JPH05201879A - Percutaneous administration pharmaceutical - Google Patents

Abstract

PURPOSE:To obtain the subject pharmaceutical excellent in skin permeability and safety and useful as ointments, etc., by blending a medicine having a high solubility in triethylene glycol with the triethylene glycol and terpenes. CONSTITUTION:The objective pharmaceutical is obtained by blending a medicine such as dantrolene sodium having a high solubility in triethylene glycol in an amount of preferably 0.1-10wt.% based on the weight of a plaster with the triethylene Glycol in an amount of preferably 1-20wt.% based on the weight of the plaster, terpenes in an amount of preferably 0.1-20wt.% based on the weight of the plaster and ethanol and/or isopropanol in an amount of preferably 1-20wt.% based on the plaster.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a transdermal preparation having excellent transdermal permeability of a drug having a relatively high solubility in triethylene glycol. More specifically, it relates to a transdermal preparation containing a drug having relatively high solubility in triethylene glycol, triethylene glycol, and terpenes.

[0002]

2. Description of the Related Art Transdermal Therap
The eutic system (TTS) has been proposed as a technology that enables systemic treatment by transdermal administration against the background of the concept of pharmacokinetics or drug delivery system and the progress of formulation technology. It has been tried with various drugs because of its advantages such as persistence, reduction of side effects, and avoidance of inactivation by first passage in the liver, and scopolamine, nitroglycerin, clonidine, and isosorbite nitrate have already been put on the market.

Generally, the epidermal tissue of animals has a barrier mechanism for preventing the invasion of foreign substances, and the transdermal absorption of a drug is determined by the interaction among the drug used, the base and the skin. well known. Therefore, the formulation of TTS can be achieved by solving several problems related to the percutaneous absorption of the drug used, and among them, enhances the permeation rate of the drug during the stratum corneum permeation process In particular, it is important to combine this increased transdermal permeability of the drug into a system without impairing it in order to exert an appropriate drug effect under the appropriate administration control. Also,
In the case of transdermal preparations intended for direct action on muscle tissue, it is also important to consider the permeability of the subcutaneous fat layer.

It is conventionally known that a specific terpene can be a transdermal absorption enhancer for a specific drug. Among them, it has been disclosed in Japanese Patent Application Laid-Open No. 63-227524 that peppermint oil enhances the percutaneous absorption of flurbiprofen. The same thing is illustrated in Japanese Patent Laid-Open No. 40420/1988. It has also been reported that menthol can be used as one of the percutaneous absorption enhancers of diclofenac sodium (Abstracts of the 5th Annual Meeting of the Pharmaceutical Society of Japan, 62-63).
P., September 26, 1989).

A combination of a specific terpene such as linalool or farnesol or a specific terpene such as sesquiterpene alcohol, a lower alcohol and water enhances transdermal absorption of various drugs and enables formulation. Is also known (Japanese Patent Laid-Open No. 61-24993).
4 publication). Nagai et al. Are studying various terpenes as percutaneous absorption enhancers of indomethacin, ketoprofen and diclofenac sodium, and use a hydrous gel of ethanol as the vehicle [Drug Design a
nd Delivery, 4 , 313 (1989), Japanese Society of Pharmaceutical Sciences, 109th Annual Conference, 131 (1989), 1st.
6th, Proceed. Intern. Symp. Control. Rel. Bioact.
Mater., Pp. 181-182 (1989), the 5th Annual Meeting of the Pharmaceutical Society of Japan].

Further, in the case of specific indomethacin and diazepam, for the outer skin administration, a specific terpene of p-menthane, α-terpinene, pinene and myrcene and a dissolving agent for lower alcohol, glycols and pyrrolidone are blended. It is disclosed in JP-A-63-225316 that the composition enhances transdermal absorption of these drugs. Preferred examples of the glycols include alkylene glycols such as propylene glycol and ethylene glycol (the alkylene portion preferably has 2 or 3 carbon atoms).

Further, JP-A-1-186824 discloses that a composition for external skin administration containing a specific natural essential oil and a hydrophilic solvent in a specific mixing ratio enhances transdermal absorption of ketoprofen, lorazepam and the like. As the hydrophilic solvent, methanol, ethanol, n-propanol, isopropanol, propylene glycol, ethylene glycol, hexylene glycol, glycerin and polyethylene glycol are listed, and ethanol is particularly preferable.

Furthermore, Barry et al. Investigated the effects of terpenes themselves and their combination with propylene glycol (PG) on the skin permeation properties of 5-fluorouracil. It reported that it showed a permeation enhancing effect [16th, Proceed. Int
ern. Symp. Control. Rel. Bioact. Mater., No. 33-
34 (1989)].

[0009]

[Problems to be Solved by the Invention] Terpenes are less irritating than other excellent synthetic percutaneous absorption enhancers and may be highly safe percutaneous absorption enhancers (said Nagai et al. However, the formulation without a vehicle has not yet reached a practical effect of promoting percutaneous absorption.
Therefore, the above-mentioned Japanese Patent Laid-Open Nos. 63-227524 and 64
Swiss Patent Publication No. 64134
The vehicle also has the effect of promoting the percutaneous absorption of a specific drug by the specific terpenes disclosed in No. 6 and British Patent Publication No. 2133690 or by the terpene of the specific structure disclosed in JP-A-1-228920. A formulation without is not sufficient.

On the other hand, an attempt has been made to enhance the absorption promoting ability of a specific terpene by combining it with other transdermal absorption enhancers such as Azone (trade name of Nelson Co.) and DMSO (JP-A-61-33129). No. 60-69
No. 015 and JP-A-61-129140) may reduce the absorption promoting ability of terpenes depending on the type of drug or base.

Therefore, the above-mentioned water-containing ethanol and propylene glycol as a co-solvent for enhancing the transdermal absorption promoting ability are exclusively used as vehicles for effectively exhibiting the transdermal absorption promoting ability and enabling formulation. It is the actual situation.

However, as seen in the reports of Nagai et al. And Barry et al., The permeation enhancing ability is completely different depending on the type of terpene due to the difference in drug and vehicle. In addition, not only the drugs that can be used with hydrous ethanol are limited, but also the solubility is often poor, and the ability to promote transdermal absorption has not yet been fully demonstrated, and practical T
It was not sufficient to design the formulation of TS.

Also in propylene glycol,
Due to insufficient solubility of some drugs, it was necessary to use a large amount of propylene glycol in transdermal preparations.
However, when used in large amounts, transdermal preparations, especially TTS
Not only was the formulation unstable in time, it was difficult to combine it into a system, but propylene glycol had strong skin irritation and had problems in terms of safety.

[0014]

[Means for Solving the Problems] Under such a technical level,
With the objective of developing a formulation that can effectively exert the ability of terpenes to promote percutaneous absorption of drugs, that is stable over time, has excellent safety, and can be combined as a controllable TTS system As a result of intensive research, it was found that 1,3-butylene glycol (butanediol), which is widely used in the field of TTS preparations or conventional patches, is used in place of propylene glycol to improve the transdermal absorption-promoting effect of terpenes. It was confirmed that it was attenuated rather than when.

As a result of further earnest research, surprisingly, triethylene glycol not only synergistically enhances the ability of terpenes to promote percutaneous absorption at a rate equal to or higher than that of propylene glycol, but is also superior to propylene glycol over time. Stability and safety, this property is common to drugs whose solubility in triethyl glycol is relatively higher than that of general-purpose glycols such as propylene glycol and 1,3-butylene glycol, and the non-aqueous system Of course, the present invention has been completed by finding that it is an effective vehicle even in a water-containing system for preparing a TTS preparation.

That is, an object of the present invention is to provide a transdermal preparation characterized by containing a drug having relatively high solubility in triethylene glycol, triethylene glycol and terpenes, and to provide the same. It is a thing. It is already known that triethylene glycol, like other polyhydric alcohols, can be a solubilizer for a specific drug and that it can be incorporated into a transdermal preparation such as minoxidil.

However, as a vehicle for exerting the absorption promoting ability of terpenes, there is a patent document having a general description of glycols as described above, but no examples or specific examples are shown. In addition, it is not only superior in drug solubility to propylene glycol and 1,3-butylene glycol, which are widely used in the field of transdermal preparations, but also stable and safe over time. Further, it was completely unexpected that it was equivalent to or more than propylene glycol and was useful as a vehicle that synergistically enhances the absorption promoting ability of terpenes than 1,3-butylene glycol.

Regarding the effect of promoting percutaneous absorption of the composition of the present invention, dantrolene sodium which is a skeletal muscle relaxant,
It was confirmed with non-steroidal anti-inflammatory drugs, indomethacin and ketoprofen.

Unlike many other peripheral muscle relaxants, dantrolene sodium is a drug that exerts a muscle relaxant action by directly inhibiting calcium release during excitatory contraction-related phases of the skeleton without going through the nervous system, Already in use. However, the current route of administration is oral or injection, and various side effects have been reported because the action of the drug extends to the whole body other than the affected area. Therefore, systemic administration is not preferable for local myotonic disease, and there has been a demand for the development of a TTS formulation that allows the drug to be mainly transferred into the muscle, which is the site of the disease. However, dantrolene sodium has a very poor skin absorption, and in developing a TTS formulation, a composition of a percutaneous absorption enhancer and a base suitable for a transdermal administration system for greatly improving the skin permeability of dantrolene sodium was developed. Had to develop.

When the above-mentioned Azone (trade name of Nelson Co.) is further added to the system of terpene such as dantrolene sodium and mint oil and triethylene glycol, the transdermal permeability of dantrolene sodium is rather reduced. Has been confirmed.

Further, regarding many non-steroidal anti-inflammatory agents, there is a demand for TTS preparation for the purpose of systemic treatment for reducing side effects, as seen in many known documents.

The transdermal preparation of the present invention will be described in detail below. In the present invention, a drug having a relatively high solubility in triethylene glycol means that the composition of the present invention achieves the purpose of preparing a transdermal preparation utilizing the advantages of TTS. It refers to a drug that is soluble and has a higher solubility than propylene glycol and 1,3-butylene glycol, which are widely used glycols in the field of transdermal preparations.

Specifically, propylene glycol and 1,
Compared with the solubility in 3-butylene glycol, the solubility in triethylene glycol is 1.5 times or more,
It is preferably twice or more. The therapeutic purpose of the drug may be local or systemic. Examples of the drug having such properties include, but are not limited to, dantrolene sodium, indomethacin, ketoprofen, diclofenac sodium, flurbiprofen and the like. It has been confirmed that the solubility of ketotifen fumarate and atenolol in triethylene glycol is inferior to that of propylene glycol, and therefore it is not suitable for TTS formulation.

These drugs do not prevent combination with other drugs as long as the action and effect of this system are not impaired. The amount of drug used is 0.1 to 1 with respect to the total amount of plaster.
It is 0% by weight, preferably 0.2 to 5% by weight, whereby the precise drug effect as a TTS preparation can be exerted under control.

In the present invention, the terpenes are not particularly limited as long as they are terpenes which have a relatively high solubility in triethylene glycol in the system of triethylene glycol and which have the ability to promote percutaneous absorption of drugs. Examples of terpenes having such properties include monoterpene alcohols, sesquiterpene alcohols, terpenes having a molecular formula (C ₅ H ₈ ) containing no oxygen atom, and natural essential oils containing these terpenes.

Specific examples of the monoterpene alcohol include citronellol, geraniol, nerol,
Stereoisomers such as linalool, menthol, terpiol, carveol, twill alcohol, pinocampheol, β-fentyl alcohol, cineol, dimethyloctanol, hydroxycitronellol, tetrahydrolinalool, mugol, myrcenol and their optical isomers

Specific examples of sesquiterpene alcohols include stereoisomers such as farnesol, nerolidol, lanseol, santalol, isopulegol, nobor, bornylmethoxycyclohexanol, betibenol and optical isomers thereof.

Molecular formula (C ₅ H ₈ ) _n containing no oxygen atom
Terpenes having n are half terpenes with n = 1, terpenes with n = 2, sesquiterpenes with n = 3, diterpenes with n = 4, sesterterpenes with n = 5, triterpenes with n = 6, n = 8 or more. And polyterpenes, such as acyclic myrcene, ocimene, monocyclic limonene, terpinolene, ferrandrene, terpinene,
Silvestrene, Ottoman, Bicyclic Zen, Sabinen, Karen, α-Pinene, Fengchen, Kanfel,
Santen, further bisabolene as the C ₁₅ or more, zingiberene, curcumene, cadinene, alpha-selinene, alpha-
Examples include chamigren, camphilene, santalen, α-camphorene, remuen, kaurene, and phygraden.

As the natural essential oils, bay oil, lemon leaf oil, hop oil, burdock oil, goshhi fruit oil, orange peel oil, tangerine oil, summer tangerine oil, orange oil, peppermint oil, needle oil, camphor oil. , Salamander oil, coriander oil,
Manila elemi oil, gingergrass oil, eucalyptus oil, perilla oil, hazelnut oil, cilantro oil, camphor oil, linseed oil, sabina oil, turpentine oil, basil oil, orange flower oil, Siberian needle oil, ogarkaya oil, valer Oil, sandalwood oil, malva mint essential oil, myrrh essential oil, lemon oil, ginger rhizome essential oil,
Turmeric essential oil, cedar oil, cypress oil, celery seed essential oil, taiwan cypress oil, sesame essential oil, clove oil, cinnamon oil, geranium oil, lavender oil, rosemary oil, pepper oil, ylang ylang oil, cananga oil, perilla oil, Examples include panchuri oil, vetiver oil, spearmint oil, and anise oil.

These terpenes may be used alone or as a mixture. Among these terpenes, peppermint oil, orange oil, turpentine oil, and l-menthol are particularly excellent, and especially limonene, which has been recognized as being excellent among conventional terpenes, and orange containing 90% or more thereof. Mint oil and 1-menthol are remarkably superior to oils, and these are mentioned as the optimum ones. The amount of terpenes used varies depending on the type, but is 0.1 to 20% by weight, especially 0.5
-15% by weight is advantageous.

The amount of triethylene glycol used varies depending on the combination of the drug, other bases, solvents and the like, but it is the amount that dissolves the drug and achieves the object of the present invention. It is preferable that the drug can be dissolved in this transdermal preparation system in an amount of 98% by weight, particularly as small as possible, 5 to 70% by weight for a liquid preparation, and 2 to 50% for a patch and the like.
Weight percent is preferred. Also, when ethanol or isopropanol is blended for the purpose of promoting permeation of the fat layer, the amount of triethylene glycol used is 1 to 20 as a liquid agent.
Weight percent is preferred.

The transdermal preparation according to the present invention is most preferably a patch as a preparation form of TTS, but has a usefulness as a highly safe skin application preparation having an excellent effect of promoting transdermal absorption. However, conventional patches, ointments including gel ointments, and transdermal preparations such as emulsions and solutions may be used.

The patch as a preparation form of TTS usually comprises a support and a pressure-sensitive adhesive layer capable of releasing the drug (when the drug is mixed with the pressure-sensitive adhesive layer, when the layers are separated, a special layer is used). In some cases, it may include a drug release part in the form), and a release film that protects this pressure-sensitive adhesive layer.
For simplicity, the patch of the drug-mixable pressure-sensitive adhesive layer will be described. The pressure-sensitive adhesive layer contains a drug having a relatively high solubility in triethylene glycol, triethylene glycol and Mix terpenes with other patch bases to make a plaster.

The patch base is capable of homogeneously admixing the drug, has a pressure-sensitive adhesive property at room temperature, releases the drug when applied, and does not impair the transdermal absorption of the drug promoted by the composition of the present invention. Any base can be used as long as it can be put together as a system with stability over time, and includes all general-purpose patch bases other than the base that diminishes the action of the composition of the present invention.

Specific examples of the adhesive component include natural rubber,
Styrene-butadiene rubber (SBR), polyisoprene rubber, polyisobutylene rubber, styrene-isoprene-
Acrylics such as styrene block copolymer (SIS), styrene-butadiene-styrene block copolymer (SBS), silicone rubber (organopolysiloxane rubber), (meth) acrylic acid- (meth) acrylic acid ester copolymer Natural or synthetic rubbers such as copolymers, super absorbent polymers such as starch acrylate, sodium polyacrylate carboxymethyl cellulose (CMC), sodium carboxymethyl cellulose (CMCNa),
Polyvinyl alcohol (PVA), polyvinylpyrrolidone (PVP), methyl vinyl ether maleic anhydride copolymer, sodium alginate, alginic acid propylene glycol ester, pectin, xanthan gum, xanthan gum, locust bean gum, guar gum, arabinogalactan, sodium hyaluronate, etc. Hydrophilic polymers are mentioned.

Rubber or the like can be used as the latex emulsion. Further, these adhesive components, superabsorbent polymers and hydrophilic polymers can be used in appropriate combination.
Ingredients added to these as necessary are mud-forming agents such as gelatin; kaolin, bentonite, zinc oxide,
Powder excipients such as titanium oxide, calcium chloride and zinc chloride; petroleum resins such as Quinton (trade name, Nippon Zeon Co., Ltd.) and Alcon (trade name, Arakawa Chemical Co., Ltd.), resins such as rosin, hydrogenated rosin and ester gum Tackifying components such as; polybutene, liquid paraffin, higher fatty acid esters such as isopropyl myristate, softening agents such as silicone oil and various vegetable oils; glyceryl fatty acid esters such as glyceryl monostearate, polyoxyethylene sorbitan monolaurate (eg, Nikko Chemicals: TL-1
0), interfaces of polyoxyethylene sorbitan monostearate (eg Nikko Chemicals: TS-10) and other polyoxyethylene sorbitan fatty acid esters, sorbitan monostearate (Nikko Chemicals: SS-10) and other sorbitan fatty acid esters Activator: preservative of methylparaben, ethylparaben, propylparaben, butylparaben, sorbic acid, salts of sorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), nordihydroguaiaretic acid, guaiacol esters, etc. Antioxidants; pH adjusting agents such as acetic acid, succinic acid, citric acid, malic acid, fumaric acid, maleic acid, tartaric acid and other organic acids (there are also properties that are useful as a patch base); aluminum chloride ，
Astringents such as salts that generate trivalent metal ions such as aluminum sulfate, alum, and aluminum allantoinate: moisturizers such as alkaline earth metal salts; flavoring agents; drug solvents; water and the like.

The triethylene glycol of the present invention acts as a solubilizer to enhance absorption and exerts a moisturizing effect by itself, but other polyhydric alcohols such as mannitol, sorbitol, Glycerin Diglycerin, triglycerin, etc. are used as moisturizers, and other solvents that dissolve drugs, such as dantrolene sodium, are used as N-methyl-2-pyrrolidone, ethanol, isopropanol, benzyl alcohol, phenethyl alcohol, macrogol and the moisturizers. It does not prevent the addition of glycerins that act.

In the present invention, it has been confirmed that ethanol and isopropanol have the action of promoting the permeation of the drug through the subcutaneous fat layer. Therefore, in the case of a transdermal drug intended to exert a drug effect in a local muscle site, the therapeutic effect can be further enhanced by blending ethanol and / or isopropanol.

Although terpenes are the most preferable transdermal absorption enhancers, they are preferably transdermal as long as they do not lower the transdermal absorption of the composition of the present invention like Azone (trade name, Nelson). Other transdermal absorption enhancers can be used as long as they promote absorption in an additive or synergistic manner. Examples of such transdermal absorption promoters include diethyl dibasate such as diethyl sebacate and diisopropyl adipate, and fatty acid esters such as isopropyl myristate.

The amount of these bases used is determined in consideration of the amounts of drugs, triethylene glycol and terpenes used, the types of bases, and the effects of the present invention, but the whole preparation (in this case, the plaster) To about 30 to 97% by weight, preferably 6
It is 0 to 92% by weight. It goes without saying that the types and amounts of bases used in water-based patches such as poultices and tapes differ greatly. Also, TT
As an application system for the S formulation, a water-containing system is advantageous.

To produce the patch of the present invention, the drug, triethylene glycol, terpenes, and other components of the base are kneaded uniformly, the kneaded product is spread on a support, and dried if necessary. , Peel off the film, cut it to an appropriate size, and package. Taking into consideration the physicochemical properties of each component of the drug, the base and the percutaneous absorption enhancer composition used for facilitating the preparation of a uniform plaster, the order of addition and kneading is appropriately set or the mixture is heated. ， Sonication is free.

When a poultice or tape preparation is produced by the emulsion method, the rubber and the like as an adhesive component can be prepared in advance as a latex emulsion and added and kneaded. Spreading is carried out according to a conventional method such as keeping the prepared plaster on a support or a release film at an appropriate temperature or by heating to apply the plaster evenly to a predetermined thickness. Drying is performed when a tape preparation having a low water content is produced by the solvent method or the emulsion method, and the solvent or water is volatilized. Next, when the plaster was spread on a support, a release film was attached to the plaster,
When the plaster is spread on the release film, the support is laminated on the spread plaster.

As the support, cloth, non-woven fabric, plastic film or the like is used, and flannel or non-woven fabric is particularly preferable. As the release film, a plastic film such as cellophane or polyethylene film which has been subjected to a release treatment is preferably used. Other external preparations, such as ointments based on macrogol, gels based on carboxyvinyl polymer (hydrogel or hydrophilic gel ointment), water, oily ingredients, emulsions and liquids based on emulsifiers It can be prepared according to a conventional method.

For example, as a liquid drug, a drug having a relatively high solubility in triethylene glycol, a terpene, and another drug or base added as necessary, triethylene glycol or another solvent is added to the drug. It is dissolved by adding a mixture of ethanol and isopropanol, which are fat layer permeation enhancers, to prepare a uniform solution. This is packaged by pouring a predetermined amount into an external liquid agent container.

[0045]

INDUSTRIAL APPLICABILITY The transdermal preparation of the present invention is excellent in transdermal permeability of a drug having a relatively high solubility in triethylene glycol and enables practical formulation of TTS. It is useful for achieving in-vivo absorption of a drug necessary for exhibiting an appropriate drug effect under appropriate administration control. The composition of the present invention is also useful as a transdermal preparation having excellent transdermal absorbability such as conventional patches, ointments such as gel ointments, emulsions and liquids.

In particular, the transdermal preparations using the terpenes of the present invention as a transdermal absorption enhancer are more excellent in solubility and safety than conventionally known propylene glycol.

Among terpenes, peppermint oil and l-
When using menthol, limonene, which was previously recognized as one of the best terpenes, and 9
It was totally unexpected that it showed superior transdermal permeability than orange oil containing 0% or more. In addition, when ethanol or isopropanol is used, it has an excellent property of penetrating the fat layer under the dermis layer, and is extremely useful as a transdermal preparation for delivery to muscle. The action and effect of the present invention have been confirmed by the following test methods.

Test Example 1. Solubility test of each drug in triethylene glycol- [Test method] Triethylene glycol (TEG) about 5
After taking up ml, each drug was dissolved in this solution in an excessive amount (ultrasonic dispersion and heating treatment), and then allowed to cool to room temperature to precipitate an excess amount. Then, centrifugation was performed, and the supernatant was filtered with a filter. The solubility of the obtained filtrate was calculated by the molar absorption method. [Results] Solubility (mg / ml)

[0049]

[Table 1]

Test Example 2. In-vit as a transdermal absorption test
The evaluation was performed in the ro experiment. The drugs used were indomethacin and ketoprofen. Mint oil was used as an example of the terpenes in the TEG / terpene-based solution. [Donator side solution composition]

[0051]

[Table 2]

[Test Method] Wistar, male rats (7-week-old, weight 190-210 g) were shaved on the abdomen, and the skin at the same site was cut to a diameter of 2 cm, and the skin was cut into a two-chamber diffusion cell. I attached it to. TE on the donor side
G / Mentha oil (5%) and a drug solution containing only TEG as a control (see above solution composition) and a phosphate buffer (pH 7.4) on the acceptor side were injected at regular intervals from the acceptor side. A sample was taken. The drug content in the obtained sample was quantified by liquid chromatography. [Results] 2-1) Indomethacin

[0053]

[Table 3]

2-2) Ketoprofen

[0055]

[Table 4]

Test Example 3. By the same test method as in Test Example 2, dantrolene sodium (DN) / various terpenes / TE
The skin permeation amount of the G liquid agent was measured. The absorption promoting effects of peppermint oil, orange oil, turpentine oil and 1-menthol as terpenes were evaluated in a water-containing system. [Liquid formulation]

[0057]

[Table 5]

[Results] The cumulative permeation amount of DN per unit area, Flux and Lag time are shown.

[0059]

[Table 6]

[0060]

[Table 7]

Test Example 4. The skin permeation amount of the PVA gels obtained in Examples 14 and 15 composed of DN / mint oil / TEG was measured by the same test method as in Test Example 2.
As a control, 10% of Azone (trade name, Nelson) was used in place of the peppermint oil in the component formulation of Example 15, and the gel obtained by the method of Example 15 was used. [Result] Cumulative permeation amount of DN, Flux, Lag
time is as follows.

[0062]

[Table 8]

[0063]

[Table 9]

Test Example 5. The porcine skin permeability including the fat layer was evaluated using the test method of the following component formulation consisting of dantrolene sodium / mint oil / TEG / alcohols.

[0065]

[Table 10]

The test solution was prepared by adding each component at about 60 ° C.
It was heated and dissolved in, mixed with 10 g of purified water, and uniformly dispersed by ultrasonic waves. [Test method] Two months old pig skin (LW
D, male or female) abdominal skin (skin with subcutaneous tissue having a thickness of about 2 mm) was thawed immediately before use and attached to a Franz diffusion cell. The test solution is on the donor side and the isotonic 10 mM potassium dihydrogen phosphate solution (pH) on the acceptor side.
4.5) was injected and samples were taken from the acceptor side at regular intervals. The amount of drug permeation through the obtained sample was determined by liquid chromatography. [result]

[0067]

[Table 11]

[Summary] As a result of the above, according to Test Example 1,
The drugs used in the experiment, indomethacin, ketoprofen,
Flurbiprofen, diclofenac sodium and dantrolene sodium are commonly used as moisturizers and solubilizers in the field of percutaneous preparations, and are also known as vehicles that synergistically enhance the transdermal absorbability of terpenes and propylene glycol. Similarly, 1,3-
It was clear that triethylene glycol had a much higher drug solubility than butylene glycol, indicating that it was suitable for formulation.

As is clear from the results of Test Example 2, in a system using triethylene glycol as a vehicle, compared to a control in which indomethacin or ketoprofen soluble in triethylene glycol does not contain terpenes such as peppermint oil. It shows remarkable transdermal permeability. Furthermore, according to Test Example 3, the terpenes used in the experiment all showed excellent transdermal permeability of the drug in the system combined with triethylene glycol, but among them, peppermint oil and 1-menthol had remarkable permeability. It is clear that

Furthermore, the result of Test Example 4 shows that PV with triethylene glycol added is better than that of Azone (trade name, Nelson Co.) known as an excellent percutaneous absorption enhancer.
It is clear that peppermint oil exhibits superior transdermal permeability in the A gel formulation system. It was confirmed that the combination of Azone and terpenes rather lowers the transdermal permeability of dantrolene sodium. It was also confirmed that the system cohesion was improved when a superabsorbent polymer or sugar alcohol such as sorbitol was used as a base. Next, considering the results of Test Example 5, when ethanol and isopropanol are blended, the drug permeability of the skin including subcutaneous tissue is significantly increased. This finding is useful when designing the formulation of a transdermal drug for a drug (such as a muscle relaxant or a muscle enhancer) that exerts a drug effect at a muscle site such as DN.

[0071]

EXAMPLES The present invention will be described in more detail with reference to the following examples. The examples describe the transdermal preparations of the present invention comprising the component formulations shown in the table below.

[0072]

[Table 12]

[0073]

[Table 13]

[0074]

[Table 14]

Example 1. (Natural rubber pap base, indomethacin) 5.0 parts of gelatin and 1.5 parts of methoxyethylene maleic anhydride copolymer were added to an appropriate amount of purified water, heated and dissolved, and then 20.0 parts of kaolin and 0 of zinc oxide. Add 5 parts and mix. Sodium polyacrylate 2.5
Pour, a mixture of 1.0 part of sodium carboxymethyl cellulose and 15.0 parts of concentrated glycerin while pouring, to obtain a mixture A. Separately, 5.0 parts of polybutene, 7.0 parts of liquid paraffin and 1.0 of nonionic surfactant
1 part was heated and melted, and 1.0 part of indomethacin was added to 10.0 parts of triethylene glycol and 1 part of turpentine oil.
Add a solution dissolved in 0.0 part of the mixture, and further add 7.0 parts of natural rubber latex to form a mixture B. Add Admixture B to Admixture A, mix evenly to form a plaster, apply this to a non-woven fabric with a uniform thickness, stick a plastic film on the applied surface and cut into a suitable size to give a poultice. obtain. Example 2. Is also the same.

Example 3. (Water-soluble polymer pap base, dantrolene sodium) 4.0 parts sodium polyacrylate, 1.0 part methoxyethylene maleic anhydride copolymer, 1.0 part sodium carboxymethyl cellulose, 2.0 parts gelatin, concentrated glycerin 10.0 parts, D-sorbitol liquid 30.0 parts,
15.0 parts of kaolin, 1.0 part of an aluminum compound and an appropriate amount of purified water are dissolved and kneaded at 50 ° C. to prepare a paste containing a water-soluble polymer. Add 2.0 parts of dantrolene sodium as an active ingredient to triethylene glycol 1
A solution prepared by dissolving 5.0 parts of mint oil and 1.0 part of mint oil and 1.0 part of a nonionic surfactant, and preparing a mixture while stirring at 40 ° C. to make a paste, which is a non-woven fabric. To a uniform thickness, and a plastic film is attached to the coated surface and cut into an appropriate size to obtain a poultice. Example 4. ~ 6. Is also the same.

Example 7. (Rubber plaster base, diclofenac sodium) Polybutene 18.0 parts, terpene resin 28.5 parts and liquid paraffin 5.0 parts were heated and dissolved, and then diclofenac sodium 1.0 part was added as triethylene. A solution dissolved in a mixture of 10.0 parts of glycol and 10.0 of orange oil is added and mixed with 0.5 part of dibutylhydroxytoluene. Synthetic rubber SBR
17.0 parts (solid content) of latex and 10.0 parts (solid content) of natural rubber latex were added and mixed evenly to form a plaster, which was coated on a release liner and dried with warm air. A non-woven fabric or a plastic film is attached to this and transferred to obtain a plaster.

Example 8. (Acrylic plaster base,
Dantrolene sodium) methacrylic acid / butyl acrylate copolymer 82.5
Parts (solid content), 2.0 parts of dantrolene sodium as an active ingredient was dissolved in 10.0 parts of triethylene glycol, and 5.0 parts of mint oil was added to a solution to which 0.5 parts of dibutylhydroxytoluene was added, and the mixture was evenly added. The mixture was mixed to form a plaster, which was coated on a release liner and dried with warm air. A plastic film is attached to this and transferred to obtain a plaster. Example 9. ~ 11. Is also the same.

Example 13. (SIS plaster base,
Ketoprofen) 22.0 parts of styrene / isoprene / styrene copolymer,
Liquid paraffin (40.2 parts) and terpene resin (27.5 parts) were heated and melted in a N ₂ gas stream at 130 to 170 ° C., and then the melt was cooled. To this melt, 0.3 parts of ketoprofen as an active ingredient was dissolved in 5.0 parts of triethylene glycol, and 5.0 parts of 1-menthol was dissolved in this solution, and the mixture was mixed uniformly to obtain a plaster. ， Apply this to a plastic film to obtain plaster. Example 12. Is also the same.

Example 14 PVA, CaCl in purified water
₂ , ZnCl ₂ , starch acrylate and sorbitol were added and dissolved by heating (110 ° C), and then allowed to cool to room temperature D
A TEG solution of N and peppermint oil were added and frozen at −20 ° C. for 15 hours to obtain a PVA gel agent. Example 15. A PVA gel was obtained in the same manner as in Example 14 except that the starch acrylate and sorbitol were omitted.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification number Office reference number FI technical display location A61K 31/195 8413-4C 31/415 7252-4C 47/46 E 7433-4C (72) Inventor Katsumi Saito 368-2, Mikkana, Yaizu City, Shizuoka Prefecture (72) Inventor Yoshihiro Sawai 1203-1 Toba Goho, Kosugi Town, Imizu-gun, Toyama Prefecture (72) Inventor Hitoshi Takayanagi Kosugi, Imizu-gun, Toyama Prefecture 1203-1 Machito Hagaho Takamitsu Pharmaceutical Co., Ltd. (72) Inventor Kazuki Surijiji 1203-1, Mt. Tobago Hakugo Kosugi-cho, Imizu-gun, Toyama Prefecture (72) Inventor Kiyonori Nagata 1203-1 Toho Goho, Kosugi-cho, Imizu-gun, Toyama Prefecture

Claims (6)

[Claims] 1. A transdermal preparation characterized by containing a drug having a relatively high solubility in triethylene glycol, triethylene glycol, and a terpene. 2. A transdermal preparation comprising a drug having a relatively high solubility in triethylene glycol, triethylene glycol, a terpene, ethanol and / or isopropanol. 3. A drug having a relatively high solubility in triethylene glycol, 0.1 to 10% by weight, triethylene glycol 1 to 98% by weight, and terpenes 0.1 to 20% by weight, based on the weight of the plaster. The transdermal preparation according to claim 1, which is 4. The transdermal preparation according to claim 1, wherein the terpenes are peppermint oil, menthol, orange oil and turpentine oil. 5. The transdermal preparation according to any one of claims 1 to 4, wherein the drug having a relatively high solubility in triethylene glycol is dantrolene sodium. 6. A drug having a relatively high solubility in triethylene glycol, relative to the weight of the paste, 0.1 to 10% by weight, triethylene glycol 1 to 20% by weight, terpenes 0.1 to 20% by weight, ethanol And / or 1 to 20% by weight of isopropanol, The transdermal preparation according to claim 2, 4 or 5.