwoven fabric laminated with polyethylene was applied to the applied surface. Paste together, seal and package at 40℃ for 24 hours.
A drug supplying layer in the form of a hydrous gel was formed by standing for a period of time to obtain a pharmaceutical preparation.

Using each of the pharmaceutical preparations of Examples 1-14 and Comparative Examples 1-4 as test samples, their performance was compared in 1/1 valence using the following test method IJ:. In addition, among the test samples, those without self-sufficiency were fixed with an adhesive net bandage or surgical tape in the following tests.

Test method〉 Animals used: Rabbits [3 (male) per sample] Pasting time: 24 hours for each sample Extraction method from animal plasma〉 After applying the drug, blood was collected using a heparin-treated syringe at a predetermined time. 2.5 mA was collected; 3. 1 at OOOrpm
Centrifuge for 0 min to obtain plasma. Next, plasma 1.0
mj! Add 50 μl of the internal standard 'ff (15 #g/mff verapamil hydrochloride aqueous solution) to the solution, add 5.0 m +2 t-butyl methyl ether, shake for 5 minutes,
．． Centrifuge for 5 minutes at OOOrpm. After centrifugation L-
Separate the butyl methyl ether phase and add 0.0% to it. IN
Add 200 μl of sulfuric acid, shake for 5 minutes, and then
Centrifuge for 5 minutes at Orpm.

The separated sulfuric acid phase is used as a sample for HPLC.

As the above test results, the maximum blood concentration C□X (μg/
mu>, area on the time-blood concentration curve for 24 hours AUG
(μg-hr/me) and BA, (%) determined by the above comparative method, the type (composition) of the polymer base constituting the drug supply layer of each pharmaceutical preparation, the concentration of DZH (wt%) ) and type of absorption enhancer.

It is shown in the table below along with the concentration (% by weight).

As is clear from the results in the table above, the pharmaceutical preparation according to the present invention has much better percutaneous absorption of DZH than the comparative example, and is able to fully express the original pharmacological effects of DZH. It turns out that there is something.

Claims (1)

[Scope of Claims] (1) Consisting of at least a drug-impermeable carrier layer and a drug supply layer containing a drug in a high molecular weight polymer at a saturation solubility or higher for the polymer; 1. A pharmaceutical preparation, wherein the polymer is at least one selected from the following groups a) to c), and the drug is diltiazem hydrochloride. b) (meth)acrylic acid alkyl ester monomer (
Polymer of a) b) Polymerization or copolymer of monomer (b) having a non-electrolytic group and/or cationic electrolytic group in the side chain c) Copolymer of the monomers (a) and (b) (2) ) The pharmaceutical preparation according to claim (1), wherein the content of diltiazem hydrochloride in the drug supply layer is 5 to 50% by weight. (3) It is composed of at least a drug-impermeable carrier layer and a drug supply layer containing an absorption enhancer in a high molecular weight polymer and a drug having a saturation solubility or higher in the polymer; A pharmaceutical preparation, characterized in that the combination is at least one selected from the following groups a) to c), and the drug is diltiazem hydrochloride. b) (meth)acrylic acid alkyl ester monomer (
Polymer of a) b) Polymerization or copolymer of monomer (b) having a non-electrolytic group and/or cationic electrolytic group in the side chain c) Copolymer of the monomers (a) and (b) (4) ) The pharmaceutical preparation according to claim (3), wherein the content of the absorption enhancer in the drug supply layer is 1 to 15% by weight. (5) Claim (3) or Claim 3, wherein the absorption enhancer is at least one selected from the group of sodium polyoxyethylene lauryl ether sulfate, sodium polyoxyethylene lauryl ether phosphate, and polyoxyethylene lauryl ether. The pharmaceutical preparation described in (4). (6) The content of diltiazem hydrochloride in the drug supply layer is 5 or more.
50% by weight of the pharmaceutical formulation according to any one of claims (3) to (5).