JP3471840B2 - External preparation - Google Patents

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to an external preparation, and more specifically, it contains glycerin monofatty acid ester, alcohols and water in a specific ratio in a formulation, which results in the transdermal absorption of pharmacologically active substances. It relates to a significantly promoted external preparation.

[0002]

BACKGROUND OF THE INVENTION In recent years, an external preparation for transdermal administration has been used for the purpose of systemic administration or local administration of a drug for reasons such as simple application and avoidance of drug metabolism due to first-pass effect. It is often done. However, since various barriers against drugs such as stratum corneum exist on the normal skin surface, when applying or applying such an external preparation to the normal skin surface, or when applying to the damaged skin surface or oral mucosa, It is more difficult to absorb the drug. Therefore, various preparations for promoting absorption of the drug have been made for external preparations intended for transdermal administration of the drug from normal skin.

For example, Japanese Patent Laid-Open No. 64-68314 discloses a transdermal drug administration device using ethanol and glycerol monolaurate as permeation enhancers. However, the permeation enhancer used here has been developed for use in a patch having a specific structure, and is therefore difficult to apply to other dosage forms.

Japanese Patent Laid-Open No. 2-56429 discloses that
Disclosed is an external preparation in which the transdermal absorption of morphine is enhanced by a medium-chain fatty acid monoglyceride. However, since the pharmacologically active substance of this external preparation is limited to morphine, the effect of promoting transdermal absorption is obtained only in combination with morphine. In addition, since the formulation contains a medium-chain fatty acid monoglyceride, which is a surfactant, in a high concentration, there is a problem in skin irritation.

[0005] Conventionally, a technique for promoting percutaneous absorption of a specific drug or promoting drug permeation in a limited dosage form has been known, but the skin permeation of a drug in a wide range of drug / dosage forms is known. The technology for promoting the drug has not been developed yet, and there has been a problem that if the drug or the dosage form is changed, a satisfactory absorption promotion cannot be obtained. Further, there is a problem that the component used as the permeation enhancer has strong skin irritation and lacks safety at the application site. Therefore, it is strongly desired to develop an external preparation capable of safely and sufficiently percutaneously absorbing a target drug without being limited to a specific dosage form.

[0006]

Means for Solving the Problems The present inventors have found that an external preparation containing glycerin monofatty acid ester, alcohols and water in a specific ratio provides a pharmacologically active substance satisfactorily and promptly regardless of its type. Percutaneous absorption, and
We have found that such an external preparation is extremely mild to the skin surface, and completed the present invention.

The present invention thus comprises a pharmacologically active substance,
(A) glycerin monooleate , (b) ethanol and (c) water as essential components, and (a),
The blending ratio of (b) and (c) is based on the total weight of the three: (a) 10 to 20 wt% (c) 30 to 60 wt% (c) 30 to 60 wt% To provide an external preparation.

In the external preparation of the present invention, the dosage form and the pharmacologically active substance can be selected from a wide range according to the purpose, and furthermore, the skin permeation of the drug is rapidly and remarkably promoted without irritating the skin. be able to. Therefore, the external preparation of the present invention is extremely useful in terms of formulation technology.

The present invention will be described in more detail below.

The glycerin fatty acid ester used in the present invention generally includes monoesters of saturated or unsaturated fatty acids having 12 to 20 carbon atoms and glycerin, such as monolauric acid glyceride, monomyristate glyceride and monopalmitin. Monosaturated fatty acid glyceride such as acid glyceride, monostearic acid glyceride, monoarachidic acid glyceride: monopalmitoleic acid glyceride, monooleic acid glyceride, monoricinoleic acid glyceride, monolinoleic acid glyceride, monolinolenic acid glyceride, monoeleostearic acid glyceride,
One kind or two or more kinds selected from monounsaturated fatty acid glycerides such as monoarachidonic acid glyceride can be used in combination. Among them, monolauric acid glyceride or monooleic acid glyceride is preferable, and monooleic acid glyceride is particularly preferable. .

The alcohols are preferably lower alcohols such as methanol, ethanol, propanol and isopropanol, with ethanol being particularly suitable.

The water is not particularly limited, and distilled water or ion-exchanged water used in ordinary pharmaceutical formulations is preferable.

The amounts of (a) glycerin monofatty acid ester, (b) alcohols and (c) water used in the external preparation of the present invention should be varied depending on the type and the type of pharmacologically active substance to be percutaneously absorbed. However, the glycerin monofatty acid ester is (a), (b) and (c)
1-30% by weight, preferably 1-25% by weight, particularly preferably 2-25% by weight, based on the total weight of
Can be used within the range.

Alcohols are generally preferably used within the range of 10 to 80% by weight, based on the total weight of (a), (b) and (c). In particular, glycerin monofatty acid monoglycerin is used as glycerin. When glycerin oleate is used, it is preferably used in the range of 10 to 80% by weight, and when glyceryl monolaurate is used, it is preferably used in the range of 10 to 70% by weight.

Further, water is (a), (b) and (c)
It is generally preferable to use within the range of 10 to 70% by weight, particularly 10 to 70% by weight when glyceryl monooleate is used, and 25 to 50% when glyceryl monolaurate is used. It is preferably used within the range of 70% by weight.

The external preparation of the present invention can be prepared by using glycerin monofatty acid ester, alcohols and water in the above proportions, and adding various pharmacologically active substances depending on the purpose to the mixture and mixing them.

The type of pharmacologically active substance that can be used here is not particularly limited, and various active substances can be used. For example, ethyl benzoate, dibucaine hydrochloride, tetracaine hydrochloride, hydrochloric acid as a local anesthetic. Procaine, lidocaine, etc .: Methyl guaiazulene salicylate as an anti-inflammatory, analgesic, antipyretic, bendazac, indomethacin, glycyrrhetinic acid, ketoprofen, flurbiprofen, ibuprofen, ibufenacku, bufuexamatuc, diclofuenatucum, diclohuenatucu, natriuim, diclofuenaecuku, natriuim, cloquienafuricum, diclofuenaecku, nacloiitum , Fuenbufuen, 4-biphenylenylacetic acid, etc .; analgesics such as morphine, codeine, nalorphine, pentazocine, acetanilide, aminopyrine, etc .; antipruritic agents ictamol, molybdenum Tar, camphor, thymol, diphenhydramine, chlorpheniramine, promethazine hydrochloride, triperenamine, incypendyl, etc .; hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, fluorocinolone acetonide, flumethasone pivalate, fluocinonide as adrenocortical hormones. , Fluorometholone, beclomethasone propionate, dexamethasone, dexamethasone sodium phosphate, dexamethasone acetate, fludroxocortide, petamethasone valerate,
Betamethasone dipropionate, triamcinolone acetonide, prednisolone, methylprednisolone, methylprednisolone acetate, diflucortron valerate, clobetatal propionate, amcinonide, halcinonide, prednisolone valerate acetate, hydrocortisone butyrate, epinephrinene as catecholamines and catecholamines. Isoproterenol, etc .; phenedramine, ehuedrin hydrochloride, etc .; belladonna alkaloids, atropine sulfate, scopolamine hydrobromide, etc .; sulfamonomethoxine, sulfamethizole, etc. as sulfa drugs; penicillins as antibiotics,
Cephalosporins, erythromycin, tetracycline hydrochloride, minocycline, carbapenems, chloramphenicol, streptomycin, etc .; naphthomate, clotrimazole, etc. as antifungal agents; 5-fluorouracil, cyclophosphamide, as antineoplastic agents,
Busulfan, actinomycin, etc .; hypnotics, barbital, thiopental, etc .; psychotropic agents, chlorpromazine, reserpine, chlordiazepoxide, etc .; antiparkinsonian diseases, chlorzoxacin, levodopa, etc .; cardiotonic agents, digitoxin, digoxin, etc .;
Procainamide hydrochloride, propranolol hydrochloride, etc. as antiarrhythmic agents; dipyridamole, amyl nitrite, etc. as antianginal agents; reserpine, guanethidine sulfate, etc., as antihypertensive agent; paraaminobenzoate ester, etc. as UV inhibitor; melanin formation Examples include hydroquinone, vitamin C esters, para-hydroxycinnamate, etc. as inhibitors; 8-methoxypsoralen, disranol, etc. as therapeutic agents for psoriasis; other herbal medicine ingredients, vitamins, moisturizers, keratin softeners, etc. You can

The amount of these pharmacologically active substances to be compounded is not particularly limited and can be varied over a wide range according to the type of the active substance and the degree of activity, and
In the external preparation of the present invention, good percutaneous absorption can be obtained regardless of whether it is in a dissolved state or a suspended state.
Generally from 0.01 to 50% by weight, preferably from 0.05 to 30% by weight, particularly preferably with respect to the total weight of the above (a) glycerin monofatty acid ester, (b), alcohols and (c) water. It can be blended in a proportion of 0.1 to 20% by weight.

Further, the external preparation of the present invention may further contain, if necessary, bases and additives commonly used in pharmaceutical science, such as, for example,
Hydrophilic petrolatum, purified lanolin, water-absorbing ointment, hydrous lanolin and other water-absorbing bases; hydrophilic ointment and other hydrophilic bases; macrogol ointment and other water-soluble bases; liquid paraffin, cetanol,
Oily bases such as beeswax and isopropyl myristate; natural water-soluble polymers such as starch, pullulan, gum arabic, tragacanth, gelatin, dextran, methylcellulose, ethylcellulose, carboxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose; carboxyvinyl polymer, carboxy Synthetic water-soluble polymers such as methylcellulose sodium, polyacrylic acid (sodium), polyvinyl alcohol, polyvinylpyrrolidone; humectants such as glycerin, propylene glycol, sorbitol, polyethylene glycol; gelling agents such as dihydroxyaluminum aminoacetate; purified water Soybean lecithin, purified hydrogenated egg yolk lecithin, glyceryl monostearate, propylene glycol monostearate, Emulsifiers such as reglycerin fatty acid esters, sorbitan fatty acid esters, polyethylene glycol fatty acid esters, polyoxyethylene (hardened) castor oils, polyoxyethylene alkyl ethers; stabilizers such as sodium edetate; tartaric acid, lactic acid, A pH adjusting agent such as diisopropanolamine; one or more preservatives such as paraoxybenzoic acid esters and sorbic acid can be blended, whereby,
Preparation in the form of tinctures, liquid sprays, lotions, ointments, creams, gels, sols and aerosols, and further spreading them on tapes, non-woven fabrics, etc. to make butps, plasters and tapes. You can also

The blending ratio of the above-mentioned bases and additives is not particularly limited, and they can be blended in accordance with the prescription examples of the external preparations that are usually practiced in pharmaceutics. Among them, (a) glycerin monofatty acid ester,
The total weight of (b) alcohols and (c) water is preferably at least 20% by weight or more, and particularly preferably 40% by weight or more, based on the total weight of the preparation.

When the external preparation of the present invention is prepared, it is not necessary to use (a) glycerin monofatty acid ester, (b) alcohols and (c) water in an integrated mixed state in advance, It suffices if they are appropriately compounded in the preparation step and contained in the resulting formulation in the above-mentioned specific compounding ratio.

For example, when only the pharmacologically active substance is added to the above-mentioned (a) glycerin monofatty acid ester, (b) alcohols and (c) water, glycerin monofatty acid ester, alcohols, water and pharmacologically active substance are used respectively. The external preparation of the present invention obtained by mixing in an appropriate amount can be directly applied to the skin surface or sprayed.

The creams, gels and patches are
It can be prepared according to a formulation method known per se, and can be produced, for example, according to the method described in the production examples below.

As described above, the external preparation of the present invention contains glycerin monofatty acid ester, alcohols and water in specific proportions as essential components. If this external preparation is used, it can be selected from a wide range. The selected pharmacologically active substance can be rapidly and efficiently transdermally administered. Further, the external preparation of the present invention does not lose the effect of promoting the percutaneous absorption of the pharmacologically active substance even if the base or additive other than the above-mentioned three components is blended. Furthermore, the external preparation of the present invention is extremely mild to the skin surface to which it is applied.

The external preparation of the present invention having the excellent characteristics as described above is extremely useful in the field of pharmaceutical technology for transdermal or topical administration of drugs.

Hereinafter, the present invention will be described more specifically with reference to Examples, pharmacological tests and formulation examples, but it goes without saying that the present invention is not limited to these descriptions.

[0027]

Examples 1 to 8 Glycerin monolaurate (lauric acid: carbon number 12) was used as glycerin monofatty acid ester (GMFE), and ethanol and water were mixed in various ratios shown in Table 1 below, Add 1% of propranolol hydrochloride to this mixture.
In addition to the weight percentage, the external preparation of the present invention (Example 1
~ 8) were prepared.

Examples 9-18 Glycerin monofatty acid ester (GMFE) glycerin monooleate (oleic acid: carbon number 18, double bond 2) was used, and ethanol and water were added to each of them as shown in Table 2 below. Propranolol hydrochloride was added to the mixture at a ratio of 1% by weight to prepare external preparations (Examples 9 to 18) of the present invention.

Example 19 Glycerin monooleate (oleic acid: C18, double bond 2) was used as glycerin monofatty acid ester (GMFE), and ethanol and water were mixed in the proportions shown in Table 3 below. Then, 4-biphenylylacetic acid was added to this mixture in an amount of 2% by weight to prepare an external preparation of the present invention (Example 19).

Example 20 Glycerin monooleate 10% by weight, ethanol 60
% Of water and 30% by weight of water were mixed, and hydrocortisone butyrate was added to this mixture so as to be 1% by weight to prepare an external preparation of the present invention (Example 20).

Example 21 Glycerin monooleate 10% by weight, ethanol 60
% By weight and 30% by weight of water were mixed, and lidocaine hydrochloride was added to this mixture so as to be 1% by weight to prepare an external preparation of the present invention (Example 21).

Example 22 Glycerin monooleate 10% by weight, ethanol 60
The external preparation of the present invention (Example 22) was prepared by mixing 30% by weight of water and 30% by weight of water and adding 2% by weight of diclofenac sodium to the mixture.

Example 23 Glycerin monooleate 10% by weight, ethanol 60
% By weight and 30% by weight of water were mixed, and promethazine hydrochloride was added to this mixture so as to be 1% by weight to prepare an external preparation of the present invention (Example 23).

Example 24 Glycerin monooleate 10% by weight, ethanol 60
% By weight and 30% by weight of water were mixed, and amyl nitrite was added to this mixture so as to be 5% by weight to prepare an external preparation of the present invention (Example 24).

[0035]

[Reference Examples] Reference Examples 1 to 9 Glycerin monolaurate (lauric acid: carbon number 12) was used as glycerin monofatty acid ester (GMFE), and ethanol and water were mixed at various ratios shown in Table 1 below, Propranolol hydrochloride was added to each mixture in an amount of 1% by weight to prepare external preparations (Reference Examples 1 to 9).

Reference Example 10 Glycerin monooleate (oleic acid: carbon number 18, double bond 2) was used as glycerin monofatty acid ester (GMFE), and ethanol was mixed with it at various ratios shown in Table 2 below. Then, propranolol hydrochloride was added to the obtained mixture so as to be 1% by weight to prepare an external preparation (Reference Example 10).

Reference Example 11 Ethanol and water were mixed in the proportions shown in Table 3 below,
To this mixture, 4-biphenylylacetic acid was added so as to be 2% by weight to prepare an external preparation (Reference Example 11).

Reference Examples 12 to 22 Monocaprylic acid glycerin (caprylic acid: carbon number 8) was used as glycerin monofatty acid ester (GMFE), and ethanol and water were mixed at various ratios shown in Table 4 below, Propranolol hydrochloride was added to each mixture in an amount of 1% by weight to prepare an external preparation (Reference Examples 12 to 22).
Was prepared.

Reference Examples 23 to 28 Glycerin monocapric acid (capric acid: carbon number 10) was used as glycerin monofatty acid ester (GMFE), and ethanol and water were mixed in various ratios shown in Table 5 below, Propranolol hydrochloride was added to each mixture in an amount of 1% by weight to prepare an external preparation (Reference Examples 23 to 28).
Was prepared.

Reference Example 29 Glycerin tricaprylate 50% by weight, ethanol 50
% By weight and 1% by weight of propranolol hydrochloride were mixed to obtain an external preparation (Reference Example 29).

[0041]

[Pharmacological Test] Skin Permeability Test (1) Method: Franz type diffusion cell (effective diffusion area: 3.14c) of the abdominal excised skin of a female hairless rat.
m ² ), the test sample is on the stratum corneum side, and the pH is 7. on the dermis side.
0 of 1/30 M isotonic phosphate buffer was added to evaluate the permeability of the drug in the test sample. Permeability was determined by quantifying the drug in the buffer with time using HPLC, and the flux value (μg / cm ² /
hr) was calculated and compared.

As test samples, 1 g each of the external preparations of the present invention obtained in Examples 1 to 18 and the external preparations obtained in Reference Examples 1 to 28 were used.

Results: (1) The results of Examples 1 to 8 and Reference Examples 1 to 9 are the following first
Shown in the table.

[0044]

[Table 1]

As is clear from the above results, the external preparation of the present invention showed good skin penetration of propranolol hydrochloride.

(2) The results of Examples 9 to 18 and Reference Example 10 are shown in Table 2 below.

[0047]

[Table 2]

As is clear from the above results, the external preparation of the present invention showed remarkable skin permeation of propranolol hydrochloride.

(3) The results of Example 19 and Reference Example 11 are shown in Table 3 below.

[0050]

[Table 3]

As is apparent from the above results, the external preparation of the present invention showed remarkable skin permeation of 4-biphenylylacetic acid.

(3) Table 4 shows the results of Reference Examples 12 to 22.

[0053]

[Table 4]

(4) Table 5 shows the results of Reference Examples 23 to 28.

[0055]

[Table 5]

Skin Permeability Test (2) Method: Using the external preparation of the present invention obtained in Example 12 and the external preparation of Reference Example 29 as test samples, the external preparation was applied to the skin and then the drug The time (lag time) until the start of permeation was compared. The test was carried out by a method according to the above-mentioned “skin permeability test (1)”.

Results: The results are shown in Table 6 below.

[0058]

[Table 6]

As is clear from the above results, the external preparation of the present invention markedly shortened the time until the skin permeation of the drug started.

Skin irritation test Method: 1 g of the test sample was applied to the inner part of the upper left arm of 5 adult males, left for 6 hours, and then rinsed with water to confirm whether there was any abnormality in the applied part.

Results: When the external preparation of the present invention (Example 12) was used as a test sample, no abnormality such as redness was observed in the applied part. On the other hand, Reference Example 1 as a test sample
When 0 external preparation was used, redness was observed in 2 subjects.

From the above results, it is clear that the external preparation of the present invention has extremely low skin irritation.

[0063]

[Production Example] Production Example 1: Cream hydrocortisone acetate 1.0 g liquid paraffin 10.0 g cetanol 5.0 g beeswax 5.0 g isopropyl myristate 5.0 g glyceryl monostearate 3.0 g polyoxyethylene (20) cetyl ether 2 0.0 g Glycerin monooleate 10.0 g Propylene glycol 5.0 g Ethanol 25.0 g Purified water 29.9 g Methylparaben 0.1 g Liquid paraffin 10.0 g, Cetanol 5.0 g, Beeswax 5.0 g, Isopropyl myristate 5.0 g, Glycerin monostearate (3.0 g), polyoxyethylene (20) cetyl ether (2.0 g) and glyceryl monooleate (20.0 g) are heated to 80 ° C. and dissolved to form an oil phase. On the other hand, hydrocortisone acetate (1.0 g), propylene glycol (5.0 g), purified water (29.9 g) and methylparaben (0.1 g) were heated to 80 ° C. and dissolved to form an aqueous phase. The aqueous phase was gradually added to the oil phase with stirring, and the mixture was cooled to 30 ° C. with stirring to obtain a cream.

Formulation Example 2: Gel agent 4-biphenylylacetic acid 1 g Carboxyvinyl polymer 1 g Diisopropanolamine 2 g Glycerin monooleate 5 g Ethanol 40 g Propylene glycol 10 g Purified water 41 g 4-Biphenylyl acetic acid 1 g Purified water 10 g, ethanol 40 g, monoolein It is dissolved in a mixed solution of 5 g of acid glycerin and 20 g of diisopropanolamine. To 1g of carboxyvinyl polymer dispersed in 31g of purified water,
The above mixed solution and 10 g of propylene glycol were added, and the mixture was stirred until it became uniform to obtain a gel agent.

Formulation Example 3: Adhesive patch Propranolol hydrochloride 1.0 g Sodium polyacrylate 8.0 g Sodium carboxymethyl cellulose 2.0 g Dihydroxyaluminum aminoacetate 0.7 g Glycerin 27.0 g Glycerin monooleate 10.0 g Tartaric acid 0.5 g Purified water 30.6 g Ethanol 20.0 g Sodium edetate 0.2 g Sodium polyacrylate 8.0 g, carboxymethyl cellulose sodium 2.0 g, dihydroxyaluminum aminoacetate 0.7 g and glycerin 27.0 g
To prepare a glycerin dispersion liquid. Separately, 0.5 g of tartaric acid and 1.0 g of propranolol hydrochloride were added to purified water 3
After dissolving in a mixed solution of 0.6 g and ethanol 25.0 g,
Add this to the glycerin dispersion and stir until uniform. The obtained mixture is spread on a non-woven fabric, and a releasable plastic film is laminated and then cut into a predetermined area,
A sheet-shaped patch was obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP-A-4-234314 (JP, A) JP-A-3-109321 (JP, A) JP-A-2-207018 (JP, A) JP-A 1- 290616 (JP, A) (58) Fields surveyed (Int.Cl. ⁷ , DB name) A61K 47/14 A61K 9/06 A61K 9/08 A61K 9/70 A61K 47/10

Claims (2)

(57) [Claims] 1. A pharmacologically active substance and (a) monooleic acid.
Glycerin , (b) ethanol and (c) water are contained as essential components, and the compounding ratio of (a), (b) and (c) is based on the total weight of the three: (a) 10-20 % By weight (c) 30 to 60 % by weight (c) 30 to 60 % by weight An external preparation characterized by the above-mentioned. 2. (a) Glycerin monooleate ,
The external preparation according to claim 1 , wherein the total weight of (b) ethanol and (c) water is at least 20% or more based on the total weight of the preparation.