JPS60149531A - Durative pharmaceutical preparation for local purposes - Google Patents

Abstract

PURPOSE:The titled composition that is obtained by adding a specific vehicle and a cationic surface active agent to an aqueous medium containing pharmaceutically active ingredients, thus showing increased absorption of the active ingredients through skins and mucosas. CONSTITUTION:The objective durative preparation for local purposes is obtained from 0.005-0.5wt% of a cationic surfactant, 0.001-60wt% of active ingredients such as antiseptic, sulfa drug, local anesthetic, hemostatic, angiotonic, antitussive, expectorant, hormone drugs, cell activators, antibiotics, nonsteroidal anti- inflammatory, steroid drugs, herb drug, endobiotic dermatopathy drug, enzyme preparation or local stimulant, and a vehicle dispersion containing at least one of ethoxylates selected from polyoxyethylene castor oil ether and polyoxyethylene hydrogenated castor oil ether and 3-30pts.wt. per 100pts.wt. of the ethoxylate, of long-chain fatty acid sorbitol polyester.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention provides sustained release properties by increasing the adsorption of medicinal ingredients to the skin, mucous membranes, etc. and improving their retention, thereby sustaining the medicinal efficacy over a long period of time. The present invention relates to a topical layer composition. In more detail,
The present invention relates to a long-lasting topical layer composition in which specific vesicles are blended with a cationic surfactant in an aqueous medium containing a medicinal ingredient to increase adsorption of the medicinal ingredient to the skin, mucous membranes, etc. It is.

It has been known that amphiphiles form vesicles, or endoplasmic reticulum, in water, and for example, vesicles and vesicles such as liposomes made of phospholipids and ufasomes made of unsaturated fatty acids also exist in natural products. . Since loincloth vesicles are a stable dispersion, they are being applied to cosmetics, pharmaceuticals, etc. However, the naturally occurring vesicles mentioned above are expensive, even if they have no safety issues. Therefore, it was unsuitable for mass consumption.

However, recently, vesicles using nonionic surfactants, ie, nioseems, have been discovered, and vesicle dispersions can be formed from easily available raw materials, for example, with the general formula % (where R is the number of carbon atoms). 12 to 30 fatty hydrocarbon groups, n
is an integer from 1 to 6) Formation of vesicles by a nonionic surfactant (JP-A-52-6375), an ethylene oxide adduct of glycerin dialkyl ether and an ethylene oxide adduct of myristate stearylamide Formation of vesicles (J, C!oloid engineering n-terfaCe
SCl, I'', Volume 82, No. 2, Nos. 401-417
page) etc. have been reported.

On the other hand, it is known that polyoxyethylene hydrogenated castor oil ether and polyoxyethylene sorbitol tetraoleate form concentric lamellar liquid crystals ('
Japan Chemical Magazine”, 1981, No. 11, No. 1691~
1696 pages).

By the way, vesicles can be said to be a special form of concentric lamellar liquid crystal, and the difference is that the surfactant forms a bimolecular membrane or a multilayer membrane, and a substantial hydrophilic cavity is formed inside the vesicle, allowing water to flow through the vesicle. Or it contains an aqueous solution. Therefore, in order to form this vesicle, it is necessary to orient the surfactant molecules so as to form a lamellar bilayer film having a curvature that facilitates the formation of vesicles.

However, although the polyoxyethylene hydrogenated castor oil ether forms a concentric lamellar liquid crystal, 1. As is well known, since it is a mixture of multiple compounds with different numbers of added moles of ethylene oxide, the state of the concent-linked liquid crystal it forms is not uniform, and no clear vesicle structure is observed.

The present inventors conducted extensive research in order to develop a vesicle dispersion using a surfactant that is approved for use in foods and cosmetics by public institutions and is easily available. By using nonionic polyoxyethylene castor oil ether or polyoxyethylene hydrogenated castor oil ether as a surfactant, and adding sorbitan polyester, which is a long chain fatty acid, at a predetermined ratio, the surfactant can be We found that vesicles can be easily formed by orienting them with a curvature that facilitates vesicle formation.As a result of further research to put this vesicle to practical use, we found that this vesicle can be easily formed in the coexistence of a cationic surfactant. In this study, we discovered that the adsorption to the skin and mucous membranes increases, and therefore, when incorporated into a topical preparation, it has a sustained release property with high retention.Based on this knowledge, we have developed the present invention. Ta.

That is, the present invention provides (a) cationic surfactant 0;
'005~0.5% by weight, (b) Effective amount of medicinal ingredient, (
c) (A) at least one ethoxylate selected from polyoxyethylene castor oil ether and polyoxyethylene hydrogenated castor oil ether; and (B) 3 to 30 parts by weight per 100 parts by weight of this ethoxylate. The present invention provides a long-acting topical composition comprising a vesicle dispersion of a long-chain fatty acid sorbitan polyester.

The ethoxylate used as component (A) of the composition of the present invention is polyoxyethylene castor oil ether or haphoryoxyethylene hydrogenated castor oil ether, which has a structure represented by the general formula. .

These ethoxylates may be used alone or in combination of two or more, and the average number of added moles of ethylene oxide (A+m+n+x+y in the above formula)
+z) is preferably in the range of 7 to 20, particularly 8 to 15.

Regarding the long 'JA fatty N sorbitan polyester used as component (B) in the vesicle dispersion of the present invention, those whose long chain fatty acid residues have 14 to 18 carbon atoms;
Particularly preferred are those from 16 to 18. The degree of esterification is preferably in the range of 2.5 to 3.5, particularly preferably in the range of 2.8 to 3.2. Examples of such substances include sorbitan tripalmitate, sorbitan triolate, sorbitan tallow fatty acid triester, and the like.

The ratio of component (A) and component <El) in the composition of the present invention is 3 to 30 parts by weight of component (B) per 100 parts by weight of component (A).
It is safe to keep the value within the range of 10, preferably 10.
It ranges from 0:5 to 100:25.

When component (A) is used alone, concentric lamellar liquid crystals are formed, but no vesicle formation is observed by electron microscopy.

However, when a small amount of component (B) is added, the surfactant is oriented with a curvature that facilitates the formation of vesicles, and vesicles are formed. When the ratio of component (A) to component (B) is within the above range, almost all of the aggregates formed by the surfactant used will form vesicles. Further, a preferable range is selected in consideration of the stability of the vesicle and the ability of the supported wings to retain the medicinal ingredient. In addition, the content of component (A) and component (B) is 0.1 to 5% based on the total amount of the composition.
A range of 0% by weight is desirable, and a range of 1 to 35% by weight is more preferred.

Next, in the composition of the present invention, examples of the cationic surfactant to coexist with these vesicles include benzalkonium chloride, benzethonium chloride, alkylpyridinium salts such as cetylpyridinium ammonium chloride, palmityl, stearylamine, hardened Long-chain alkylamines with 14 to 22 carbon atoms such as tallow alkylamine and salts thereof, and 14 to 22 carbon atoms such as civalmitylamine, distearylamine, and dicured tallow alkylamine.
di-long-chain alkyl amines and their salts, mono-long-chain alkyl tri-short-chain alkyl type quaternary ammonium salts such as palmityltrimethylammonium salt, stearyltrimethylammonium salt, oleyltrimethylammonium salt, hardened tallow alkyltrimethylammonium salt, etc. , dialkyl type quaternary ammonium salts having two alkyl groups having 14 to 22 carbon atoms, such as distearyldimethylammonium salt, dihardened tallow alkyldimethylammonium salt, bishydroxyethylstearylamine, bishydroxyethyl hardened tallow alkylamine, Alkylene oxide adducts of long chain alkyl amines with 14 to 22 carbon atoms such as polyoxyethylene stearylamine and salts thereof, and quaternized products of cyclized dehydration products of stearic acid and hydroxyethylethylenediamine with 14 to 22 carbon atoms. Examples include 2-alkyl-substituted imidazolinium salts having an alkyl group.

Moreover, the medicinal ingredient that can be included in the composition of the present invention is not particularly limited, and may be any medicinal ingredient that is commonly used as a medicinal ingredient in ordinary topical preparations. As such medicinal ingredients, for example, those shown below are used.

(1) Disinfectant benzalkonium chloride, benzethonium chloride, cetylpyridinium chloride, chlorhexidine, chlorhexidine gluconate, palmityltrimethylammonium chloride, thymol, decanium chloride, thimerosal, mercurochrome, flotine silver, chloramine, sodium hypochlorite, Potassium chlorate, iodine, sodium iodide, iodo tincture, povidone-iodine, iodoform, oxidol, potassium permanganate, sodium perborate, ethanol, impropatol, phenol, cresol, bithionol, acrinol, mayy-lurosaniline chloride, nitrofurazone, Resorci, N, Domifuene Bromide, Tego 51. Biosol, chlorobutanol,
Salicylic acid, hexachlorophene, benzyl alcohol, benzoic acid, creosote, acriflavine, phenyl salicylate, sodium N-lauroylsarcosinate, berberine chloride, berberine sulfate.

(2) Sulfa drugs homosulfamine, sulfamine, sulfisoxazole, sodium sulfisoxazole, sulfamethoxazole, sulfisomidine, sulfadiazine, sodium sulfisomidine, sodium sulfamethoxazole.

(3) Local anesthetics dibucaine hydrochloride, procaine hydrochloride, hexocaine hydrochloride, benzyl alcohol, ethyl aminobenzoate, pensicaine, tetracaine hydrochloride, tecaine hydrochloride, lidocaine, lidocaine hydrochloride, mepivacaine hydrochloride, pvircaine hydrochloride, salt 112 cocaine , katacaine hydrochloride, propitocaine sulfate, butadicaine hydrochloride, oxybutanicaine hydrochloride, meprilputanicaine hydrochloride, salt cough piperoin, chlorobutanol, mepril tyroin hydrochloride, evirocaine hydrochloride, thecaine.

(4) Hemostatic agent, vasoconstrictor Naphazoline nitrate, phenylethaline hydrochloride, naphazoline hydrochloride, tetrahydrozoline hydrochloride, oxymetazoline hydrochloride, dramazoline hydrochloride, ephedrine, thrombin, calcium gluconate, calcium chloride, calcium aspartate, cyclonamine, chloride Ferric iron, ε-aminocaproic acid, tranexamic acid, carbazochrome, sodium carbazochrome sulfonate, adrenochrome monoaminoguanidine sodium methanesulfonate, rutin,
Hesveridin, methylephedrine, methylephedrine hydrochloride, hinokitiol, shrimp dihydrocholesterin.

(5) Antihistamines, antiallergic agents crotamiton,
Tonzylamine hydrochloride, diphenhydramine hydrochloride, methosilazine hydrochloride, glomethazine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, chlorpheniramine, chlorpheniramine maleate, tesittecitin, isothipendyl hydrochloride, diphenhydramine, ibroheptine hydrochloride, diphenylimidazole.

(6) Antitussive and phlegm preparation, asthma treatment Methyl ephedrine hydrochloride, ephedrine hydrochloride, noscapine, codine phosphate, dextromethorphan, oxolamine, tipevidine, methylephedrine, isoproterenol, chlorophyllin, salbutamol, trimethoquinol, nokuno Kuberine, aminophylline, penproperine, apomorphine, emetine, pilocarpine, cysteine, turpentine oil, eucalyptus oil, guaiacol.

(7) Vitamins lecithin, nicotinamide, ergocalciferol, calciferol, tocopherol, tocopherol acetate, ictamol, retinol acetate, retinol palmitate, vantothenyl ethyl ether, riboflavin butyrate, thiamin oil, cicapril, pyridoxine, ascorbic acid, Pyridoxine hydrochloride, riboflavin, calcium pantothenate, dianocobalamin, vitamin A1 (
Retinol, water-soluble vitamin A1 dextrinol, flavin adenine dinucleotide.

(8) Hormone agents estradiol benzoate, hexestrol, methyltestosterone, glopion and testosterone.

(9) Cell activator azulene, water-soluble azulene, chlorophyllin, sodium chondroitin sulfate, urea, aminoethyl sulfonic acid, allantoin, L-asunolagin-sugar potassium, L-
Asparagine, magnesium potassium, chlorophyll,
Sodium copper chlorophyne, sodium guarenate,
Potassium guaiacol sulfonate.

Alpha antibiotics chloramphenicol, temethylchlortetracycline LM, fradiomain sulfate, tricomycin, clotrimazole, bacitracin, colistin sulfate, colistin sodium methanesulfonate, lactobioerythromycin.

(11) Non-steroidal anti-inflammatory agents glycyrrhizic acid, flufenamic acid, mefenamic acid, indomethacin, methyl salicylate, glycol salicylate, dipotassium glycyrrhizin, Glyter, phenylbutacin.

02 Steroids hydrocortisone, dexamethasone, betamethasone, prednisolone, methylprednisolone, hydrocortisone acetate, dexamethasone acetate, betamethasone walerate, triamcinolone acetonide, fluoromethasone, betamethasone.

(To) Herbal medicines, Chinese herbal medicines Rosemary extract, Corydalis extract, Powou extract, Shinshu extract, Licorice extract, Amber extract, Shoma extract, Carrot extract, Bellflower extract, Chamomile tincture, Ephedra extract, Angelica extract, Orensis extract, Bellflower root extract, Safflower extract , aloe extract,
Ratania tincture, Myrrh extract, Clove oil, Cinnamon oil, Auronicum extract, Cannabis extract, Angelica extract, Peony extract, Capsicum extract, Capsicum tincture, Ardioxa, Safflower extract, Kouka extract, Rohto extract, Mokukinbi tincture, Hinokitiol,
Sanshin infusion, Soju tincture, Citrus extract, Eucalyptus oil, Sanfuron powder extract, Cucumber extract, Guiou extract, the above extracts, and plant oleoresins used in tinctures.

a→ Parasitic skin disease therapeutic agents simazole hydrochloride, thianthol, nystatin, haloglodin, undecylene chloride, phenyl iodo undedinoate, bisdepotassium acetate, tolnaftate, griseofulvin, pyronidrine, cytucanin.

Qf9 Enzyme preparations dextranase, lysozyme chloride, amylase, lipase, protease.

(To) Local irritants camphor, d-borneol, caffeine, menthol, tannic acid, ictamol, nonyl-aromatic vanillylamide.

Q71 Peptic ulcer therapeutic agent Methylmethionine sulfonium chloride, pipetanate hydrochloride, L-glutamine, impramide iodide, histidine hydrochloride, oxasein, sulpiride, urogastrone, sucralfate, aldioxa, gelphanate, glycyrrhizin, sodium guarenate, chlorbenzoxamine hydrochloride, Penchenate bromide, glycopyrronium bromide (t), parasympathomimetic agent neostigmine methyl sulfate.

Q-moan hair tonic Capronium chloride.

These medicinal ingredients may be used alone or in combination of two or more, if necessary.

In addition, when using a cationic surfactant such as benzalkonium chloride, benzethonium chloride, or cetylpyridinium chloride, which itself can be a medicinal ingredient, it is especially important to avoid adding other medicinal ingredients. It is also possible to prepare a desired coating composition without using the coating composition.

The amount of these medicinal ingredients added varies depending on the site and symptoms, but is usually 0.001 to 6% based on the total amount of the composition.
It is selected within the range of 0% by weight.

There are no particular restrictions on the method for preparing the composition of the present invention, and for example, component (A), component (B), component (A), etc.
- A method in which water is added to a mixture of the cationic surfactant and the component (b), that is, the medicinal ingredient.

A method in which a mixture of components (A), <B), (a) and (b) is added to water and mixed. An aqueous solution in which component (B) was dissolved in advance was mixed with (→component, (B) component and (
b) A method of adding and mixing ingredients to a mixture. Alternatively, it can be carried out by adding and mixing an aqueous solution in which components (A) and (B) are dissolved into a mixture in which components (A) and (B) are mixed in advance. Moreover, it can also be prepared according to an addition order other than these.

The vesicle dispersion thus obtained can be diluted to any concentration as desired and used.

The composition of the present invention is such that substantially all of the aggregates formed by the surfactant used form vesicles, has long-term stability, and is inexpensive and safe. Moreover, since it uses a surfactant substance that is easily available, it has the advantage of being extremely practical.

Furthermore, the composition of the present invention has the following characteristics, so it can be used as a topical bactericidal disinfectant, a purulent disease treatment, a topical analgesic, an antipruritic agent, an astringent, an anti-inflammatory agent, a skin disease treatment agent, and a skin disease treatment agent. It is suitable as a softening agent, a hair preparation, a dental or oral treatment agent, a nasopharyngeal liniment, an eye drop, a gastrointestinal system treatment agent, and the like.

(1) The medicinal ingredient is retained and stabilized inside the vesicle (aqueous phase) or within the membrane, or both.

(2) Because the membranes that make up vesicles have a structure similar to cell membranes, they have strong interaction with biological membranes and have excellent adsorption to biological tissue, and can remain on the biological surface for a relatively long time, The active ingredients incorporated into the membrane are also well absorbed into the body.

(3) Because the vesicles are cationized, they have high adsorption and retention properties even in areas that are wet with blood, body fluids, water, etc., or areas where they are flowing, and are easily released by washing with water. Never.

(4) Vesicles are more stable than emulsions (including microemulsions and multiphase emulsions);
It exists stably even in dilute solutions.

Although vesicles are basically confirmed by observation using an electron microscope (visual judgment, photography, etc.), some estimation can be made based on the presence or absence of crossed Nicols under a polarizing microscope.

Next, the present invention will be explained in more detail with reference to Examples.

Example 1 Polyoxyethylene hydrogenated castor oil (average number of added moles of ethylene oxide + o) c+r, sorbitan trioleate 11 and benzethonium chloride 0.22 were mixed, and naphazoline hydrochloride 0.11. Zipcaine hydrochloride 0. An external application composition was prepared by adding 0.22% of chlorpheniramine hemaleate and 0.17% of allantoin, and adding ethanol and water to make the total amount 100%.

The composition obtained in this way was diluted 50 times with water, and 8.0 m7 of the composition was diluted with water. into a test tube9, add keratin powder 0.11 to this, shake for 2 minutes, and then mix at 3000 r.
After centrifugation at pm for 5 minutes, the content of medicinal ingredients in the supernatant was measured.

Next, 8 rnl of tap water was added to the remaining keratin powder layer, stirred for 2 minutes, centrifuged again, and the content of medicinal ingredients in the resulting supernatant was measured.

After repeating water washing and centrifugation three times in this way,
At each time, the amount of adsorption and retention on the keratin powder was calculated from the amount of each medicinal ingredient in each supernatant.

On the other hand, as controls, benzethonium chloride o, 21, naphazoline hydrochloride 0.11F, dibucaine hydrochloride o, i y
.

A solution was prepared by mixing 0.2 f of chlorpheniramine maleate, 0.12 f of allantoin, and 10 f of ethanol, and diluting this to 100 with water, and adsorbing and retaining each medicinal ingredient on the keratin powder in the same manner as above. The amount was calculated.

Table 1 shows the results of comparing the amount of adsorption and retention of each medicinal ingredient in the sample obtained in this way with the amount of adsorption and retention in the control.

Table 1 As is clear from this table, the composition of the present invention has high adsorption and retention on the skin.

Example 2 Polyoxyethylene hydrogenated castor oil (average number of added moles of ethylene oxide 1o) c+r and sorbitan triolate 1
2 and cetylpyridinium chloride 0.2f, and to this, as medicinal ingredients, diphenhydramine hydrochloride 0.5f, lidocaine hydrochloride 0.12f, and aloe extract 1.07g were added.
An external application composition was prepared by diluting with water until the total amount was 1001 nl.

A 4 cm long incision was made on the dorsal skin of 10 male Wistar rats weighing around 1,501 kg, and the wound was closed with Mutsher forceps, and approximately 2 ml of the above liniment composition was applied twice a day for 7 consecutive days. , and its therapeutic efficacy was tested. On the 8th day, the back skin was peeled off and the tensile strength of the cut area was measured using an Instron tensile tester.

For comparison purposes, no treatment (control), cetylpyridinium chloride 0.21, diphenhydramine hydrochloride 0.5f, lidocaine hydrochloride o, if, and aloe extract 1. A similar test was also conducted when an aqueous solution containing only Of was applied (comparative example).

The results obtained are shown in Table 2.

Table 2 As is clear from this table, healing is promoted by the application of medicinal ingredients.

Next, the tensile strength of the cut portion was measured in the same manner as described above, except that each sample was applied and washed with water. The results are shown in Table 3.

Table 3 As is clear from this table, the composition of the present invention exhibits high retention on the skin IR even after washing with water, and therefore has a better therapeutic effect than the comparative example.

Example 3 A small amount of fragrance and saccharin are added to polyoxyethylene hydrogenated castor oil (average number of added moles of ethylene oxide xo) crt, 1 t of sorbitan trioleate, 0.2 t of benzethonium chloride, and rosemary extract i, ot, and further ethanol toy A cleaning agent was prepared by adding water to make the total volume 100+nl.

The mouthwash thus obtained was mixed with 0.1M phosphate buffer (p
After diluting the sample 40 times with H9), four people with high amounts of methyl mercaptan were selected as a panel for a deodorization experiment. That is, after repeating twice the process of soaking 40+nl of the above diluted liquid in the subject's oral cavity for 15 seconds and spitting it out,
After gargling with tap water, the intensity of bad breath after using mouthwash and rinsing was evaluated by three evaluators.1. ll1Lehachi. Oh. The ratings are as follows. It is expressed as the relative strength of the mouthwash against bad breath compared to the standard.

+2 The smell of mouthwash is very strong +1 Strong +0.5 Slightly strong 0 Normal -0.5 Slightly weak -1 Weak -2 Very weak The results obtained in this way can be used to compare the relative strength of bad breath over time. The changes are shown in the accompanying drawings as a solid line graph.

For comparison, a mouthwash containing no polyoxyethylene hydrogenated castor oil or sorbitan trioleate was prepared, and the results of a deodorization experiment conducted using this in the same manner as above are also shown as a broken line graph.

As is clear from this graph, the composition of the present invention has an excellent deodorizing effect and is long lasting.

Example 4 The amounts of each component shown in Table 4 were weighed into a 100-capacity beaker and mixed well. Next, an amount of water as shown in Table 4 was added to this mixture, and the mixture was thoroughly mixed using a magnetic stirrer so as to be uniform. From Samples 1 and 2, fluid, slightly transparent, opalescent vesicle dispersions were obtained. The formation of vesicles in this dispersion was confirmed by electron microscopy, and the particle sizes were all in the range of 0.1 to 5 microns.

Table 4 The dispersion thus obtained was diluted with 20 times the amount of physiological saline and used as the test solution.Meanwhile, as a model of biological surface area, 4 crl (surface area) of the mucous membrane at the site of the golden hamster's unarch pouch was peeled off. Then, the sections were washed with physiological saline, and the cheek pouch mucosa was placed in a test solution (the amount of flufenamic acid in the test solution is A) at a temperature of 40℃.
Shake at ℃ for 5 minutes. Measure the amount of flufenamic acid in the supernatant after shaking. (Regarded as B■.) The cheek pouch mucosa was prepared by adding physiological saline 4- and shaking at 40°C for 5 minutes.
The supernatant liquid at the time of washing twice was measured (C++y), and the adsorption and retention amount of flufenamic acid on the cheek pouch mucous membrane was calculated using the following formula.

The adsorption and retention amount of flufenamic acid in the sample obtained as in -A-B- on the cheek pouch mucous membrane was compared with the adsorption and retention amount in the control (sample 3) each time. Shown in the table.

Table 5 As is clear from this table, the vesicle dispersion of sample 2 has higher adsorption to mucous membranes than sample 3 (control), and the medicinal ingredient (flufenamic acid) is released by washing, but sample l ( The present invention) has a high initial adsorption amount to mucous membranes and maintains high adsorption even after washing operations (8) Stain retention)
are doing.

Next, a formulation example of the composition of the present invention will be shown.

Prescription example 1 Purulent skin disease treatment agent Benzethonium chloride 0.2 Sulfamethoxazole 4 Monoethanolamine 0.99 Polyoxyethylene hydrogenated castor oil (¥1-10) 9 Sorbitan trioleate l Fradiomycin sulfate 1 Ethanol 10 Water Total volume 100m7! Prescription example 2 External anti-inflammatory analgesic t-menthol 2 dt-camphor 2 Thymol 0.5 Tocopherol acetate 0.2 Methyl salicylate 3 Glycol salicylate Benzalkonium chloride 0.1 Capsicum extract 0.25 Polyoxyethylene hardening Castor oil (p=io) 9 Sorbitan trioleate l Ethanol 30 Water Until the total amount is 100rnl Prescription example 3 Parasitic skin disease treatment agent clotrimazole l Benzalkonium chloride 0.2 Polyoxyethylene hydrogenated castor oil (¥=to ) 9 Rubitan Trioleate 1 Ethanol 10 Water Total amount 100tn1. Prescription example 4 Hair preparation Estradiol benzoate o, ooi Hydrocortisone 0.0016 Capronium chloride 0.5 Polyoxyethylene hydrogenated castor oil (p=10) 9 Sorbitan trioleate l Benzalkonium chloride 0.02 Ethanol 10 Water Prescription example 5 until the total amount becomes 100- Disinfectant Benzethonium chloride 0.2 Lysozyme chloride 0.5 Polyoxyethylene hydrogenated castor oil (p=10) 9 Sorbitan trioleate 1 Ethanol 10 Water Prescription example until the total amount becomes 1'0 Otd 6 Mouthwash Benzethonium chloride 0.2 Sodium guarenate 0.3 T-menthol 0.6 Thymol 0.1 d-borneol 0.1 Ascorbic acid 0.2 Chlorpheniramine maleate 0.2 Methylephedrine hydrochloride 0. 2 Polyoxyethylene hydrogenated castor oil (p=10) 9 Sorbitan trioleate 1 Ethanol 10 Water This is diluted 20 times with water until the total amount becomes 100-100% and used.

Prescription Example 7 Nasopharyngeal liniment Ingredients Content (2) Naphazoline hydrochloride 0.05 Dipotassium glycyrrhizinate 0.3 Lysozyme chloride 0.5 Procaine hydrochloride 0.1 Benzalkonium chloride 0.02 Polyoxyethylene hydrogenated castor oil (〒 = 10) 9 Sorbitan trioleate l Ethanol 10 Water Prescription example 8 Eye drops A Benzalkonium chloride 0+01 7 Ravin adenine dinucleotide 0.02 Sulfamethoxazole 4 Monoethanolamine, 0 .99 Neostigmine methyl sulfate 0.002 Polyoxyethylene hydrogenated castor oil (T) = 10) 3-sorbitan trioleate 0.3 Water Until the total amount is 100- Prescription example 9 Eye drops B Ingredients Content (2) Benzalcochloride Nitrium 0.01 Fluorometholone 0.l Polyoxyethylene hydrogenated castor oil (p=10) 3-sorbitan trioleate 0.3 Boric acid 1.5 Water Prescription example 10 Eye drops C Benzalkonium chloride 0. 01 Erythromycin lactobionate 0.5 Colistiy Sodium methanesulfonate 0.5 Polyoxyethylene hydrogenated castor oil (〒=10) 3 Sorbitan trioleate 0.3 Water Until the total amount becomes 100- Prescription example 11 Gastrointestinal drug Benzalkonium chloride 0.05 Methylmethionine sulfonium chloride) 0.5 Glycyrrhizin 0.7 Copper chlorofin sodium 0.1 Polyoxyethylene hydrogenated castor oil (〒-10) 9 Sorbitan trioleate 1 Water Add any of the above until the total amount becomes 100- In the formulation examples, no separation of the vesiculating agent was observed, indicating good stability.

[Brief explanation of the drawing]

The drawing is a graph showing the deodorizing effect of the mouthwash according to the present invention and the conventional wellhead agent. Patent Applicant Lion Co., Ltd. Agent Akira Agata Time (minutes)

Claims (1)

[Scope of Claims] 1 (a) 0.005 to 0.5% by weight of a cationic surfactant, (b) an effective amount of medicinal ingredients, and (c), (4) polyoxyethylene castor oil ether and polyoxyethylene castor oil ether. At least one selected from oxyethylene hydrogenated castor oil ethers
(B) this ethoxylate 10
93 to 30 parts by weight of a vesicle dispersion of a sorbitan polyester of long IA fatty acids per 0 parts by weight. 2 (A) component has an average number of added moles of ethylene oxide of 7 to 2
A sustained topical layer composition according to claim 1, wherein the composition is an ethoxylate of 0.0 ethoxylate. 2. The long-lasting topical layer composition according to claim 1, wherein component 3 (B) is a sorbitan polyester of a long chain fatty acid having 16 to 18 carbon atoms.