JPS60214730A - Ointment base - Google Patents

Abstract

PURPOSE:To obtain an ointment base having realized improved percutaneous absorbability of a chemical, by incorporating a water-soluble protein having percutaneous absorption promoting action in the base. CONSTITUTION:An ointment base obtained by incorporating a water-soluble protein, preferably gelatin, solubilized collagen, casein or soybean protein, etc. in the base. The percutaneous absorbability is found to be increased by incorporation of the water-soluble protein. The amount of the water-soluble protein to be incorporated is 0.3-30wt%, preferably 0.5-25wt% based on the total base. The above-mentioned ointment base of this invention can be incorporated with the conventionally well-known dissolvent, thickener, wetting agent, oily material, emulsifying agent, etc. by suitable selection in addition to the water-soluble protein. Not only local but also systemic drug effect can be expected due to good percutaneous absorption.

Description

[Detailed description of the invention] The present invention relates to ointment bases containing water-soluble proteins.

Ointments are semi-solid preparations in the form of gels, creams, etc. for topical administration of drugs that are applied to the skin (or mucous membranes) to release and penetrate the drug.

Therefore, it is important for ointments to release the compounded drug quickly and reliably onto the skin surface and to be able to penetrate to the affected area. It must be usable in all respects. In order to meet these conditions, various ointment bases have been proposed, but none have yet been found to be satisfactory. In particular, the skin acts as a barrier to drug absorption, the systemic effects of transdermal absorption cannot be expected due to problems with drug release and permeability, and the drug is more difficult to administer than drugs administered by other routes such as oral preparations. Problems remain, such as extremely poor bioavailability. Therefore, it has been desired to develop an ointment base that does not have such drawbacks.

In view of this technical situation, the present inventors have conducted extensive research with the aim of developing an ointment base that solves the above problems.
It was discovered that excellent transdermal absorption of drugs can be achieved by using an ointment base containing water-soluble protein, and as a result of detailed studies based on this knowledge, the present invention was completed. Ta. Such a transdermal absorption promoting effect by incorporating water-soluble proteins has not yet been found in conventional ointment bases.

That is, the present invention relates to a special plaster base characterized by containing a water-soluble protein that exhibits an effect of promoting transdermal absorption.

The above-mentioned water-soluble protein is not particularly limited as long as it exhibits an effect of promoting transdermal absorption of the drug to be blended. Such water-soluble proteins are natural or non-natural proteins, and examples of natural proteins include animal proteins and vegetable proteins, and examples of non-natural proteins include artificially obtained peptides. Although there are technical fields in which peptides are distinguished from proteins, in the present invention they are included in proteins from the viewpoint of their effects.

Specific examples of the above animal proteins include gelatin, solubilized collagen, casein (or its sodium salt),
Examples include glue and their hydrolysates. Gelatin and solubilized collagen are soluble protein products obtained by hydrolyzing proteins contained in animal bones, skins, etc. with acid or alkali or by treating them with hot water, as well as suitable chemical modifications ( Examples: succinylation, maleylation, heptatalation).
Its molecular weight is on the order of several ga to several hundred thousand. In addition, the above-mentioned vegetable protein includes soybean protein (eg, one obtained by precipitating and enzymatically treating the water-soluble portion of defatted soybean soapstock).

A typical example is soybean casein. Further, the above-mentioned peptides include peptides obtained by condensing the same or different amino acids by chemical synthesis, fermentation, semi-synthetic means, etc., and the molecular weight thereof is usually in the order of several hundred to several hundred. Therefore, various amino acids such as neutral, basic and acidic amino acids; optically active forms and racemic forms; natural and synthetic amino acids can be employed as the constituent amino acids of these peptides. In the present invention, one or more of these water-soluble proteins are used. For example, gelatin alone or a mixture of gelatin and casein can be used. Furthermore, among one or more water-soluble proteins, gelatin, solubilized co2-glucose, casein, soybean protein, etc. are selected, taking into consideration their absorption promoting effect on drugs, compatibility or dispersibility with other ingredients, difficulty in obtaining them, etc. Generally preferred.

The amount of the above-mentioned water-soluble protein to be blended may be an amount sufficient to achieve the object of the present invention, and preferably an amount sufficient to promote drug absorption through the skin. For this purpose, a water-soluble protein is often used in an amount equivalent to or more than that of the drug, and is usually 0.3 to 30% by weight, preferably 0.5 to 25% by weight based on the entire base of the present invention. About % by weight is blended.

In the ointment base of the present invention, in addition to the above-mentioned water-soluble protein, components used in conventionally known ointment bases can be blended. As such components, a combination of a plurality of components appropriately selected from solubilizers, thickeners, wetting agents, oily substances, and emulsifiers depending on the purpose can be blended. For example, if a solubilizer, thickener, or wetting agent is used in addition to the above-mentioned water-soluble protein, a gel-like ointment base is generally obtained; Use - mu el + r ka II p
Tonto j) Yu 6111 needle light [Bye Dan Nao-↓tsu
Acceptable in ding.

Any material that can improve solubility or dispersibility may be used. Specific examples of such a dissolving agent include monohydric alcohols (eg, ethanol, lower alcohols such as isopropyl alcohol), acetonate, etc., and ethanol is generally preferred in many cases. When these solubilizers are used, their amount should be 1%, even if the amount is sufficient to achieve the above-mentioned purpose.
, preferably about 5 to 35% by weight.

As the above-mentioned thickener, one is used that can contribute to necessary formulation properties such as imparting rheological properties to the preparation and improving skin affinity by increasing the viscosity of the entire ointment. Thickening agents that cause thickening include toshiteha, celluloses, polysaccharides, carboxyvinyl polymers, polyvinyl alcohol-borivinylpyrrolidone, and the like.

The cellulose mentioned above has an average molecular weight of 40,000 to 20
Alkylcellulose and hydroxyalkylcellulose in which carbon ii of the alkyl moiety is 1 to 4 (e.g. methylcellulose, ethylcellulose, propylcellulose, methylpropylcellulose, hydroxymethylcellulose, hydroxyethylcellulose,
(hydroxyglobil cellulose), carboxymethyl cellulose or its alkali metal salts.

Specific examples of the polysaccharides mentioned above include starch and its derivatives (eg, carboxymethylated starch, hydroxyglobil starch), dextrin, dextran, and chitin.

Examples include alginic acid or its sodium salt, single polysaccharides such as Glycoguts and Pullula/(trade name, manufactured by Hayashi N.), and complex polysaccharides such as mannan, pectin, and gum arabic. The carboxyvinyl polymer has an average molecular weight of about 900,000 to 3,000,000, and includes polyacrylic acid, polymethacrylic acid, and alkali metal salts thereof, and more specifically, polyacrylic acid, polymethacrylic acid, and alkali metal salts thereof.
=r - (trade name, manufactured by Aiko Pure Chemical Industries, Ltd.), Carbopol (trade name, manufactured by Gutdrich), Rubiscoll (trade name, manufactured by EA)
Commercially available products such as those sold by SF's company can be advantageously used. In the present invention, one or more of the thickeners listed above can be used. When these thickeners are used, their amount may be sufficient to achieve the above-mentioned purpose, and is usually 0.2 to 10% by weight, preferably 0. It is about .5 to 5%.

The humectant is not particularly limited as long as it serves the purpose of improving the quality characteristics of the ointment, such as moisturizing properties, spreadability, gloss, and texture. Typical such humectants are polyhydric alcohols and amino acids, and the polyhydric alcohols include glycols, triols, and polyols, and the amino acids include various known natural amino acids. The above-mentioned glycols include glycols having 2 to 6 carbon atoms (e.g. ethylene glycol, fluoropylene gellicol, phethylene gellicol), polyethylene glycol (average molecular weight: 200 to s, ooo, preferably 200 to 6
Examples of triols include glycerin and trimethylolpropane, and examples of polyols include sorbitol. In the present invention, one or more of the above-mentioned wetting agents can be used, and the blending amount may be sufficient as long as it can achieve the above-mentioned purpose of use. It is usually 1 to 25% by weight, preferably about 3 to 20% by weight based on the entire invention base, and when water is not added, it is usually 20 to 90% by weight based on the entire invention base.
, preferably about 30 to 85% by weight. In addition, in the latter case of not using water, a creamy base is mainly obtained.

The above-mentioned oily substance protects the epidermis from invasion of foreign substances and irritation by covering the epidermis.

Those that have skin softening and derma softening functions are used,
Among these, those that cause less skin irritation and have dispersibility and compatibility with other ingredients are preferred.

Such oily substances include hydrocarbons, animal/vegetable oils, higher fatty acids, aliphatic higher alcohols, fatty acid esters, Plastibase (trade name, manufactured by Squibb), silicone oil, and the like.

The above hydrocarbons include liquid paraffin.

Vaseline, squalane, squalene, etc. are used as animal/vegetable oils such as pork fat, beef tallow, spermatozoa.

Lanolin, beeswax, carnauba wax, coconut oil.

Olive oil, castor oil, sesame oil, etc., and the above-mentioned higher fatty acids include saturated or unsaturated fatty acids having 16 to 18 carbon atoms (e.g., valmitic acid, stearic acid, oleic acid,
Examples of the aliphatic higher alcohols include cetanol and stearyl alcohol. Furthermore, as the above fatty acid esters,
Alkyl ester or glycerin ester of mono(di)carboxylic acid (carboxylic acid moiety having 2 to 30 carbon atoms and ester moiety having 1 to 30 carbon atoms. Examples: inglovir myristate, octyldodecyl myristate.

Ethyl laurate, methyl ricinoleate, triacetin, caprylic acid di(tri)glyceride, capric acid di(tri)glyceride, mixed acid group triglyceride consisting of caprylic acid and capric acid, oleic acid di(tri)glyceride, linoleic acid di(tri)glyceride Typical examples include triglyceride, mixed acid group triglyceride consisting of oleic acid and linoleic acid, diethyl adipate, diimpropyl adipate, diethyl sebacate).

In the present invention, one or more of the oily substances listed above can be used. When these oily substances are used, their amount may be sufficient to achieve the above-mentioned purpose, and is usually 0.5 to 30% by weight, preferably 1 to 30% by weight based on the entire base of the present invention. It is 25% by weight.

The emulsifier may be any emulsifier as long as it has the function of uniformly and stably emulsifying or dispersing the ingredients to be mixed into the formulation. As such emulsifiers, those having surfactant action are generally preferred, and therefore various nonionic, anionic and cationic surfactants can be used. Examples of the surfactant include polysorbate) 80. Sorbitan fatty acid ester, fatty acid monoglyceride, sucrose fatty acid ester, polyoxyethylene derivative of fatty ts alcohol, polyoxyethylene derivative of fatty acid, polyoxyethylene derivative of fatty acid ester of polyhydric alcohol, sodium lauryl sulfate, lecithin, dioctyl sulfosuccinate Examples include.

The raw fatty acids in the above examples include palmitic acid, stearic acid, oleic acid, lauric acid, etc.
Further, as the raw material aliphatic alcohol, stearyl alcohol, lauryl alcohol, oleyl alcohol, cetyl alcohol, etc. are used.

In the present invention, one or more of the emulsifiers listed above are used. When these emulsifiers are used,
The amount to be blended may be sufficient to achieve the above-mentioned purpose of use, and is usually 0.2 to 6! based on the entire base of the present invention. amount%,
Preferably it is about 0.5-4Ji amount %.

In addition to the above components, an appropriate amount of water may be added in order to maintain the formulation properties of the base of the present invention. That is, the amount of water blended is usually 0 to 801i%, preferably O
It is about 70% by weight.

Furthermore, in the base of the present invention, a preservative (
Example: Methyl paraoxybenzoate.

Parabens such as ethyl and propyl esters.

Known formulation ingredients used in conventional ointments can be added, such as (rubic acid, dehydroacetic acid). In the case of a cream base, the above preservative is often added in an amount of 0.01 to 2% by weight based on the total formulation, and in the case of a gel base, this preservative is generally unnecessary.

The base of the present invention having the above structure is used for medical and cosmetic purposes. When used primarily for medical purposes, various drugs are added during the manufacturing process depending on the purpose. Such drugs are not particularly limited as long as they can be absorbed transdermally, and include both locally applied drugs and systemically applied drugs. Topically applied drugs are used to treat cutaneous and subcutaneous diseases, or to adjust the skin condition to protect the skin, and are mainly drugs that exert their medicinal effects locally. Can be mentioned.

In addition, examples of drugs that are applied systemically include drugs that are absorbed through the skin surface where they are applied, reach tissues, organs, etc. in the body through the blood, and mainly exert systemic medicinal effects. Among these drugs, there are drugs with little or no transdermal absorption when used alone, and drugs with low bioavailability when administered orally (e.g., bioavailability is 80%). The following drugs), drugs with many side effects, drugs that must be administered by injection because they are degraded by digestive juices, drugs that are susceptible to the first-pass effect in the liver, etc. are effective when combined with the base of the present invention. It is beneficial to employ it as an ingredient.

Examples of drugs to be mixed are shown below.

■Analgesic and anti-inflammatory agents: acetamin 7ene, aspirin, salicylic acid, methyl salicylate, choline salicylate, glycol salicylate,! - Menthol, camphor, mefenamic acid, flufenamic acid, indomethacin, diclofenac.

Alclofenac, Ibuprofen, Ketoprofen, Naproxen, Pranoprofen.

Fenoprofe/l Salindac, Fenbufen, Clidanac, Flurbiprofen, Indoprofen, Butisic acid, Fentiazac, Tolmetin, Tiaprofenic acid, Benzadac, Bufexamac, Piroxicam, Phenylbutacin, Oxyphenbutacin, Clo7
Ezone, pentazocine, mevirizole, etc.; ■Steroidal anti-inflammatory agents: hydrocortisone, glednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonite, fludrocortiscin acetate, etc.; ■Antihistamines or antiallergic agents: chlorpheniramine, glycyrrhizin Acid, diphenhydramine, periactin, etc.;■Local anesthetics: benzyroine, procaine, ziglycoin, lidocaine, etc.;■Antimicrobial agents, etc.
(including antibacterial, antifungal, antifungal, and antiviral agents):
Tetracyclines such as chlortetracycline, penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin, macct-lights such as erythromycin, chloramphenicol, iodine compounds, nitro-7-lantoin, nystatin, a Antihypertensive agents: clonidine, α-methyldopa, reserpine, syrosingobine, recinamine, cinnarizine, hydralazine, prazosin, etc.: ■Antihypertensive diuretics: theophylline, trichloromethiazide, 70 ceside,
Tripacid, methyclothiazide, penflucito, hydrothiazide, spironolactone, metolazone, etc.;
■ Cardiac drugs: digitalis, ubidecarenone, ≠ヰ＊≠; calyx dopamine, etc.; ■ Coronary vasodilators dinitroglycerin, insorbitol cinitrate, erysto-stetranitrate, pentaerytol tetranitrate, diviridamol, dirazep, trapidil , trimetazidine, etc.: [Phase] Vasoconstrictors: dihydroergotamine, dihydroergotoxin, etc.; ■β-blockers or antiarrhythmic drugs: pindolol, propranolol, etc.; @
Calcium antagonists: diltiazem, nifedipine, nicardipine, verapamil, benzicran, dirazep, etc.;
0 Antiepileptic drugs 22trazepam, meprobamate, phenytoin, etc.: ■Anti-vertigo agents; insulin, betahistine, scopolamine, etc.; [Phase] Tranquilizers: diazepam, lorazepam, flunitrazepam, fluphenazine, etc.; [Phase] Hypnosedatives = Pheno Barbital, amobarbital, cyclobarbital, etc.; 0 Muscle relaxants nitrivericin, baclofen, dantrolene sodium, cyclobenzavirine, etc.: [Phase] Autonomic nerve agents niatropine, levodopa, etc.; [Phase] Respiratory agents: codeine, ennidrine, Improterenol. Dextromethorphan, orciprenaline, ipratropium bromide,
Cromolytic acid, etc.: @Hormonal agents Anti-hormonal agents: Corticotropin, oxytocin, vasopressin, testosterone, glogesterone, estradiol, salivary gland hormones, thyroid hormones, adrenal hormones, kallikrein, insulin, oxendron, etc.; [Phase] Vitamins: Vitamins A, B .

C, D, E, and their derivatives, calche 7erols, mecobalamin, etc.: [Phase] Antitumor agents: 5-fluorouracil and its derivatives, krestin, picibanil, ancitabine, cytarabine, etc.: @ Enzymes: urokinase, etc. [Phase] Chinese herbal medicine or herbal medicine extract: Licorice,
Aloe, purple root, etc.; O anti-ulcer agents niarantoin, aldioxa, alcloxa, etc.; O prostaglandins;
ODiabetes treatment, etc.

Two or more of the above drugs can be used in combination, if necessary. In addition, the above drugs are used in the free state, those that can be used to form salts are in the form of acid or base salts, those that have a carboxylic acid group are in the form of their esters, and those that have a carboxylic acid group are used in the form of their esters. can be used in its ester form. The above-mentioned acids include organic acids (e.g. methanesulfonic acid, lactic acid, lactic acid, maleic acid, acetic acid) and inorganic acids (e.g. hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid). However, bases also include organic bases (eg, ammonia, triethylamine) and inorganic bases (eg, sodium hydroxide, potassium hydroxide). Furthermore, the above-mentioned esters include alkyl esters, aryl esters, and aralkyl esters! It is mentioned that. The amount of these drugs to be blended is sufficient as long as the amount is sufficient for the expression of the drug's efficacy, and in most cases, the amount is 0.01-2.
0% by weight, preferably 0.05-10% by weight. Further, the dosage may be adjusted as appropriate depending on the type of drug, therapeutic purpose, patient's age/body weight, degree of disease progression, etc.

The base of the present invention containing the above drug as an active ingredient can be applied to the skin and mucous membranes of various parts of the human body (oral cavity, nasal cavity, rectum, vagina) in the required amount depending on the purpose. For example, for local treatment of trauma, skin ulcers, muscle pain, arthritis, etc., the drug should be placed directly at or near the affected area, and for systemic treatment of internal organs, etc., the drug should be placed in areas where the drug is easily absorbed ( For example, it is preferable to apply it to areas where keratin has not developed. When used for cosmetic purposes, the base of the present invention may be used as it is, or may be mixed with a drug selected from the above drugs or a known cosmetic ingredient for skin cleansing, packs, measures against sunburn and rough skin, moisturizing, etc. It can be used for the purpose of

For practical convenience and storage needs, the base of the present invention and the above-mentioned medical and cosmetic ingredients should be sealed and stored in glass or plastic containers, metal tubes, etc. Good.

In preparing the ointment base of the present invention, a method in which an appropriate modifier is added to a conventionally known method for producing an ointment base can be employed. In a typical manufacturing method, (1) first, a water-soluble protein and a thickener are dissolved in the necessary amounts of water, and (11) this solution is then added to a wetting agent, a solubilizer, an emulsifier, an oil-based The desired ointment base is obtained through a series of steps in which a substance selected from among the substances is added, and finally, the mixture is thoroughly stirred until the whole is homogeneous. A similar operation can be performed without adding water.
Can be implemented. Here, if you want to obtain a gel-like base,
In the above step (II), the wetting agent and solubilizing agent are mainly
Furthermore, if a creamy base is to be obtained, it is common to mainly use wetting agents, emulsifiers, and oily substances. Also,
The above steps (1) to (il) can be carried out at room temperature, but if necessary, 30C to 8C may be carried out in some of the steps.
There is no problem even if the temperature is appropriately heated to 0C1, preferably about 50C to 60C, but this is often more convenient in terms of operational efficiency. In addition, when a drug or the like is blended into the base of the present invention, it is preferable to carry out the above step (11).

Next, the method for producing the base of the present invention will be explained in more detail with reference to Examples.

Example 1 According to the recipe shown in Table 1, 3g of gelatin was mixed with 22g of purified water.
After moistening to 9.5 g, it was heated and dissolved at 50C;
■ 2 g of hydroxyethyl cellulose was dissolved in 20 g of purified water: ■ 0.5 g of sodium polyacrylate was dissolved in 10 g of purified water: ■ 30 g of ethanol and 4 g of 1.3-butylene glyco-/I were mixed; ■ The above Add ■ and ■ to ■, and use a homomixer until the whole is homogeneous.
Stirred at 0G; ■Added ■ to this ■, and stirred at 50C with a homomixer until the whole was homogeneous. A gel-like ointment base was obtained by the above operations.

Separately, in the step (2) above, ifenprodil tartrate I
g was added and the same procedure was performed to obtain an ointment.

According to the formulation shown in Table 1, a gel-like ointment base was obtained by carrying out the same operation as in Example 1 above. Separately, in the following examples, ointments containing the indicated drug amounts were prepared.

Example 2: Prazosin hydrochloride 0.5g, clonidine hydrochloride 0
．． 5 g or Clidanac 0.5 g; Example 3: Pindolol 0.5 gy Example 4: Indomethacin 1.0 g;
Example 5: Pentazocine hydrochloride 1.0 g or dipyridamole 1.0 g; Example 17: Ifenprodil tartrate 1
．． 0g0 Example 22 According to the recipe shown in Table 2, ■ 3g of gelatin was mixed with 55g of purified water.
After moistening with 4gK, heat and dissolve at 5oc. , :
;■Hydroxyethylcellulose Ig remaining and 1.3
- Added 1 og of butylene glycol and stirred; ■ Added ■ to the above ■ and stirred at 50C in a homomixer until it became uniform; ■ Added ■ to this ■, initially at the same temperature in a homomixer, then at about 3 The mixture was stirred in a homomixer until the mixture was homogeneous. A cream-like ointment base was obtained by the above operations.

Separately, an ointment was prepared in which 0.5 g of Clidanac was added in step (1) above.

Examples 23 to 39 According to the formulations shown in Table 2, the same operations as in Example 22 above were carried out to obtain creamy ointment bases.

Separately, in the examples below, ointments containing the indicated drug amounts were prepared.

Example 31: Clidanac 0.5 g; Example 25: Ifenprodil tartrate 1 g; Example 29: Pentazocine hydrochloride 1 g0 The ointment base of the present invention obtained by the above method can be stored while maintaining a stable state, It has a good feel when used, and when used as it is or mixed with various active ingredients such as the aforementioned drugs, it has the following characteristics and is very useful medically and industrially.

(b) Good transdermal absorption of active ingredients such as drugs is achieved. Therefore, not only local medicinal effects but also systemic medicinal effects, which are difficult to achieve with conventional ointments, can be expected.

(b) Drugs that have problems with side effects (gastrointestinal disorders, etc.) and bioavailability using other administration methods such as oral administration can be effectively improved (delayed metabolism, etc.).

(c) When oral administration is performed several times a day, if you forget to take the dose or dislike taking it, or if you need to take multiple doses and doses, the ointment base of the present invention can be used once or twice a day. When used, 1iJJ has a long-term medicinal effect, is easy for patients to use, and is easy for doctors to manage both the disease and the drug effect.

Next, test examples regarding the ointment base of the present invention will be shown.

Test Example 1 (Drug release test) (Method) (A) 3 g of the indomethacin-containing ointment of Example 4 was
15 phosphate buffer wave buffer 5.5; 37C) 200
The indomethacin released into the buffer solution through this artificial membrane was analyzed by HPLC (high performance liquid chromatography). ). That is, this buffer 11111
Each sample was collected over time, extracted with 5111 dichloromethane, and then the solvent was distilled off from the extract, and the resulting residue was
A sample dissolved in 0.2 mK of 5% acetonitrile was used as a measurement sample.

In HPLC, the column is Nucleosil (
Nucleosil) ClB as mobile phase and acetonitrile 10. o1m Potassium dihydrogen phosphate (75:
25), the flow rate was 211 LL/min, and the ultraviolet region was 31 LL/min.
Quantification was performed by measuring absorbance at 8 nm K. (
B) For comparison, a similar test was conducted using the same amount of a commercially available ointment containing 1% indomethacin (Idomesin Kowagle ■, manufactured by Kowa).

(result) The above results are shown in Table 3.

Table 3 Release amount of indomethacin (μg/ml) The results show that the ointment base of the present invention releases the contained drug quickly and exhibits drug release properties that are approximately twice as high as those of existing ointments. There was.

Test Example 2 (Preparation containing prazosin hydrochloride) (Method) (A) Male SD rats (body weight 200-3
The ointment containing prazosin hydrochloride of Example 2 was applied to the backs of the mice (6 to 8 animals per group), and the ointment was covered with tape.

(B) Separately, a 1% gum arabic suspension of prazosin hydrochloride was orally administered. The dosage for both administrations was 10,020 cm/day per day, and administration was continued for 3 days. 24 hours after the final administration, norepinephrine (3 μg/kg) was administered intravenously under anesthesia with bentoparbital sodium (dose 4 oa/kg; intraperitoneal administration), and the external pressure response at this time was observed, and no treatment was performed. compared with a control group.

(Results) Nevertheless, it is understood that the drug exhibited drug efficacy (suppression of pressor response) comparable to oral administration.

Table 4 *: There is a significant difference compared to the control group with a risk rate of 5%.

(There is no significant difference between groups A and B.) Test Example 3 (Preparation containing indomethacin) (Method) A white male rabbit whose hair was shaved 24 hours before drug administration (body weight 2
．． 4-2. s n ) Dorsal surface K, 2 g of indomethacin-containing ointment of Example 4 (containing 20 ■ indomethacin)/
The body was applied. 0.5 to 7 hours after application,
Collect 3 ml of blood at appropriate times and use the plasma separated by centrifugation using the method of Arbin (J, Chromatog,
.

144, p. 85 (1977)], and
Indomethacin was quantified by mass fragmentography monitored at m/e 137 in a C-MS (gas chromatography mass spectrometer) device.

(Results) The above results are shown in Table 5. From this result, prompt and sustained transdermal absorption of the drug was confirmed.

Table 5 Test Example 4 (Preparation containing clonidine hydrochloride) (Method) White male domestic rabbits (body weight 2
．． 5-2.9 kK) On the back surface, apply 2 g of clonidine hydrochloride-containing ointment of Example 2 (containing clonidine hydrochloride 710 ■)/b
oay was applied (7 hours after application, the drug remaining on the skin was wiped off with absorbent cotton). 0.5 to 24 hours after application, 3 ml of blood was collected at appropriate times, and the plasma collected by centrifugation was used according to the method of &lund et al.
Pharmacol Toxicol,, 40 volumes,
145 (1977)], clonidine was quantified using an ECD-gas chromatography apparatus.

(Results) The above results are shown in Table 6. From this result, prompt and sustained transdermal absorption of the drug was confirmed.

Table 6: February 13, 1985 Manabu Shiga, Director General of the Patent Office 1, Indication of the case Vertical, 1985 Patent Application No. 66111 2, Title of the invention Ointment base 3 Relationship with the person making the amendment Patent application Person 4, Agent 〒532 6 Number of inventions increased by amendment 0 7, Subject of amendment 11) “Moisturizing agent” is corrected to “humectant” in the 5th line from page 8 of the IJI specification doodle. To do.

(2) On page 23 of the specification, from line 6 to line 7, ``Clonidine hydrochloride o, 5g J'' has been corrected to ``Clonidine hydrochloride o, o5gj.''

(3) In Table 1 on page 24 of the specification, the amount of water, which is a compounded component in Example 4, is 15+, 3J, which is j55.
3JK will be corrected.

that's all

Claims (1)

[Claims] An ointment base characterized by containing a water-soluble protein that exhibits a transdermal absorption promoting effect.