JP3050917B2 - Transdermal administration base composition and pharmaceutical composition thereof - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a base composition for transdermal administration, which enhances percutaneous absorption of a drug and has low irritation to the skin, and a pharmaceutical composition thereof. .

BACKGROUND ART As methods for administering drugs, methods such as oral administration, rectal administration, intradermal administration, and intravenous administration have been known, and among them, oral administration has been widely adopted. However, in the case of oral administration, there are drawbacks such as that the primary metabolism is liable to occur in the liver after absorption of the drug, and that the drug concentration is higher than necessary temporarily after administration. In addition, many side effects of oral administration such as gastrointestinal disorders, vomiting sensation and anorexia have been reported.

In recent years, for the purpose of overcoming the drawbacks of oral administration, transdermal administration has attracted attention as a method that can safely and sustainably absorb drugs. The development of agents
The product is already on the market. However, in many cases, the transdermal absorbability of the drug in this transdermal administration preparation is still insufficient, and it is difficult to say that the purpose has been sufficiently achieved.

In other words, normal skin originally has a barrier function to prevent foreign substances from penetrating into the body, and it may be difficult to obtain sufficient transdermal absorption of the compounded medicinal ingredients with the base alone used in ordinary transdermal administration preparations. Many. Therefore, there is a need for a device that controls the permeability of the drug through the stratum corneum of the skin and enhances the transdermal absorption of the drug. For this reason, it has been generally attempted to incorporate a so-called transdermal absorption enhancer into the base. For example, dimethylacetamide and ethyl alcohol, isopropyl alcohol, isopropyl myristate, etc. (U.S. Pat. No. 3,472,931) as absorption promoters combined with lower alkylamides, 2-pyrrolidone and suitable oils, and esters of linear fatty acids and alcohols are used. Example of combination (US Pat. No. 4,017,641), lower alcohol and alcohol having 7 to 20 carbon atoms, 5 to 5 carbon atoms
Examples of a combination of a fatty acid hydrocarbon having 30 carbon atoms, an alcohol ester of a fatty acid carboxylic acid having 19 to 26 carbon atoms, a mono or diether having 10 to 24 carbon atoms, a ketone having 11 to 15 carbon atoms, and water (JP-A-61-249934). Has already been proposed.

However, in the case of these conventional absorption enhancers and absorption enhancer compositions, it is hard to say that their safety on the skin is still sufficient. In addition, a hypoallergenic absorption-enhancing composition (Japanese Patent Application Laid-Open No. 2-115131) has also been proposed. Irritating.

Under such circumstances, in the transdermal administration method, the use of the drug has not been practically sufficient, and the stability of the drug in the formulation, the absorption and hypoallergenicity to the skin, and further, the development of the drug effect Sex is still not satisfactory.

For example, tulobuterol is a β-stimulant having a selective bronchodilator effect and is known as a therapeutic agent for bronchial asthma, chronic bronchitis, respiratory distress based on airway obstruction disorder, and is generally orally administered as tablets and dry syrup. Orally administered tulobuterol preparations may cause palpitations or cardiovascular side effects such as increased heart rate, headaches, side effects of the nervous system such as excitement and dizziness, or vomiting, appetite Gastrointestinal side effects such as poor performance have become a problem, and it is thought that the cause is a temporary increase in the blood concentration of the drug after oral administration. In the case of oral preparations, the duration of action is still insufficient, and sufficient effects may not be obtained for seizures that occur frequently at dawn. Therefore, as a measure for solving such a drawback, a formulation that maintains the blood concentration of tulobuterol transdermally for a long time is desired, and as one such formulation, tulobuterol is administered transdermally. (Japanese Patent Application Laid-Open (JP-A) No. 63-10716) has been proposed. These preparations are intended to suppress a temporary increase in blood concentration after drug administration by using a novel dosage form mainly composed of creams and patches. Further, for the purpose of promoting percutaneous absorption of a drug, an example in which a medicinal component is contained in a composition comprising a lower alcohol, an alcohol having 7 to 20 carbon atoms, an aliphatic hydrocarbon having 5 to 30 carbon atoms, and water, and water. (JP-A-61-249934). In this example, it is proposed that the composition can be applied as various preparations such as an ointment, a plaster, a lotion, an adhesive tape, an impregnating agent, and a gel. Also, a patch comprising a composition of polyisobutylene as a synthetic rubber and tulobuterol as a medicinal ingredient (Japanese Patent Laid-Open No. 4-9972)
No. 0) is also presented.

However, even with these conventional methods and compositions for them, it is still difficult to say that the stability of the drug in the preparation, the absorption and irritation to the skin, or the efficacy of the drug are still insufficient.

Such a situation is not limited to the case of tulobuterol described above, and is a common problem in application of various drugs.

The present invention has been made in order to solve the problems of the prior art as described above, and enhances the transdermal absorption of a drug, and has low irritation to the skin that is the administration site. An object of the present invention is to provide a base composition and a drug composition for transdermal administration having excellent stability using the same.

DISCLOSURE OF THE INVENTION The present invention solves the above-mentioned problems by providing 10 to 60% by weight of a lower alcohol, 10 to 50% by weight of a humectant which is an aliphatic polyhydric alcohol or a sugar alcohol, and 10% by weight of water. ~ 70% by weight, medium or long chain fatty acid ester or sorbite
Transdermal skin comprising 0.1 to 15% by weight of a stimulant reducing agent which is a fatty acid ester or a mixture thereof, and 0.1 to 15% by weight of an absorption enhancer which is a medium- or long-chain fatty acid or fatty alcohol. An administration base composition is provided.

The present invention also provides a drug composition for transdermal administration obtained by compounding a drug with the base composition.

That is, by containing a drug in the above-described base composition comprising a lower alcohol, a humectant, water, a stimulant reducing agent and an absorption enhancer and administering the drug to the skin, the drug is efficiently absorbed, and irritation at the administration site is also achieved. Sex is reduced.

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, there are provided a transdermal administration base composition as a composition of a specific component having a specific mixing ratio as described above, and a pharmaceutical composition using the same. As the lower alcohol as a component in this case, an aliphatic alcohol having about 1 to 5 carbon atoms, for example, ethanol, propanol,
Isopropanol, butanol, isobutanol and the like can be used. Among them, ethanol or isopropanol is preferred. These lower alcohols are 1
One or more species can be used. Also,
As the humectant, an aliphatic polyhydric alcohol or a sugar alcohol is used. Examples of these are preferably one or more of sorbitol, polyethylene glycol, diglycerin, propylene glycol, butylene glycol, dipropylene glycol, sodium pyrrolidone carboxylate, ethyl carbitol, D-xylitol, glycerin, and hyaluronic acid. As an example. Among them, glycerin or polyethylene glycol is particularly preferred. The water component is particularly preferably a buffer having a pH of 6 to 7. As the stimulant-reducing agent, a medium-chain long-chain fatty acid ester or sorbitol fatty acid ester or a mixture thereof is used as an excellent stimulant-reducing effect. Among them, glycerin monooleate, glycerin monolaurate or Sorbitan monolaurate or a mixture thereof is preferred as having a significant irritation-reducing effect.

As the absorption promoter, a medium-chain or long-chain fatty acid, a fatty alcohol or a fatty acid ester is preferable.
Approximately 20 to 20 are preferably used. In particular, lauryl alcohol and myristyl alcohol exhibit particularly high absorption promoting properties and are preferably used as those having relatively little irritation to the skin.

Regarding each of these components, in the present invention,
Lower alcohol 10-60% by weight, humectant 10-50% by weight, water
The proportion is preferably 10 to 70% by weight, 0.1 to 15% by weight of the irritation-reducing agent and 0.1 to 15% by weight of the absorption enhancer, more preferably 10 to 40% by weight, particularly preferably 15 to 40% by weight, of the lower alcohol.
To 30% by weight. And about a water component, Preferably it is 20-70 weight%, Especially preferably, it is 30-50 weight%.

For humectants such as glycerin and polyethylene glycol, preferably 20 to 40% by weight, particularly preferably 20 to 40% by weight.
30% by weight. The stimulus reducing agent such as glycerin monooleate, glycerin monolaurate and sorbitan monolaurate is preferably used in an amount of 1 to 10% by weight, particularly preferably 3 to 10% by weight.

Further, the content of the absorption enhancer which is an aliphatic alcohol or a fatty acid is preferably 0.2 to 5% by weight.

As for the lower alcohol as an essential component of the base composition, if the concentration exceeds 60% by weight, and more than 30% by weight, irritation is observed on the applied skin, and the degree of the irritation increases with the concentration of the lower alcohol. Tend to increase. When the concentration of the lower alcohol is less than 10% by weight or less than 15% by weight, no irritation to the applied skin is observed, but no promotion of skin permeability of the drug incorporated in the base is observed.

When the concentration of the humectant exceeds 50% by weight or even 30%, the skin permeability of the drug tends to be remarkably reduced.
In the case of a formulation having a humectant concentration of 10% by weight or less than 20% by weight, irritation to the applied skin is observed.

In addition, as for the absorption enhancer, the skin permeability of the drug is increased with an increase in the concentration, but irritation on the applied skin is observed in a preparation exceeding 15% by weight, or even more than 5% by weight.

As for the irritation-reducing agent, its effect is not recognized at 0.1% by weight or further less than 3% by weight, and when it exceeds 15% by weight, irritation on the applied skin is recognized.

With respect to the base composition of the present invention having such a formulation, the pH value is adjusted within the range of 4 to 9, preferably within the range of 4 to 7.5.

The drug used for the transdermal administration base composition of the present invention for the transdermal administration drug composition of the present invention is not particularly limited as long as it is a drug that can be absorbed transdermally. Sedatives (nitrazebam, barbital, etc.), antipyretic and anti-inflammatory analgesics (ketoprofen, indomethacin, ketorolac, loxoprofen, denidap, etc.), stimulants / stimulants (methamphetamine, bemeglide, etc.), agents for mental and neurological disorders (meprobamate, imipramine, etc.), local anesthetics (Such as lidocaine and procaine), skeletal muscle relaxants (such as tizanidine, eperisone, and dantrolene), agents for autonomic nerves (such as carpronium and neostigmine), antiparkinson agents, antihistamines (such as mequitazine and diphenhydramine), and cardiotonic agents (such as digoxin and aminophylline) , Hypotensives (nifedipine, a Purenororu etc.), coronary vasodilators (nitroglycerin, etc. nitric Isosorubaito)
Peripheral vasodilators (Nicametate, cyclandate, etc.),
Cardiovascular agents (flunarizine, ibudilast, etc.), antitussive expectorants (tranilast, tulobuterol, etc.), anti-vertigo agents (betahistine, difenidol, etc.), narcotics (buprenorphine, morphine, fentanyl, etc.), corticosteroids (prednisolone, betamethasone, etc.) ), Androgen (testosterone, etc.), follicular progestin (estradiol, estriol, etc.), bactericidal disinfectant for skin, wound protectant, external preparation for purulent diseases (kanamycin, etc.), parasitic dermatitis agent (miconazole, etc.) ). These agents may be used alone or in combination of two or more, and are usually used in a range of about 0.001 to 20% by weight.

Among the drugs for the transdermally administered drug composition of the present invention, skeletal muscle relaxants (tizanidine), antitussive expectorants (tulobuterol), antivertigo agents (difenidol), narcotics (buprenorphine, fentanyl), circulatory organs A suitable agent (ibudilast) is mentioned.

The composition for transdermal administration of the present invention is appropriately administered to the skin as an external preparation such as a lotion, an impregnating agent, a gel, a gel cream, a cream, a liniment, a nasal drop, and a reservoir patch. Is done. In these external preparations, a gelling agent (thickener) may be added as necessary. For example, examples of the gelling agent include a suitable gelling agent such as carboxyvinyl polymer, sodium polyacrylate, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, carboxymethylcellulose and the like.

Further, additives such as an ultraviolet absorber, an antioxidant, and a preservative may be added as necessary. For example, as an ultraviolet absorber, known P-aminobenzoic acid derivatives, anthranilic acid derivatives, salicylic acid derivatives, coumarin derivatives, amino acid derivatives, benzotriazole derivatives, tetrazole derivatives, imidazoline derivatives, pyrimidine derivatives, dioxane derivatives, furan derivatives, pyrone derivatives , Camphor derivatives, nucleic acid derivatives, allantoin derivatives, nicotinic acid derivatives, shikonin or vitamin 6 derivatives, and benzophenone derivatives such as 2-hydroxy-4-methoxybenzophenone derivatives are particularly preferred. Examples of the antioxidant include ascorbic acid, stearic acid ester, sodium ascorbate, and tocopherol (α-tocopherol, β-tocopherol,
d-forms such as γ-tocopherol and δ-tocopherol, 1
Isomer, d1 isomer) and ester derivatives thereof, nordihydroguaseletinate, dibutylhydroxytoluene, butylhydroxyanisole, tert-butylhydroxynone gallate (esters such as ethyl, propyl and isoamyl), 1-oxo-3 Suitable antioxidants such as -methyl-4-isopropylbenzene are exemplified.

As the preservative, benzoic acid, sodium benzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, butyl paraoxybenzoate and the like are appropriately used.

The drug composition for transdermal administration of the present invention comprises a solution, and the drug contained therein is efficiently and continuously absorbed into the circulating blood efficiently via the skin. The irritation on the skin, which is the site of administration, is extremely low. A sustained effective blood concentration can be obtained without undergoing drug metabolism due to the first-pass effect in the liver seen during oral administration. It is also expected to avoid possible side effects associated with a rapid increase in blood concentration caused by oral administration. Thus, the drug composition for transdermal administration of the present invention is particularly useful as an external preparation for transdermal application.

Examples Examples of the present invention are shown below, and will be described more specifically. In Examples, "%" means "% by weight".

Example 1 Ethanol 24% Buffer aqueous solution 43% Glycerin retention 25% Absorbed lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% Carboxymethylcellulose sodium salt 3.5% (CMC Na) total amount 100% Hydrochloric acid Tulobuterol (3%) was added and mixed to obtain a drug composition for transdermal administration of the present invention.

Example 2 Ethanol 24% Buffer aqueous solution 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Sorbitan monolaurate 1% Glycerin monooleate 3% Hydroxypropyl methylcellulose-4000 (HPMC 4000) 2% Total amount 100% Citric acid Fentanyl 2% was added and mixed to obtain a transdermal drug composition of the present invention.

Example 3 Ethanol 24% Buffer aqueous solution 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Glycerin monolaurate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% Add and mix alprenolol hydrochloride 5% Thus, a transdermal drug composition of the present invention was obtained.

Example 4 Ethanol 20% Buffer aqueous solution 45% Polyethylene glycol 300 30% Myristyl alcohol 1% Glycerin monooleate 2% HPMC 4000 2% Total amount 100% Add 5% ibudilast to this and mix it. A drug composition was obtained.

Example 5 Ethanol 24% Buffer aqueous solution 46% Polyethylene glycol 300 26% Myristyl alcohol 1% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% This was mixed with 5% tulobuterol hydrochloride and then transdermally administered according to the present invention. A drug composition was obtained.

Example 6 Isopropanol 40% Buffer aqueous solution 20% Polyethylene glycol 300 35% Myristyl alcohol 1% Sorbitan monolaurate 2% HPMC 4000 2% Total amount 100% To this, 1% tulobuterol hydrochloride was added and mixed. A drug composition was obtained.

Example 7 Ethanol 10% Buffer aqueous solution 65% Polyethylene glycol 400 20% Lauryl alcohol 1% Sorbitan monolaurate 2% HPMC 4000 2% Total amount 100% This was mixed with 10% tulobuterol hydrochloride and then transdermally administered according to the present invention. A drug composition was obtained.

Comparative Example 1 Moisturizing, no stimulation reduction Ethanol 49% Buffered aqueous solution 47% Absorbed lauryl alcohol 1% CMC Na 3% Total amount 100% Fentanyl citrate 2% was added thereto and mixed.
A comparative example pharmaceutical composition was obtained.

Proportional example 2 No absorption promotion Ethanol 40% Buffer aqueous solution 37% Stab glycerin monooleate 10% Glycerin retention 10% CMC Na 3% Total amount 100% This was mixed with 5% of ibudilast to obtain a comparative composition. .

Comparative Example 3 Stimulation reduction, no absorption promotion Ethanol 30% Buffer aqueous solution 47% Glycerin retention 20% CMC Na 3% Total amount 100% To this, 5% of alprenolol hydrochloride was added and mixed to obtain a composition for Comparative Example.

Comparative Example 4 No irritation reduction Ethanol 30% Buffered aqueous solution 42% Myristic acid 5% Glycerin 20% CMC Na 3% Total amount 100% To this, 3% of tulobuterol hydrochloride was added and mixed to obtain a comparative example composition.

Using the pharmaceutical compositions obtained in Examples 1 to 7 and Comparative Examples 1 to 4 above, using incised skin of a hairless mouse
The results of the skin permeability test of the drug in vitro and the results of the skin irritation test of the pharmaceutical composition are shown in Table 1 below.

Example 8 With respect to the base composition for transdermal administration of the present invention, the amount of ingredients was changed and the skin irritation of only the base was evaluated.

(Example 8-1) Ethanol 24% buffer aqueous solution 51% glycerin 25% total amount 100% (Example 8-2) Ethanol 24% buffer aqueous solution 51% polyethylene glycol 300 25% total amount 100% (Example 8-3) ) Ethanol 24% Buffer aqueous solution 46% Glycerin 25% Lauryl alcohol 1% Glycerin monooleate 3% Sorbitan monolaurate 1% Total amount 100% or more Table 3 shows the results of evaluation of skin irritation.

On the other hand, if the lower alcohol is more than 60% by weight, the humectant is less than 10% by weight, the absorption enhancer is more than 15% by weight, and if the irritation reducing agent is more than 15% by weight, skin irritation is caused. Was much higher than the above results.

In addition, when a drug was blended in the base composition, the characteristics of the composition of the present invention were evaluated in comparison with the following Example 9 and Comparative Examples 5 to 9.

Example 9 Ethanol 24% Buffer aqueous solution 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this, 3% tulobuterol hydrochloride was added. A transdermal drug composition of the invention was obtained.

Comparative Example 5 Ethanol 0% Buffer aqueous solution 68.5% Glycerin retention 25% Lauryl-absorbed alcohol 0.5% Stab glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% Tulobuterol hydrochloride 3% was added thereto. A comparative composition of the invention was obtained.

Comparative Example 6 Ethanol 60% Buffered Aqueous Solution 13.5% Glycerin 20% Lauryl Alcohol 0.5% Glycerin Monooleate 3% Sorbitan Monolaurate 1% HPMC 4000 2% Total 100% To this, 3% Tulobuterol hydrochloride was added. I got

Comparative Example 7 Ethanol 24% Buffer aqueous solution 48.5% Glycerin 25% Lauryl alcohol 0.5% Glycerin monooleate 0% Sorbitan monolaurate 0% HPMC 4000 2% Total amount 100% To this, 3% tulobuterol hydrochloride was added. I got

Comparative Example 8 Ethanol 24% Buffered aqueous solution 13.5% Glycerin 55% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this, 3% tulobuterol hydrochloride was added, and the composition of the comparative example was added. I got

Comparative Example 9 Ethanol 24% Buffered aqueous solution 60% Glycerin 10% Lauryl-absorbed alcohol 0% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this, 3% tulobuterol hydrochloride was added. I got something.

Table 4 below shows the evaluation results of the skin permeation amount and skin irritation index for Example 9 and Comparative Examples 5 to 9 described above.

Example 10 Ethanol 24% Buffered aqueous solution 44.5% Glycerin 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this was added 1% tizanidine hydrochloride. A drug composition for skin administration was obtained.

Example 11 Ethanol 24% Buffered Aqueous Solution 44.5% Glycerin 25% Lauryl Alcohol 0.5% Glycerin Monooleate 3% Sorbitan Monolaurate 1% HPMC 4000 2% Total 100% Diphenidol 1% was added thereto, and the transdermal composition of the present invention was added. A drug composition for administration was obtained.

Example 12 Ethanol 24% Buffer aqueous solution 44% Glycerin 25% Lauryl alcohol 1% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this, 1% buprenorphine hydrochloride was added. A drug composition for skin administration was obtained.

The transdermal administration drug compositions of the present invention of Examples 10 to 12 were evaluated for the amount of skin permeation and the skin irritation index.
The results are shown in Table 5 below, all of which had excellent performance.

Example 13 Ethanol 24% Buffered aqueous solution 43% Glycerin 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% Carboxymethylcellulose-sodium salt (CMC Na) 3.5% Total amount 100% In addition, tulobuterol hydrochloride 3% Was added and mixed to obtain a drug composition for transdermal administration of the present invention.

Example 14 Ethanol 24% Buffer aqueous solution 44.5% Polyethylene glycol 300 26% Lauryl alcohol 0.5% Glycerin monolaurate 3% Sorbitan monolaurate 1% Hydroxypropyl methylcellulose-4000 (HPMC 4000) 2% Total amount 100% Tulobuterol hydrochloride 3% was added and mixed to obtain a drug composition for transdermal administration of the present invention.

Example 15 Ethanol 24% Buffer aqueous solution 43.5% Polyethylene glycol 400 25% Lauryl alcohol 0.5% Glycerin monolaurate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% This was mixed with 0.5% tulobuterol hydrochloride. A transdermal drug composition of the present invention was obtained.

Example 16 Ethanol 20% Buffer aqueous solution 45% Polyethylene glycol 400 30% Myristyl alcohol 1% Glycerin monooleate 2% HPMC 4000 2% Total amount 100% This was mixed with 5% tulobuterol hydrochloride, and then transdermally administered according to the present invention. A drug composition was obtained.

Example 17 Ethanol 24% Buffer aqueous solution 46% Polyethylene glycol 300 26% Myristyl alcohol 1% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% To this, 3% tulobuterol hydrochloride was added and mixed. A drug composition was obtained.

Example 18 Isopropanol 40% Buffer aqueous solution 20% Polyethylene glycol 400 35% Myristyl alcohol 1% Sorbitan monolaurate 2% HPMC 4000 2% Total amount 100% To this, 1% tulobuterol hydrochloride was added and mixed. A drug composition was obtained.

Example 19 Ethanol 10% Buffer aqueous solution 65% Polyethylene glycol 400 20% Lauryl alcohol 1% Sorbitan monolaurate 2% HPMC 4000 2% Total amount 100% This was mixed with 10% tulobuterol hydrochloride and then transdermally administered according to the present invention. A drug composition was obtained.

Comparative Example 10 (See JP-A-61-249934) Ethanol 49% Buffered aqueous solution 47% Lauryl alcohol 1% CMC Na 3% Total amount 100% To this, 3% tulobuterol hydrochloride was added and mixed to obtain a comparative example pharmaceutical composition. .

Comparative Example 11 (refer to JP-A-2-115131) Ethanol 40% Buffer aqueous solution 37% Glycerin 10% Stab glycerin monooleate 10% CMC Na 3% Total amount 100% To this, 3% tulobuterol hydrochloride was added and mixed. A composition was obtained.

Using the pharmaceutical compositions obtained in the above Examples 13 to 19 and Comparative Examples 10 to 11, using hairless mouse excised skin
As a result of the skin permeability test of tulobuterol in vitro,
Table 6 shows the results of the human skin irritation test of the pharmaceutical composition.

In addition, about the skin irritation test, the skin irritation index was calculated | required using the judgment of following Table 7.

Example 20 Ethanol 24% Buffer aqueous solution (pH 6.8) 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% Tulobuterol hydrochloride 2% Was added to obtain an example composition of the present invention.

Comparative Example 12 Ethanol 24% Buffered aqueous solution (pH 4.0) 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total amount 100% Tulobuterol hydrochloride 2% Was added to obtain a composition of Comparative Example.

Comparative Example 13 Ethanol 24% Buffered aqueous solution (pH 9.0) 44.5% Polyethylene glycol 300 25% Lauryl alcohol 0.5% Glycerin monooleate 3% Sorbitan monolaurate 1% HPMC 4000 2% Total 100% Tulobuterol hydrochloride 2% Was added to obtain a composition of Comparative Example.

The skin permeation amount and skin irritation index were evaluated in the same manner for Example 20 and Comparative Examples 12 and 13 described above. The results are shown in Table 8 below.

As is clear from Table 8, it is well understood that it is preferable to use a buffer having a pH of 6 to 7.

Example 21 The blood concentration of tulobuterol at the time of rat administration was evaluated for the transdermally administered drug composition obtained in the above Example 20, while comparing with the case of oral administration.

The results were as shown in Table 9 below. Table 9 shows that the composition of the present invention is a drug excellent in absorbability.
I understand more.

INDUSTRIAL APPLICABILITY The base composition for transdermal administration of the present invention and the pharmaceutical composition thereof promote drug absorption while suppressing skin irritation at the site of administration, and are directly retained in the circulating blood via the skin. The drug can be absorbed by the target. A sustained effective blood concentration can be obtained without undergoing drug metabolism due to the first-pass effect in the liver seen during oral administration. It is also expected to avoid possible side effects associated with a rapid increase in blood concentration caused by oral administration.

Therefore, the present invention is extremely useful as a new drug formulation.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification code FI A61K 31/4453 A61K 31/4453 31/4468 31/4468 47/10 47/10 47/14 47/14 (56) References Kaihei 2-115131 (JP, A) (58) Field surveyed (Int. Cl. ⁷ , DB name) A61K 9/00-9/72 A61K 47/00-47/48

Claims (19)

(57) [Claims] A humectant whose composition is a lower alcohol 10-60 aliphatic polyhydric alcohol or a sugar alcohol as a weight percentage 10-50 water 10-70 Medium or long chain fatty acid ester or A transdermal administration base composition comprising a sorbitol fatty acid ester or a mixture thereof, a stimulant reducing agent 0.1 to 15; an absorption enhancer 0.1 to 15 which is a medium- or long-chain fatty acid or fatty alcohol. Stuff. 2. A humectant whose composition is a lower alcohol 10-40 aliphatic polyhydric alcohol or a sugar alcohol as a weight percentage. 20-40 Water 20-70 Medium- or long-chain fatty acid ester or 2. A transdermal administration base composition according to claim 1, comprising a stimulant reducing agent 1-10 which is a sorbitol fatty acid ester or a mixture thereof, and an absorption enhancer 0.1-10 which is a medium-chain or long-chain fatty acid or fatty alcohol. . 3. The base composition for transdermal administration according to claim 1, wherein the humectant is glycerin or polyethylene glycol. 4. The stimulant reducing agent is glycerin monooleate,
The base composition for transdermal administration according to claim 1 or 2, which is glycerin monolaurate or sorbitan monolaurate or a mixture thereof. 5. The base composition for transdermal administration according to claim 1, wherein the absorption enhancer is lauryl alcohol or myristyl alcohol. 6. The base composition for transdermal administration according to claim 1, wherein the lower alcohol is ethanol or isopropanol. 7. The base composition for transdermal administration according to claim 1, wherein the pH of buffer water as a water component is 6 to 7. 8. The base composition for transdermal administration according to claim 1, wherein the pH of the composition is 4 to 9. 9. A drug composition for transdermal administration comprising a pharmacologically active ingredient in the base composition according to any one of claims 1 to 8. 10. The pharmaceutical composition for transdermal administration according to claim 9, which comprises an antitussive expectorant as an active ingredient. 11. The pharmaceutical composition for transdermal administration according to claim 10, comprising tulobuterol or a salt thereof as an active ingredient. 12. The pharmaceutical composition for transdermal administration according to claim 9, comprising a skeletal muscle relaxant as an active ingredient. 13. The pharmaceutical composition for transdermal administration according to claim 12, comprising tizanidine or a salt thereof as an active ingredient. 14. The pharmaceutical composition for transdermal administration according to claim 9, which comprises an anti-vertigo agent as an active ingredient. 15. The pharmaceutical composition for transdermal administration according to claim 14, which comprises diphenidol or a salt thereof as an active ingredient. 16. The pharmaceutical composition for transdermal administration according to claim 9, which comprises a drug as an active ingredient. 17. The pharmaceutical composition for transdermal administration according to claim 16, comprising buprenorphine or fentanyl or a salt thereof as an active ingredient. 18. The pharmaceutical composition for transdermal administration according to claim 9, comprising a circulatory organ agent as an active ingredient. 19. The pharmaceutical composition for transdermal administration according to claim 18, comprising ibudilast or a salt thereof as an active ingredient.