JPS6277316A - Medicinal member for external use - Google Patents

Abstract

PURPOSE:A medicinal member for external use, obtained by specifying molecular weight and molecular weight distribution of an acrylic copolymer laminated on a carrier and having improved percutaneous absorbability of a drug contained in the above-mentioned copolymer. CONSTITUTION:A medicinal member for external use obtained by adjusting the number-average molecular weight (Mn) of an acrylic copolymer, preferably a copolymer consisting of 10-60wt% alkyl (meth)acrylate having preferably ether group in the molecule thereof and 40-90wt% alkyl (meth)acrylate to 90,000-250,000 and ratio (Mw/Mn) of (Mn) to the weight-average molecular weight (Mw) to 6-12 in a medicinal member consisting of a laminate obtained by incorporating a percutaneously absorbable drug in the above-mentioned acrylic copolymer and directly forming on a carrier or indirectly forming thereon through an undercoating member. Thereby, the solubility and diffusivity of the drug in the above-mentioned copolymer are improved to remarkably enhance the absorption efficiency of the drug from the integument and/or mucosa.

Description

[Detailed description of the invention]

(a) Industrial application field The present invention provides a method for controlling the molecular weight and molecular weight distribution of an acrylic copolymer formed on a carrier to a specific range. Transdermal drug delivery 1
The present invention relates to a medicinal component for external use that has improved absorbability. (b) Prior Art Conventionally, the following are known as external medicinal components containing a transdermally absorbable drug and absorbing this into the body through the skin. The first external medicinal component is one in which a transdermal absorbable drug is dissolved or dispersed in an acrylic homopolymer or an acrylic copolymer (hereinafter referred to as an acrylic polymer) having pressure-sensitive adhesive properties. . Further, the second external medical member is the first external medical member 1.
This drug contains additives such as transdermal absorption promoting agents and drug solubilizers. (c) Problems to be Solved by the Invention However, in the above-mentioned first topical medical component, the solubility and diffusion rate of the drug in the acrylic compound may not be sufficient, and the drug may not be absorbed in the body. hope for

[7] There were cases where the therapeutic effect could not be expected due to poor absorption or absorption. Further, although the second external medical device is an improved version of the first external medical device, it has the following problems. Transdermal absorption promoting aids improve drug absorption by modifying the skin surface, or allow drugs to be absorbed through the skin along with the transdermal absorbable drug. There are some promoting aids that have safety problems with regard to the development of stinging properties and the in vivo absorption of the transdermal absorption promoting aids themselves, and their selection is complicated. In addition, many of the above-mentioned transdermal absorption promoting aids and solubilizers exhibit their effects when added in large amounts, resulting in a decrease in cohesive force and a blooming phenomenon due to the plasticizing effect of the acrylic copolymer. There is a so-called "adhesive residue" phenomenon in which the acrylic copolymer remains on the release paper or the skin surface to which it is applied, and the acrylic copolymer protrudes from the side surface of the medicinal product for external use [
In some cases, a secondary extrusion phenomenon may occur, causing γrj staining on the skin surface and externally used medicinal materials. In addition, a chemical interaction between the additive and the drug may cause a chemical reaction of the drug, which may cause problems such as inactivation of the drug. (d) Means for Solving the Problems The present inventors have conducted extensive research into the relationship between various acrylic polymers and the transdermal absorption of drugs, and have found that:
We have discovered that acrylic copolymers are preferable for improving the transdermal absorption of drugs, and that there is a correlation between the transdermal absorption of drugs and the molecular weight and molecular weight distribution of the acrylic copolymers. An application has already been filed for the application of this to indomethane, which is an anti-inflammatory agent.
1). As a result of subsequent research, the present inventors obtained the knowledge that even when this acrylic copolymer was applied to other transdermal absorbable drugs, excellent effects could be obtained by 9U, leading to the completion of the present invention. It is something that That is, the present invention provides a laminate in which a transdermally absorbable drug is contained in an acrylic copolymer, and this is formed directly on a carrier or indirectly through a coating member, the number of the acrylic copolymers being Average molecular weight is 90.000-250.000
, and the number average molecule ffi (Mn) and the weight average molecule f
The ratio (M ar / M n) to fi (M + u) is 6 to 1
2. The acrylic copolymer used in the present invention is preferably one that can be attached with adhesive force when applied to the skin surface.
In order to further increase the utilization rate by improving the solubility of the drug and its release from external pharmaceutical components, (meth)acrylic acid esters having an ether group in the molecule and (/ri)acrylic acid alkyl esters are recommended. A copolymer with is more preferably used. (Meth)acrylic acid esters having an ether group in the molecule improve the solubility of drugs in acrylic copolymers, and also improve the solubility of drugs in acrylic copolymers due to the electron 17 nature of the ether group. It has the characteristic of improving the diffusion rate of drugs in the interior. Specific examples of (meth)acrylic acid esters having an ether group in the molecule include tetrahydrofurfree-
acrylate, tetrahydrofurfuryl methacrylate, meloxypolyethylene glycol acrylate,
Methoxypolyethylene glycol/tafrylate, Nidoxin' ethylene glycol acrylate, butoxynoethylene glycol acrylate, butylene glycol acrylate, butylene glycol methacrylate, methoxyethyl acrylate, methoxyethyl methacrylate, 3-ethoxypropyl acrylate, ethoxyethyl acrylate, ethoxyethyl methacrylate, Examples include butoxyethyl acrylate, butoxyethyl methacrylate, and the like. In addition, the (meth)acrylic acid alkyl ester used in the present invention is a component that imparts adhesiveness and cohesiveness to the externally used pharmaceutical member of the present invention, and specifically, (meth)acrylic acid having 4 to 14 carbon atoms. Alkyl esters, such as ropetyl acrylate, 1]-butyl 7-tacrylate, hexyl acrylate, 2-ethylbutyl acrylate,
Examples include inoctyl acrylate, 2-ethylhexyl acrylate-1,2-ethylhexyl methacrylate, ethylene acrylate, decyl methacrylate, dodecyl acrylate, dodecyl methacrylate, tridecyl acrylate, tridecyl acrylate, tetradecyl acrylate, and tetradecyl methacrylate. be able to. The preferred blending ratio of the above-mentioned (meth)acrylic acid ester (A) having an ether group in the molecule and the (meth)acrylic acid alkyl ester (B) is the above-mentioned (A).
It is desirable to adjust the amount of (A) to be in the range of 10 to 60% by weight based on the entire mixture of (A) and (B), and if (A) is less than 10% by weight, it may not be good for skin adhesion. However, it has poor cohesive force and may cause contamination of the skin adhesive surface.
Problems arise such as the effect of combining the ingredients is not sufficiently expressed. On the other hand, when (A) is 130 inffi% or more, the fg decomposition and release properties of the drug are good, but (
B) This is not preferable because the blending ratio of the component is reduced, which may result in poor skin adhesion. Apart from the present invention, the acrylic copolymer includes the above-mentioned (
J (not limited to polymers of A) and (13), other acrylic or vinyl polar monomers copolymerized with the above (A) and (13) (referred to as eyebrows, bottoms, and C) ) is also included. Specific examples of the above (C) include (meth)acrylic acid, itafonic acid, maleic acid, maleic anhydride, hydroxyethyl acrylate, hydro Examples include functional monomers such as quinpropyl acrylate, acrylamide, and trimethylacrylamide, and polar monomers such as vinyl esters such as acrylonitrile, vinyl acetate, vinyl propionate, vinylpyrrolidone, and vinylcaprolactam, and these monomers may be used alone or in combination. The above (C) is used in combination with the above (A) and (B).
) and (C) is preferably in the range of 10 to 40% by weight. The most significant feature of the present invention is the number average molecular weight (Mn
) is 90.000-250.000, and the ratio of the number average molecular weight (M n ) to the weight average molecular weight (MW) (
M III/M n ) is in the range of 6 to 12. The above-mentioned number average molecular weight (hereinafter simply referred to as Mn) and weight average molecular weight (hereinafter simply referred to as M-) are values obtained by calculating the average molecular weight in terms of polystyrene by GPC using polystyrene as a reference material. If the Mn value exceeds the above range, the cohesive force of the acrylic copolymer may become high, resulting in poor skin adhesion, and the diffusion and movement of the drug is likely to be inhibited. This is not preferable because the initial release amount may decrease or the transdermal absorption amount may decrease.Also, if Mn is less than the above range, the diffusion mobility of the drug will increase and the utilization rate may improve. However, on the other hand, the cohesive force of the acrylic copolymer becomes poor, which causes undesirable problems such as contamination of the skin surface and misalignment after application when used as a topical medicine key for application to the skin. On the other hand, if the value of M I A / M n exceeds 12,
Because the cohesive force decreases, the external medicinal material is separated from the outer skin.
When the acrylic copolymer is removed, a portion of the acrylic copolymer remains on the skin, which is undesirable because it causes discomfort to the user. The present invention also includes the above-mentioned acrylic copolymer,
If the M u+ / M n value is less than 6, the drug release properties and skin adhesion properties will be poor. If it is within the range! ! f
ft+ polymer alloys are also included. The acrylic oligomer has a number average molecular weight of 70
Acrylic oligomers having a molecular weight of 0 to 5,000 are preferably used, such as Plus Size L-201 (acrylic acid ester low polymer, number average molecular weight about 1,500: manufactured by Gooh Kagaku Kogyo Co., Ltd.), Plus Size L-3C) 1 (acrylic acid ester low polymer, number average molecular weight approximately 2.500; Gooh Kagaku Kogyo Co., Ltd., polymerization of monomers such as the above-mentioned (meth)acrylic acid alkyl esters in the presence of 18 Glynor) Examples include acrylic oligomers obtained by In the case of 20 ff, the blending ratio was too low and no particular effect was observed.
If it exceeds 1Bi%, the cohesive force decreases, so that a part of the acrylic copolymer may remain on the skin tFt when peeled from the skin, which is not preferable. The transdermal absorbable drug used in the present invention is not particularly limited as long as it is a drug that is absorbed in the body and excludes indomethacin. Examples of such drugs include the following. b) Flutifosteroids: For example, hydrofutisone, prednisolone, beclomethasone probionate, flumethacin, triamcimerone, triamci/ronacetonide, fluocimerone, fluocimerone acetonide,
Fluoxy/lonacetonide acetate, clobetasol propionate, etc.; oral) analgesic anti-inflammatory agents: e.g. acetamide/phen, mefenamic acid, flufenamic acid, diclo-7ena, noclofena/cunatrium, alclofena/li, oquin-7-embutazone, phenyl butacin, iafuro7ene, flurbipro7ene, salicylic acid, methyl salicylate, r-
Menthol, Kan7a, Slingunk, Tolmetin Sodium, Naf. Loxene, fenbufen, etc. (excluding indomethacin), c) Hypnosedatives: e.g. 7e7barbital, amobarbital, cyfrobarbital, triazolam, nitrazepam, lorazepam, halobe 17F-1, etc., 2) Tranquilizers: e.g. Flufenamic acid, teolitanone, noazepam, flunoazebam, flunitrazebam, haloperidol, chlorpromazine, etc. e) Antihypertensive agents: e.g. croninone, croninone hydrochloride,
Pindolol, propranolol, propranolol hydrochloride, 17-70-l, indenolol, nivanovin, nimodipine, lonzenoxin, nidorenzvin, nibranol, bucumolol, nifedipine, etc.) Antihypertensive diuretics: e.g. hydrothiazide, pendroflumethiazide, cyclobenziazide g) Antibiotics: e.g. penicillin, tetracycline, etc.
Oxytetracycline, 7-radiomycin sulfate, erythromycin, chloramphenicol, etc.; 1) Anesthetic agents, such as lidocaine, nobucoin hydrochloride, pensicaine, ethyl aminobenzoate, etc.; 3) Antibacterial substances: such as penzalfnium hydrochloride, 7) Antifungal substances: such as pentamycin, amphoterine B, pyrrolniF, clotrimazole, etc.; l) Vitamins: such as vitamin A, ergocalciferol, calciferol, octothiazine, riboflavin butyrate, etc., 2) Anti-epileptic drugs: e.g. nitrazepam, /probamate, clonazepam, etc. 4) Coronary vasodilators: e.g. nitroglycerin, nitroglycol, insorbido nonitrate, erythritol tetranitrate. , pentaerythritol tetranitrate, probatyl nitrate-F, etc.) Antihistamines: for example, noaenhydramine hydrochloride,
chlorpheniramine, nophenylimixol, etc. ii) Antitussives: e.g. dextromethorphan hydrobromide, terbutasone sulfate, ephedrine, ephedrine hydrochloride, salbutamol sulfate, isoproterenol hydrochloride, isoprotelemer sulfate, etc. ri) Sex hormones: e.g. propsterone, nistranol, etc.) Anti-inflammatory agents: e.g. doxebin) Cerebral circulation reforming agents: e.g. hydergine, ergonto alkaloids, iaen-7-lonol, etc.; t) Anti-emetics, anti-ulcer agents: e.g. metoclopramide, clebopride, etc. tonperiton, sufboramine, sufboramine hydrobromide, etc.) Biopharmaceuticals: For example, polypeptides (TRH, Ll-
(derivatives of RH), prostaglandins, etc., etc.: For example, 7-entanyl, novoxin, desmobrecin, 5-fluorouracil, mercaptopurine, etc.
Two or more of these drugs can be used in combination if necessary. The blending ratio of the drug is desirably adjusted to be 0.01 to 30% by weight, preferably 2 to 20% by weight, based on the total weight of the acrylic copolymer and drug. The drug-containing acrylic copolymer obtained as described above can be used as a plastic film/sheet, rubber and/or synthetic resin foam sheet/film, or piece, paper, nonwoven fabric, cloth, flexible metal foil, or a laminate thereof. Directly on a carrier such as a film or sheet, or an undercoat member that does not contain drugs,
For example, it is formed indirectly on the entire surface or in part through a pressure-sensitive adhesive layer mainly made of rubber and/or synthetic resin. The formation method is to create a drug-containing acrylic material (such as emulsion polymerization or heavy liquid polymerization), coat it directly on the carrier or indirectly through an undercoating material, and dry it. Alternatively, method 7) may be employed, such as coating a drug-containing acrylic copolymer solution on a release liner in advance and drying it to form a film, and then transferring it onto a carrier. (e) Effect In the present invention, the molecular weight distribution of the acrylic copolymer is defined as 1, ? By changing the range, the solubility of the drug in the acrylic copolymer may be improved, or the diffusibility of the drug in the acrylic copolymer or the release of the drug from the acrylic copolymer may be improved. The reason why the release properties are excellent is not clear, but adjusting the molecular weight distribution to a relatively wide range may affect the viscosity τ of the acrylic copolymer, and it may also be possible to create a fairly strong electricity between the drug and the acrylic copolymer. Is this due to interaction between dipoles or hydrogen bonding between the drug and acrylic copolymer? 1; The liquid state is stabilized, and it is presumed that these factors influence each other, resulting in excellent solubility, diffusibility, and release of the drug. (f) Examples Hereinafter, the present invention will be explained in detail with reference to Examples, but the present invention is not limited thereto. In the text, parts or % are all units of weight conversion. The molecular weight is a value obtained by measuring the molecular weight by GPC using polystyrene as a reference material and converting it into polystyrene. Example 1 Inoctyl methacrylate 80 parts 2-ethoxyethyl acrylate 20 parts Benzoyl oxide
0.1 part ethyl acetate
25 parts The above formulation was charged into a 4-mouth, 7-glass tube, diluted by dropping ethyl acetate under an inert gas atmosphere, and the temperature of the outer tank was adjusted to achieve a reaction temperature of 60 to 63° C. 1: Polymerization by heating for 4 hours while controlling the reaction temperature. and further aged at 80°C for 3 hours, Mn 180,000, Mud/Mn = 7,
Dissolution of the acrylic copolymer of No. 8) [(solid content 30%) was obtained. Diazepam, a tranquilizer, is added to this acrylic copolymer solution, and Dissolve I! Then, apply this onto the release liner to a dry thickness of 40 μm and hold it at 80°C.
and dried for 7 minutes. By bonding and transferring this onto a polyethylene film, the external medical member of the present invention is obtained. The amount of diazepam, a tranquilizer, added was adjusted to 400 μg/cm 2 at the above thickness. Comparative Example 1 The same procedure as in Example 1 was carried out except that the aging time was changed to 1 hour.
Obtain a solution of the acrylic copolymer of 5.2. A medicinal material for external use was obtained by the same operation as in Example Y. Example 2 2-ethylhexyl acrylate 60 parts 2-methoxyethyl acrylate 40 parts Azobisisobutyronitrile 0. ethyl lemmate
25 parts of the above mixture was charged into a fourth flask, and the mixture was heated for 4 hours to polymerize while controlling the reaction temperature to 60-63°C by diluting by dropping ethyl acetate under an inert gas atmosphere and adjusting the external temperature. , further aged at 80°C for 4 hours, Mn 135,000, M W / M n = 9
. Solution of acrylic copolymer of No. 7 (solid content 3097; )
get. Clonidine, an antihypertensive agent, was blended and dissolved in this acrylic copolymer solution, and this was applied to the allllll Biliner so that the thickness after drying was 40 μm.
Dry at 0°C for 5 minutes. This is bonded to a polyethylene film and transferred to obtain the external medicinal member of the present invention. The amount of clonidine, which is an antihypertensive agent, added was adjusted to 100 μB/cw2 at the above thickness. Comparative Example 2 The same procedure as in Example 2 was carried out except that the aging time was changed to 7 hours. Mn95,000, M+u/Mn=13.5
Acrylic copolymers also yield solutions. Thereafter, the same procedure as in Example 2 was performed to obtain a medicinal material for external use. Example 3 In Example 2, flurbipro-7ene, which is an analgesic and anti-inflammatory agent, was added to the polymer solution of IHI acrylic-based No.
Peel this off and add the liner to a thickness of 40 μm after drying.

[
Apply it so that it is self-adhesive and dry it for 5 minutes at 1°C.
did. By attaching this to a polyester film and transferring it, 7U of the externally used medicinal member of the present invention is obtained. In addition, the amount of flurbiprofen added in Nail 1 Persimmon 2 No. 11 Flame Cutting is 3! so that it is 200 μg/cJ at the above thickness! I have adjusted it. Example 4 2-ethyl \quinle acrylate 5 parts 2-methoxyethyl acrylate 25 parts Vinyl acetate
25 parts azobisisobutyronitrile 0.1 part ethyl acetate
25 parts Four of the above formulations were placed in a flask, and the reaction temperature was controlled at 60 to 63°C by diluting by dropping ethyl acetate under an inert gas atmosphere and adjusting the external temperature.
Polymerize by heating for 4 hours, then ripen at 80°C for 4 hours,
Mn No. 10,000, Mw/hri! 1=8. A solution of the acrylic copolymer No. 7 (solid content: 30%) was obtained. Flurbiprofen, an analgesic and anti-inflammatory agent, was mixed and dissolved in this acrylic copolymer solution, and this was applied onto the release liner to a dry thickness of 30 μm.
It was dried at 00°C for 5 minutes. By attaching this to a polyester film and transferring it, the external medicine part of the present invention is obtained. The amount of flurbiprofen, which is an analgesic and anti-inflammatory agent, was adjusted to 200 μg/cI at the thickness. Comparative Example 3 The same operation as in Example 4 except that the aging time was changed to 2 hours, Mn 230,000, Muh/Mn = 4,
A solution of the acrylic copolymer No. 2 (solid content: 30%) was obtained. Thereafter, a medicinal material for external use was obtained by the same operation as in Example 4. Example 5 A solution of acrylic copolymer (solid content 30
%), 5 parts of an acrylic acid ester low molecular weight compound (number average molecular weight approximately 1,500, trade name Plus Size L-201; manufactured by Gooh Kagaku Kogyo Co., Ltd.) was added and mixed, based on 85 parts of the solid content. A solution (solid content 30%) of an acrylic copolymer with Mn 145,000 and Mud/Mn = 7.0 is obtained. Following the same procedure, flurbipro 7, an anti-inflammatory agent, was prepared.
A pharmaceutical component for external use of the present invention containing ene is obtained. Example 6 Insorbide dinitrate, a coronary vasodilator, was blended and dissolved in the acrylic copolymer solution obtained in Example 2, and this was spread on a release liner to a thickness of 40 μm after drying. It was applied and dried at 100°C for 5 minutes. This was bonded to a polyester film and transferred to obtain the external medical member of the present invention. The amount of insorbide nonitrate, which is a coronary vasodilator, was adjusted to 800 μg/et02 in step 17 above. Comparative Example 4 The acrylic copolymer solution obtained in Comparative Example 2 was subjected to the same procedure as in Example G to prepare 40 medicinal components for external use. Table f51 shows the test results of Examples 1 to 6 and Comparative Examples 1 to 4. Table 1 f in Table 1 and measuring force method! "L Ai Naokan" IV - 疋 - F 1 - Method -: Hair was removed from the back of a white rabbit weighing 2.3 mm using clippers and an electric razor, and the hair was cut into 5 c+o The external medicinal members of Examples and Comparative Examples were pasted. Paste it 2°/1. , 7 , 24 After opening IIS, blood was collected from the ear vein, and plasma was collected by centrifugation. The drug was extracted from this plasma and quantified using a gas chromatograph equipped with an electron r+tl capture model. In addition, the measurement results are summarized as AU C (A leu Undcr the
Curve, indicated by nB・1st/+nl. [''1: When measuring the blood concentration above, when the drug-containing acrylic copolymer on the carrier does not remain on the rat skin surface at all when each externally used medicinal member is peeled off, the drug-containing acrylic copolymer is ○. A case where the substance became stringy and remained partially on the skin surface was rated as ×. Drug Utilization Rate 2 In the above blood concentration test, the remaining drug in each peeled external medical member was extracted 24 hours after application, and the remaining amount was quantified using high performance liquid chromatography. In addition, the initial content was determined using the same fabrication method for the unattached external medicinal materials. The utilization rate was calculated using the following formula. As is clear from the test results of each Example and each Comparative Example shown in Table 1, the AUG and drug utilization rates of the external pharmaceutical components of each Example are significantly improved compared to the Comparative Example, and It is acknowledged that effective use of drugs is being achieved. (8) Effects of the Invention The external pharmaceutical component of the present invention has a specific molecular weight and molecular weight distribution of the acrylic copolymer that dissolves the drug, thereby improving the solubility and diffusibility of the drug in the copolymer. As a result, the absorption efficiency of the drug from the integument and/or mucous membrane is significantly improved. In addition, although the medicinal material for external use of the present invention improves the solubility and diffusibility of the drug contained therein, it is not necessary to add a drug solvent or a transdermal RYI absorption promoting aid (hereinafter referred to as an auxiliary agent, etc.). Therefore, problems that arise when using adjuvants, such as skin irritation, in-vivo behavior and safety of adjuvants, etc., or chemical interactions between adjuvants and drugs, can be avoided. There is no need to consider problems such as effects, and the effect is such that it can be used with peace of mind.

Claims (3)

[Claims] (1) A laminate in which a transdermally absorbable drug is contained in an acrylic copolymer and this is formed on a carrier directly or indirectly through an undercoat member, wherein the number average molecular weight of the acrylic copolymer is 90,000 to 250,000, and the ratio of the number average molecular weight (Mn) to the weight average molecular weight (Mw) (Mw/Mn) is 6 to 12. (2) The above acrylic copolymer has an ether group in the molecule (meth)acrylic acid alkyl ester 10 to 6
0% by weight and (meth)acrylic acid alkyl ester 40~
Claim 1, which is a copolymer consisting of 90% by weight
External medicinal components described in Section 1. (3) The acrylic copolymer contains 80 to 99.5% by weight of the acrylic copolymer and 0.5 to 99.5% by weight of the acrylic oligomer.
20% by weight of a polymer alloy for external use according to claim 1.