JPS60199832A - Antioxidative pharmaceutical preparation for external use - Google Patents

Abstract

PURPOSE:To prepare the titled preparation minimizing the oxidative decomposition reaction of the drug and the substrate material, by compounding a substrate containing a drug for transcutaneous absorption with powdery polymer having phenolic hydroxyl group. CONSTITUTION:A substrate containing a drug for transcutaneous absorption (e.g. corticosteroid, analgesic and anti-inflammatory agent, hypnotic sedative, tranquillizer, hypotensive drug, anesthetic, etc.) is compounded with 2X10<-4>-2wt%, preferably 5X10<-4>-5X10<-1>wt% powdery polymer having phenolic hydroxyl group [e.g. the compound of formula (X is OH, methyl, methoxy, etc.; R is H or t-butyl) and having a molecular weight of about 1,000-9,000]. The obtained drug for external use is preferably used in the form of ointment, suppository, poultice, liniment, lotion or tape. A tape is one of extremely desirable drug forms from the viewpoint of the improvement in the effective utility of the drug and the simplicity of application.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to an external preparation for percutaneously administering a transdermally absorbable drug into the body. External preparations containing anti-oxidants as much as possible are desirable.Depending on the dosage form, the base substance may be a hydrophilic ointment base, an oleaginous ointment base, an oily substance, or a com-based polymer. It is used in a wide variety of substances, and most drugs also have active functional groups such as hydroxyl groups, carboxyl groups, and amino groups, making them difficult to use during the manufacture of external preparations and long-term storage. Sometimes, the above-mentioned base or drug undergoes oxidative decomposition reactions due to oxygen in the air, trace amounts of metal compounds, peroxides, radicals, etc., often leading to deterioration phenomena and a decrease in the pharmacological activity content of the drug.

In order to prevent the above-mentioned oxidative decomposition reactions, amine antioxidants and phenolic antioxidants have been conventionally added and used, but while they have the desired effect, they have problems with absorption in the body, which has become important in recent years. In view of this situation, as a result of extensive research, we have found that powdered polymeric substances that contain phenolic hydroxyl groups are used as base materials and drugs used in various external preparations. It was discovered that the polymer substance is not absorbed transdermally even if the oxidative decomposition reaction is prevented and a large amount is added, leading to the present invention.

That is, the present invention provides an antioxidant preparation for external use, which comprises a base containing a transdermally absorbable drug and a powdered polymeric substance having a phenolic hydroxyl group. The powdered polymeric substance is a repeating unit of the following formula (where X is selected from the group of hydroxyl group, methyl group, methoxy group, t-buterme, 4-hydroxyphenylisopropyl group). shi, R is a hydrogen atom or t
-butyl group. ,) with a molecular weight of about 1000~
This is an anti-oxidant external preparation containing 9,000 ingredients.

The powdered polymeric substance having phenolic hydroxyl groups that can be used in the external antioxidant preparation of the present invention exhibits the same action structure as generally known phenolic antioxidants, but because it has a high molecular weight. It is not absorbed into the body and is therefore sufficiently safe from chronic toxicity, acute toxicity, and other safety issues. There is no particular restriction on such a powdered polymeric substance as long as it has a phenolic hydroxyl group and is solid at room temperature, but a powdered substance is preferable for ease of use during compounding, and more preferably hydroxyanisole, t −
A repeating unit of the following formula having a structural unit of butylhydroquinone, t-butylphenol, bisphenol A1 para-cresol ←However, X is a hydroxyl group, methyl group, methoxy group, t-butyl group, 4-hydroxyphenylinopropyl R is a hydrogen atom or a t-butyl group. ) has a molecular weight of approximately 1000
~9000 polymeric substances are satisfactory in terms of antioxidant ability and safety.

The polymer substance is a phenolic antioxidant having the above-mentioned repeating unit, and is made to have a high molecular weight through an ortho-alkylation condensation reaction with dihinylbenzene to make it difficult to absorb into the body, and the molecular weight is = 100+i is the most effective as it exhibits the most antioxidant properties, so it should be used at 2X10' to 2xi% based on the base containing the transdermal drug.
More preferably, it is blended in a range of 5×10 4 to 5×1° per cent.

The percutaneously absorbable drug that is not included in the antioxidant topical preparation of the present invention is one that is absorbed transdermally into the body and exerts a pharmacological effect when the topical preparation is applied to the outer skin or mucous membranes. If available, local drugs 1' may also be systemic drugs, such as a) corticosteroids; for example, hydrocorticin, bledonibrone, beclomethasone probionate, flumetazosi, triamcinolone, triamcinology; Acetonide, fluocinolone, fluocinolone ace1-
0) Mn anti-inflammatory agents: such as acetaminophen, mefenamic acid, flufenamic acid, indomethacin, diclofenac, diclofenac sodium, alclofenac, oxyfecibutazone, phenylbutasone, ifprofen, flurhyprofecin, salicylic acid, meral zalitate, l-menthol, casifer, sulindac, tolmetin sodium, naproxen, fenbufen, etc.; c) drowsiness sedatives; for example, phenoharhiquur, amobalhital, 2) Tranquilizers, such as fluphenazine, teoritazine, diazepam, flunitrasepam, and chlorpromazine; 3) Antihypertensive agents, such as clonidine, clonidine hydrochloride, etc.
pindolol, propranolol, propranolol hydrochloride, bufranol, indenolol, bucumolol, nifedipine, etc.; f) antihypertensive diuretics; for example, hydrocytazine, pendrifluna thiazide, g) anti-4L drugs; ↓; Examples include penicillin, tetracycline, xytetracycline, frasiomycin sulfate, erythromycin, and chloramphenicol.

h) Anesthetics such as ``Niji 1'', such as ``Niji 1'', Bensof Jin, 7-minobenzoic acid ether, etc.

b) Antibacterial substances; for example, benosarkonium chloride, nitrofurasone, buistatesi, acetosulfamine, clotrimassol anide; g) Antibacterial substances; for example, pentamycin, amphotericin B1, virolni-1-rino, clotrimasol, etc.

Nori Vitamin preparations such as vitamin A1 ergocalciferol, cholecalciferol, octothiazine, riboflavin butyrate, etc.

w) Anti-epileptic drugs; e.g. nitrazepam, mebropamate, clonase, !:', w) coronary vasodilators; e.g. 21-lochrycerin, nitroglycol, isosolhydrinitrate, erythritol tetranitrate, penta Erythritol tetranayate] rate,
Proparal nitrate, etc.) Antihistamines; such as diphenhydramic acid hydrochloride, chlorpheniramine, diphenylimitazole; E) Antitussives; such as dextromethorphan, tilbutamine, ephedrine, ephedrine hydrochloride, etc. Sex hormones: e.g. progesterone, estradiol, etc.; c) Antibiotics: e.g. doxepin; c) Others; e.g. 5-fluorouracil, dihydroergotamine, fentanil, desmopressin, dicoxi, metoclopuraside, domperid, scopolamine, scopolamine hydrobromide, etc. Two or more of these drugs can be used in combination as necessary. The amount of the above drug added varies depending on the target treatment and/or administration effect.
Pharmacologically, it is necessary to have a melon effect, but approximately 0. A range of O1 to 15 i% is desirable.0 The base containing the transdermal absorbable drug is a substance that does not form the main body of the antioxidant external preparation of the present invention, and the base is selected. The following formulations were selected for use as external preparations: soft tablets, suppositories, buffs, liniments, lotions, and tapes. It is desirable to select 1゜ as the ointment according to the present invention, oleaginous cartilage, hydrophilic and water-absorbing ointment using oils, waxes, hydrocarbons, etc.
Either an emulsion ointment using Macropool or a water-soluble ointment using Macropool etc. can be used, and it can be manufactured by kneading a transdermal absorbable drug and a phenolic hydroxyl group with a commercially available powdered polymeric substance. I can do it.

For suppositories, mix thoroughly with bases such as cacao butter, macrogol, glyceroceratin, etc., add surfactants as necessary, make external preparations with a melting point of around 35°C, and store by solidifying at low temperatures) and use it.

A poultice agent based on hagelatin, cellulose ethers, gum arahia, 4-component comb, polyacrylic acid or its metal salt, etc., and a powdered polymeric substance capable of absorbing transdermal drugs and phenolic hydroxyl groups, and as necessary. and add water 1
After sufficiently mixing, it can be spread on a base fabric such as cloth.

Liniment agents and lotions are made by adding drugs and powdered polymeric substances in a solution state to a liquid such as water or ethanol, and using a surfactant or suspending agent as necessary to form a micro-uniform milk powder. It can be made into a liquid preparation for external use by curing or suspending it, and can be rubbed or applied to the skin or mucous membranes for daily use.

As a tape agent, a polymer material that is sticky at room temperature, such as natural rubber, synthetic rubber, acrylic thread, silicone comb thread, etc., is placed on a carrier such as a plastic film that has virtually no moisture permeability. The above-mentioned drug and a powdered polymer substance free of phenolic hydroxyl groups are blended into the drug, and additives such as a tackifying resin, an oily substance, a filler, a transdermal absorption promoting substance, and a release aiding substance are added as necessary. It can be manufactured by laminating the blended adhesive I4), and is always one of the desirable dosage forms in terms of improving the effective utilization rate of the drug and convenience.

Since the antioxidative external preparation of the present invention has the above-mentioned structure, it contains a powdery compound containing phenolic hydroxyl groups. Molecular substance 1
The human antioxidant effect suppresses oxidative decomposition and oxidative virilization of transdermal absorbable drugs and base materials, and also has non-bioabsorbability, which is one of the excellent properties of the powdered polymer material. This has the effect of providing highly safe topical preparations that are improved for men and women, even if they have problems such as toxicity.

In the following, production examples and working examples of the present invention will be shown and explained in detail, but the present invention is not limited to these, and various applications are possible without departing from the technical idea of the present invention. . In addition, parts in the text mean parts by weight.

Production Example 1 In a 16 flask, 0.8 g of metal aluminum, 12.7.9 (0.12 mol) of baracresol, and 6 xylene were added.
01 was added, stirring was continued until no hydrogen gas was generated, and after the reaction was completed, 50 g (0.4 mol) of hydroxyanisole, 22.9' (0.13 mol) of t-butylhydroquinone, and 22.9 mol of bisphenol A were added. l (0.1 mol), -butylphenol 37.5. li' (0.25 mol) and 150 me xylene were added, and then divinylbenzene (line 80%) 162i 1 mol) was added dropwise with stirring.
A small amount of xylene was added to clean the walls. Next, the internal temperature was heated to 125°C, stirred, and gradually raised to 140-150°C while continuing the polymerization reaction, and the reaction was carried out for about 2 hours. After the reaction was completed, the internal temperature was cooled to 60°C or higher, and the reaction product was extracted with diethyl ether.
C washing and finally dehydration with anhydrous sodium sulfate.

The resulting dry diethyl ether solution fL2 as precipitant
Add 0 times the amount of If-hexane, precipitate the polymeric substance with phenolic hydroxyl groups, over-separate it, and pulverize the molecular substance to the dried product obtained by over-separating it with IA to remove the phenolic hydroxyl groups. A powdered polymeric material having an average molecular weight of 8,500 was obtained.

Production Example 2 HydrodiFcyanisole used in Production Example 1, t-butylrenone, bisphenol A, t-butylpheno-)L/(f″all-C-butylated hydroxytoluene (
2,6-di-tert-butyl-p-fresol) was used, and a powdered polymeric substance with an average molecular weight of 5800 containing phenolic hydroxyl groups was added using the same procedure as in Production Example 1.

Example 1 (Ointment) The phenolic hydroxyl group obtained in Production Example 1 was added to 100 parts of an indomethacin-containing ointment base consisting of 1 part of indomethacin, 5 parts of glycerin, 30 parts of stearyl alcohol, and 9264 parts of rough. 0.1 part of a powdered polymeric substance was blended to obtain an antioxidant external preparation containing indomethacin.

Example 2 (Poultice) 5 parts of monoglycol salicylate, 25 parts of styrene-isoprene-styrene block copolymer, 1 part of liquid paraffin
7.5 parts, polybutene 2.5 parts, rosin resin 25 parts,
Titanium white 17.5 parts, sorbitan monooleate 2.5 parts
0.5 part of the powdered polymeric substance having a phenolic hydroxyl group obtained in Production Example 2 was blended with 100 parts of a poultice base containing monoglycol salicylate and 5 parts of water. After cross-mixing, true-melt coating was applied to one side of a polyester nonwoven fabric at 120° C. to a thickness of 150 μm to obtain an antioxidant external preparation containing monoglycol salicylate.

Example 3 (Lotion) 100 parts of 5-fluorouracil-containing lotion base consisting of 4.5 parts of 5-fluorouracil, 30 parts of ethanol, 1.5 parts of lauryl sulfate, 5 parts of glycerin, and 60 parts of water. Against,! ! ! In example 2? 1/'
Powdered polymeric substance containing phenolic aqueous group and acid group0.
Two capitals? C-Dissolved 10 parts of the 7j ethanol solution was gradually blended with strong stirring to uniformly disperse the 5-nor.
[1 Uracil-containing LR-forming topical preparation]
Example 4 (Tape) Acrylic acid 2-ethylhexyl ester 9 (1 part).

A monomer mixture consisting of 10 parts of anlylic acid was solution-polymerized in ethyl acetate (solvent) using 0.2 parts of azobisisobutyanitrile as an initiator to obtain a copolymer solution.

- 1η and chopped into 100 parts of solid content of IC copolymer solution and 51. 01 parts of IJ powder-like polymeric substance (obtained in step 1/contains phenolic hydroxyl). A clonidine-containing anti-oxidant external preparation was obtained by coating and drying it to a thickness of 40 μm.

Comparative examples 1 to 4 Comparative examples 1 to 4 are rounded up to Examples 1 to 4, and all C name examples except for the secret powdered polymer having a phenolic hydroxyl group are excluded from each example. The external preparation was prepared by performing the same procedure as 1t3J.

The external preparations obtained in Examples 1 to 4 and Comparative Examples 1 to 4 were stored in a thermostat at 40°C for 6 days, and the decomposition rate of the self-weighting drug was calculated by W and l. The results are shown in Table 1. Indicated.

Detailed table *) The decomposition rate was calculated using the following formula.

In addition, when the external preparations prepared in Examples and Comparative Examples were applied to the skin, they all showed sufficient pharmacological effects in the treatment of diseases.

patent applicant Nitto Electric Industry Co., Ltd. Representative: Tsuchi Chikara, Department 3

Claims (1)

[Scope of Claims] 1) An antioxidative external preparation comprising a base containing a transdermally absorbable drug and a powdered polymeric compound having a phenolic hydroxyl group. 2) Powdered polymer O having a phenolic hydroxyl group has approximately 9 units of the following formula (4kl L% In one selected type, R is a hydrogen atom or a t-butyl group. ) with a molecular weight of approximately 1000
9,000 to 9,000. 3) The antioxidant according to claim 1, wherein the dosage form of the antioxidant external preparation is one selected from the group of ointments, suppositories, poultices, linimetics, lotions, and tapes. External preparations.