WO2004002452A1

WO2004002452A1 - Drug composition

Info

Publication number: WO2004002452A1
Application number: PCT/JP2003/007511
Authority: WO
Inventors: Hideaki Sasagawa; Madoka Ito; Takuji Nakashima; Akira Nozawa
Original assignee: Pola Chemical Industries Inc.
Priority date: 2002-06-27
Filing date: 2003-06-12
Publication date: 2004-01-08
Also published as: JPWO2004002452A1; AU2003242346A1

Abstract

A drug composition comprising a film forming agent (1), a water soluble plasticizer being in solid or paste form at 20ºC under 1 atm (2) and a drug (3), so that there is provided a drug composition which is capable of controlling the release of drug and is effective for application targets, such as hyperkeratinized part, joint part and part remote from lesion.

Description

Specification

Pharmaceutical composition technical field

The present invention relates to a pharmaceutical composition, and more particularly, to a pharmaceutical composition suitable for external use on the skin, and in particular, which can be used as a subject to be applied to skin at an area of hyperkeratosis, a joint or a site remote from a lesion. Background art

In the field of pharmaceuticals, DDS (drug 'delivery' system) or TTS (transdermal absorption system) is important from the pharmacokinetic point of view, and many transdermal pharmaceutical preparations have been developed for this purpose.

The challenges of such a transdermal system are to increase the transdermal absorption of the drug to a pharmaceutically effective amount and to control the characteristics of the drug over time to make it pharmacokineticly favorable. is there.

Among them, as the technology for promoting percutaneous absorption, there has been found a technology of using azone, phospholipid, higher alcohols, polyhydric alcohols, etc., and a technology of combining an adhesive material in a patch form. However, there has been no noticeable progress in controlling drug release properties. Especially in the non-patch form, the amount of drug storage is limited, and no good method of drug release control, including the chronological viewpoint, has been provided.

Therefore, there has been a demand for the development of a dermatological drug formulation that can control drug release regardless of the patch form.

On the other hand, it is not known at all that obtaining a pharmaceutical composition by combining a drug with a specific film-forming agent or a solid or paste-like water-soluble plasticizer at 20 ° C at 1 atm is known. It has never been known that a pharmaceutical composition can form a layer for storing a drug by integrating with a living tissue. Disclosure of the invention The present invention has been made under such circumstances, and it is an object of the present invention to provide a pharmaceutical preparation for external use on the skin that can control drug release in a form independent of a patch form. It is another object of the present invention to provide a pharmaceutical preparation for external use on the skin that is effective for an application target such as a hyperkeratosis site, a joint site, or a site remote from a lesion.

'' In view of such circumstances, the present inventors have made intensive research efforts to provide a pharmaceutical preparation for external use on the skin that can control drug release in a form independent of a patch form. A pharmaceutical composition comprising 1) a film-forming agent, 2) a solid or pasty water-soluble plasticizer at 20 ° C at 1 atm and 3) a drug has such properties. And completed the invention. .

That is, the present invention is as follows.

(1) A pharmaceutical composition comprising: 1) a film-forming agent; 2) a solid or paste-like water-soluble plasticizer at 20 ° C. at 1 atm and 3) a drug.

(2) The pharmaceutical composition according to (1), wherein the film-forming agent is hardly water-soluble or water-insoluble.

(3) The water-insoluble or water-insoluble film forming agent is one or more selected from the group consisting of ethylcellulose, hydroxypropylmethylcell orifice and acryl resin emulsion. Pharmaceutical composition according to (2)

(4) The pharmaceutical composition according to (2), wherein the poorly water-soluble or water-insoluble film-forming agent is ethyl cellulose.

(5) The water-soluble plasticizer in the form of a solid or a paste at 1 atmosphere and 20 ° C is a compound having a polyoxyethylene group and / or a polyoxypropylene group,

The pharmaceutical composition according to any one of (1) to (4).

(6) The pharmaceutical composition according to (5), wherein the water-soluble plasticizer in the form of a solid or a paste at a pressure of 20 ° C. is a oxyethylene propylene copolymer.

(7) If the drug is a steroid, steroid anti-inflammatory, cardiovascular drug, antihistamine, antiviral, anti-inflammatory, local anesthetic, sulfa, antibacterial, moisturizer, vitamins, antibiotic, bactericide or The pharmaceutical composition according to any one of (1) to (6), which is a blood circulation promoter. (8) The pharmaceutical composition according to any one of (1) to (7), wherein the pharmaceutical composition is used as an external preparation for skin.

(9) The medicament according to any one of (1) to (8), wherein the pharmaceutical composition is used as a target to be applied to skin at an area of hyperkeratosis, a joint or a lesion remote from a lesion. Composition. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a diagram showing the results of Example 1.

FIG. 2 is a diagram for explaining the Flange cell used in Example 1, Example 15 and Example 16.

FIG. 3 is a diagram showing the results of Example 15.

FIG. 4 is a diagram showing the results of Example 16.

FIG. 5 is a diagram showing the results of Example 17. BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in detail.

The pharmaceutical composition of the present invention is characterized by comprising 1) a film-forming agent, 2) a solid or paste-like water-soluble plasticizer at 1 atmosphere and 20 ° C., and 3) a drug.

Then, when the pharmaceutical composition of the present invention is applied to an application object, the matrix of the indefinite trait including the film-forming agent, the plasticizer, and the drug is integrated with a part of the living tissue such as the stratum corneum of the skin, Form a layer for storing drugs (hereinafter also referred to as a reservoir). And this reservoir gradually releases the drug over time.

Therefore, the present invention focuses on the function of this matrix composed of the pharmaceutical composition of the present invention, and calls it a bioactive matrix. Further description of bioactive matrices is provided below.

As the film-forming agent contained in the pharmaceutical composition of the present invention, those which are generally used in pharmaceutical compositions and the like, and those which are insoluble or poorly soluble in water can be preferably exemplified.

Here, insoluble or hardly soluble in water means, for example, that the saturated concentration in water at 20 ± 5 ° C is It refers to those having about 1 g / 10 L, preferably about 1 g Z 50 L or less.

Examples of such a film forming agent include alkylcellulose represented by ethylcellulose / hydroxypropylmethylcellulose phthalate, and Eudragit (registered trademark) NE which is a dispersion liquid of ethyl acrylate / methyl methacrylate copolymer. Acrylic resin-based emulsions such as those marketed by Higuchi Shokai under the name of 30D can be preferably exemplified. These can be used solely or in combination of two or more. Particularly preferred among these is the use of ethyl cellulose alone.

The preferable content of the film-forming agent in the antifungal pharmaceutical composition of the present invention is preferably from 0.1 to 10% by weight to the total amount of the pharmaceutical composition, more preferably from 0.3 to 10% by weight. 5% by weight to volume. This is because if the amount of the film-forming agent is too small, a film having sufficient strength may not be obtained, and if the amount is too large, the transfer of the drug may be inhibited.

Examples of the water-soluble plasticizer in the form of a solid or paste at 1 atm of 20 ° C. contained in the pharmaceutical composition of the present invention include oxyalkylene polymers or copolymers such as oxyethylene and oxypropylene. More preferably, the degree of polymerization is large. The oxyalkylene is preferably one having 1 to 4 carbon atoms, and more preferably oxalkylene and / or oxypropylene.

The preferable degree of polymerization of the polyoxyalkylene is preferably 70 or more in total, especially at least 80 or more if only oxyethylene, and at least 70 or more if only oxypropylene, and a combination of oxyethylene and oxypropylene. In this case, preferably, the propylene content is 30 to 80, the oxyethylene content is 35 to 400, and the total of both is 70 or more.

More preferably, it is a copolymer having oxyethylene and oxypropylene, in which the polyoxyethylene chain has a polymerization degree of 100 to 300, and the polyoxypropylene chain has a polymerization degree of 25 to 80. Things.

The oxyalkylene polymer or copolymer may contain only one kind or two or more kinds in combination. However, when two or more kinds are combined, a mixture of such combinations is also solid or solid at 1 atmosphere and 20 ° C. Must maintain a paste-like state.

Among such combinations of plasticizers, a particularly preferable one is a polyoxyethylene having a degree of polymerization of 140 to 180 in the polyoxyethylene portion and a polymerization degree of 20 to 40 in the polyoxypropylene portion. It is a copolymer having only polyoxypropylene ether.

The content of the plasticizer in the pharmaceutical composition of the present invention is preferably from 1 to 10% by weight, more preferably from 3 to 8% by weight, based on the total amount of the pharmaceutical composition. . Further, the content of the film forming agent is preferably 1 to 10 times, more preferably 3 to 8 times.

The drug contained in the present invention can be applied without any particular limitation as long as it can be usually considered for transdermal administration.Antifungal agents such as terbinafine, butenafine etc. ゃ Other drugs except the antifungal agent are applicable. it can.

Specific examples of the drug contained in the present invention include, for example, steroids such as estradiol, estrone, estriol, medroxyprogesterone acetate, norletisterone acetate, norletosterone acetate, mestranol, and danazol; Hydrocortisone butyrate, Propione hydrocortisone butyrate, Predzolone, Methylpredo-zolone, Methylprednisolone acetate, Prednisolone valerate, Dexamethasone, Fluorometrone, Betamethasone, Triamcinolone, Betamethasone valerate, Betamethazone Betamethasone, Butamethapionate Cetonide, Fludroxycortide, Clobetasone butyrate, Betamethasone dipropionate, Clobeta propionate Zol, No, Norecinonide, Amshinonide, Funoreosinolone Acetonide, Fluocinonide, Desoxymethasone, Dexamethasone Acetate, Flumethasone Pivalate, Di-Funoreconoredolone Valerate, Beclomethasone Propionate, Funoredronoconoretisone Steroidal anti-inflammatory agents such as acetate, paramethasone, flumethasone, and Dyke-mouth lysone, cardiovascular drugs such as ritodrine hydrochloride, nitroglycerin, difendipine, dicardipine hydrochloride, diphenhydramine, diphenhydramine hydrochloride, triberenamine, tondiamine, malein Chlorpheniramine acid, Chlorpheniramine, Isocyben dinole climizone, Diphenylimidazo monole, peractin, canolebinoxamishi , Dipheninolevirin, fenbenzamine, incibenzinole, promethazine, promethazine hydrochloride, tridylamine hydrochloride, metzilazine hydrochloride, diphenhydramine salicylate, diphenhydramine tannate, antihistamine such as isothibenzyl hydrochloride, iproheptin hydrochloride, etc. Antivirals such as ganciclovir, sorivudine, etc., bufexamac, suprofen, indomethacin, ketoprofen, ketotifen, acetaminophen, aspirin, methyl salicylate, choline salicylate, glycol salicylate, menthol, camphor, mephenamic acid, fenolefenam Acid, diclofenac, aclofenac, ibuprofen, naproxen, pranoprofen, fenoprofe , Sarindac, fenbufen, clidanac, flu / rebiprofen, butidic acid, fenthiazac, tolmetin, thiaprofenic acid, benzadak, piroxicam, fenirbutazone, oxifenbutazone, clofizon, benzothosine, meglilizin, glitilitin , Azulene, Ibufenac, Ibupu Mouth Fempiconol, Bendithamine, Isothibenzyl, Dicalidium glycyrrhizinate, Camphor, Thymol, Tesit, etc., Anti-inflammatory agents such as dibuforce in hydrochloride, proforce hydrochloride, ethyl ethyl benzoate, dimethisoquin hydrochloride , Promoxine hydrochloride, lidocaine, benzocaine, proforce, jib power, tetracaine hydrochloride, lidocaine hydrochloride, piperocaine drunkate, bramocine hydrochloride, Tetraiki hydrochloride, Mebivacaine hydrochloride, Puvircaine hydrochloride, Cocaine hydrochloride, Catahydroine hydrochloride, Probito hydrochloride, Butani hydrochloride, Oxybutani hydroin, Mebryl butani hydroin hydrochloride, Pilocaine hydrochloride, Chlorobutanol, Ensanmebril Local anesthetics such as force-in and te-force-in, homosnolefamine, snorefamine, snoreisoxazoline, sulfisoxazoline sodium, sulfamethoxazanole, sunolefisomidine, sunolefasiadin, sulfisomidine sodium, Sulfamethoxazole sodium, snorefamonomethoxin Snorfamethazol, snorefapyridine, sulfamethoxin, sulfanilamide, sulfamethoxypyridazine, etc. , Mae Nam acid, antimicrobial agents such as arsphenamine, urea, to Parinoi de, humectants such as glycerin, acetic acid tocopherol, vitamin Α tocopheryl, vitamin C, calcium Asukorubin acid, hydrochloric pyridinium Dokishin, riboflavin, Retino Vitamins, gentamicin sulfate, colistin methanesulfonate, ぺ nicillin G, chloramphenicol, demityl chlortetracycline hydrochloride, fradiomycin sulfate, tricomycin, bacitracin, colistin sulfate, lactopioerythromycin, cefmetazanomycin , Cephalexin, clindamycin, tetrocycline, erythromycin, kanamycin, metronidazonole, cephalosporin, sprebutomycin, cephatridine, amphotericin, chlamicidine, oxytetracycline, doxycycline, minocycline, lincomycin, nystatin, nystatin Antibiotics such as frant-in, bactericides such as hibitenedalconate, phenol and resorcinol, Perenyl amide, benzylene nicotinate, benzylic enolate nicotinic acid, butxineticinolester, capsaicin, gingerone, canthari tincture, dictamol, caffeine, tannic acid, α-orneol, inosinol hexanicotinate, cyclandelate, cinnarizine, Blood circulation promoters such as tolazoline, acetylcholine and verapamil can be preferably exemplified. More preferably, a cardiovascular drug, an antiviral agent, an anti-inflammatory agent, a local anesthetic, an antibacterial agent, a humectant, a vitamin or an antibiotic can be exemplified. The content of these drugs varies depending on the type thereof, but is preferably about 0.1 to 40% by weight to volume based on the total amount of the pharmaceutical composition. This is because if the amount is too small, no medicinal effect may be exhibited, and if the amount is too large, a bioactive matrix dosage form may not be formed.

The pharmaceutical composition of the present invention may contain, in addition to the above-mentioned essential components, any components used in an external preparation for normal skin, etc., as long as the function as a bioactive matrix preparation is not impaired.

Examples of such components include hydrocarbons such as petrolatum and microcrystalline wax, esters such as jojoba oil and gay wax, triglycerides such as tallow, olive oil, and higher alcohols such as cetanol and oleyl alcohol. Fatty acids such as stearic acid and oleic acid, alcohols such as ethanol and isopropanol, polyhydric alcohols such as glycerin and 1,3-butanediol, water, nonionic surfactants, anionic surfactants, and cationic surfactants , Amphoteric surfactants, thickeners such as ethanol and carbopol, preservatives, ultraviolet absorbers, antioxidants, Examples include dyes, powders, and organic solvents.

Of these, particularly preferred components to be included in the pharmaceutical composition of the present invention are anionic surfactants and organic solvents, which work more effectively when the skin permeability of the drug is poor.

The Ayuon surfactant has an effect of promoting the penetration of the drug into a part where the drug hardly penetrates, for example, the inside of hardened skin or the like, and is preferable in this sense. These aeon surfactants can be used alone or in combination of two or more.

As the anionic surfactant, any of a sulfuric acid-based anionic surfactant and a phosphoric acid-based anionic surfactant can be used, and may or may not have a polyoxyethylene chain. More preferred are an alkyl sulfate which may have a polyoxyethylene group and an anoalkyl phosphate which may have a polyoxyethylene group. More preferred are alkyl sulfates and / or tripolyoxyethylene-added alkyl phosphates, and the addition mole number of the polyethylene is particularly preferably 2 to 16. As the alkyl group, those having 10 to 20 carbon atoms are preferable, and specific examples thereof include a lauryl group, a palmityl group, and a stearyl group. As a particularly preferable combination, a form containing both lauryl sulfate and tripolyoxyethylene (also referred to as tri-POE) (4) radial ether phosphate can be exemplified. Examples of the salt of these surfactants include, for example, metal salts such as sodium hydroxide, organic amine salts such as monoethanolamine, triethanolamine, and triethylamine, ammonium salts, and arginine. Preferable examples include salts of basic amino acids such as lysine and lysine, among which alkali metal salts are preferable, and sodium salts are particularly preferable.

The preferable content of the above-mentioned surfactant in the pharmaceutical composition of the present invention is a total of 0.5 to 10% by weight based on the total amount of the pharmaceutical composition, and more preferably 1 to 5% by weight. % Weight to volume. Also preferred is a form in which 1 to 5 parts by weight of peryl sulfate and 0.5 to 3 parts by weight of triPOE (4) lauryl ether phosphate are contained per 100 parts by volume of the pharmaceutical composition of the present invention. it can. The pharmaceutical composition of the present invention can be produced by treating the above essential components and optional components according to a conventional method.

For example, when manufacturing a pharmaceutical composition containing 1) a film-forming agent, 2) a solid or paste-like water-soluble plasticizer at 1 atm and 20 ° C, and 3) a drug, a surfactant, 2 The water-soluble plasticizer of (1) is dissolved in a solvent containing an organic solvent, and the film-forming agent of (1) is added to and dissolved in this solution, and the agent is added and dissolved therein.

The thus obtained pharmaceutical composition of the present invention forms a plastic film when applied to an application object. This film itself is a solid, but shows a viscous glass state in which internal components are moving.

As described above, this coating (particularly focusing on the structure, and also referred to as a matrix in the present invention) forms a storage layer integrally with the living tissue such as the skin. The drug reserved in this reservoir is gradually released to the affected area.

In this reservoir, the entire layer is a drug permeation route, and is composed of a matrix and part or all of the skin. Is much more than when it is applied to the skin, and the release time of the drug can be extended.

In addition, the amount of the drug stored in the reservoir is much larger than that of a normal external preparation for skin, and the stored amount can be appropriately adjusted by changing the application area of the pharmaceutical composition. Release can be easily controlled.

In addition, compared to the case where a normal film-forming preparation is applied to a living body, it is more efficient to apply the pharmaceutical composition of the present invention to the living body and transfer the drug directly from the matrix to the living body. Can be.

A matrix comprising the pharmaceutical composition of the present invention exhibiting such excellent drug storage properties, drug release control properties, and drug permeability is a bioactive matrix exhibiting excellent pharmacokinetic drug release characteristics. It can be said that.

This coating can be overcoated. Thus, the medicine can be constantly replenished. In addition, even if the old matrix that has already been applied is not removed before applying the new matrix, the drug can be transferred efficiently even if the new matrix is applied over the old matrix. When the pharmaceutical composition of the present invention is applied to an affected area such as skin, the matrix can be removed by swelling with an aqueous solvent and physical scraping. Specifically, when rubbed in a humidified state such as water, the matrix composed of the pharmaceutical composition of the present invention can be easily removed.

Since the matrix composed of the pharmaceutical composition of the present invention exhibits excellent drug storage properties and drug permeability as described above, the pharmaceutical composition of the present invention is unlikely to provide a drug administration effect with a conventional external preparation for skin. It can be effectively used as an external pharmaceutical composition even when the skin on the hyperkeratotic site, the joint site or the site remote from the lesion is to be applied.

The physical properties of the above bioactive matrix are as follows: When coated on glass or the like to form a film, the film is soft and does not peel off under normal living conditions. Or exfoliation when exposed to water. Example

Hereinafter, the present invention will be described specifically with reference to Examples, but it is needless to say that the present invention is not limited to these Examples.

The abbreviations described in each example or table indicate the following.

HP-55: Hydroxypropyl methinoresenolerose phthalate

Pull mouth nick F-68: Polyoxyl: 'mouth pyrene (30) glycol

Pull mouth nick p—85: Polyoxyl mouth pyrene (39) glycol

Macro Gonore 200: Polyethylene glycolonole 200

TLP-4: tri-POE (4) lauryl ether phosphate

A pharmaceutical composition of the present invention (hereinafter also referred to as a bioactive matrix pharmaceutical composition) was prepared according to the formulation shown in Table 1 below. In addition, the nick F-68 of this bioactive matrix pharmaceutical composition was replaced with ethanol. W

11 The pharmaceutical composition of Example 1 (ordinary skin-forming external pharmaceutical composition for skin) was prepared. The production was carried out by solubilizing the ingredients with stirring.

The pharmaceutical composition of Example 1 is soft, does not peel off under ordinary living conditions, and can be easily removed when exposed to running water when coated on a glass with a doctor blade at 20 mil to form a thin film. Had. On the other hand, the pharmaceutical composition of Comparative Example 1 formed a hard film under the same coating conditions, and this film did not come off even when rubbed with running water.

Using the pharmaceutical compositions of Example 1 and Comparative Example 1, a drug permeation experiment with Franz Cell was performed under the conditions shown in Table 2 below. The results are shown in Figure 1. '

Here, in the permeation experiment, as shown in FIG. 2, 1 g of a drug was dropped on a PET sheet (reference numeral 1) to form a coating, and a partition wall (reference numeral 2) was adhered on the sheet. Place the septum in the Franz diffusion cell with the receptor facing the receptor, fill the receptor with 40% PEG (polyethylene glycol) 400 / PBS (phosphate buffer), sample at regular intervals, and use the HP LC. The drug (estradiol) concentration in the receptor solution was measured.

Thus, the drug permeation amount of the bioactive matrix pharmaceutical preparation of the present invention was superior to that of a usual film-forming pharmaceutical composition. This is in contrast to a conventional film-forming pharmaceutical composition in which the drug stays only in the film and does not migrate to the skin, whereas in the bioactive matrix pharmaceutical composition of the present invention, the bioactive matrix is integrated with the skin to form the drug. It is considered that the total amount of drug permeation was significantly improved due to the formation of a permeable reservoir.

Example 1 Comparative Example 1

Estradionore 0.1 g 0.1 g

Etinoresenorelose 2.0 g 2.0 g

Pluronic F— 68 5.0 g

Propylene glycol 5.0 g 5.0 g

Isopropyl myristate 0.5 g 0.5 g

Purified water 10.0 g 10.0 g

Anhydrous ethanol suitable amount appropriate amount

A O 10 OmL 10 OmL Table 2 Sample size: 1 g

Septum: Uses back skin extracted from WBN hairless rats

Diffusion cell: Franz diffusion cell, 5 OmL capacity, 2 cm diameter

Receptor: 40% PEG 400 / PBS (V / V)

Sampling: lmL Timely up to 24 hours Temperature: 3 7 '

HP LC measurement conditions

Column H y p e r s i 1 ODS 100 X 4 mm, 3 μm Mobile phase Water / acetonitrile / methanol mixture (65: 30: 5) Detection U V 205 nm

Injection volume 20 μL

Column temperature 40 °

The same treatment as in Example 1 was carried out in accordance with the formulations shown in Tables 3, 5, and 6 shown below to obtain a bioactive matrix pharmaceutical composition of the present invention. A normal pharmaceutical composition similar to this was also prepared as a comparative example according to the formulations in Tables 4, 5, and 6 shown below.

Table 5

Table 6

The membrane properties of the pharmaceutical compositions of Examples 2 to 13 and Comparative Examples 2 to 14 were evaluated.

100 μL of the pharmaceutical composition was applied to the inner part of the upper arm, and the membrane retention was evaluated using the chronological survival and detergency as indices. The evaluation criteria were as shown in Table 7 below. Tables 8 and 9 show the results.

Thus, the results of Examples 2 to 13 showed the physical properties characteristic of the bioactive matrix pharmaceutical composition of the present invention. Table 7

State after 2 hours ◎: Film is not removed

〇: Part of film is removed

△: About half of the film is removed

X: More than half of the film is removed

Detergency (12 hours later: washed with running water)

◎: The membrane can be easily washed off

〇: Scrubbing is required to wash off the film

X: The membrane cannot be washed away by running water washing

Table 8

Example 2 Example 3 Example 4 Example 5 Example 6 Example 7 Example 8 Example 9 Example 10 Example 1 1 Example 1 2 Example 1 3

• 1 2 hours later ◎ ◎ ◎ ◎ ◎ ◎ ◎ ◎

Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Comparative Example 8 Comparative Example 9 Comparative Example 1 0 Comparative Example 1 1 Comparative Example 1 2 Comparative Example 1 3 Comparative Example 1 4

1 2 hours X X Δ ◎ X X X ◎ ◎ ◎ ◎ X ◎ After condition

Detergency ◎ ◎ ◎ X ◎ ◎ ◎ XXXX ◎ X

Example 15>

Under the conditions shown in Table 10 below, the pharmaceutical compositions of Example 11 and Comparative Example 11 were subjected to a release test using a Franssel.

As shown in FIG. 2, 2 μL of the drug was dropped on a PET sheet to form a film, and a partition was stuck on the sheet. The septum was set in a Franz-type diffusion cell with the receptor facing the receptor, the receptor was filled with purified water, sampled at regular intervals, and the drug concentration in the receptor solution was measured by HPLC.

The results are shown in Figure 3.

From this, it has been clarified that the bioactive matrix pharmaceutical composition of the present invention can release a drug satisfactorily for a long time and has excellent pharmacokinetic properties (release properties). Table 10 Coating amount: 200 μL Drying: 40 ° 60 m i η

Partition wall: UC C—11 0—50 Cellulose tube, Sanko Junyaku

Diffusion cell: Franz diffusion cell, 50 mL capacity Receptor: Purified water Sampling: 30 min, lhr, 2 hr, 4 hr, 6 hr Temperature: 37 °

HP LC measurement 'conditions'

Column Hy p e r s i 1 OD S 1 00 X 4mm, 3 m

Mobile phase water 'acetotrinole' methanol mixture (65: 30: 5) detection UV 205 nm

Injection volume 20 μL

Column temperature 40 °

A skin permeability test was also performed on Example 12, Comparative Examples 12 and 13 in the same manner as Example 1 except that the conditions shown in Table 11 were changed. Fig. 4 shows the results. Sample size: 1 g

Septum: Uses back skin extracted from WBN hairless rats

Diffusion cell: Franz diffusion cell, 50 mL capacity, diameter 2 cm

Receptor: 40% P EG 400 / P B S (V / V)

Sampling: 1 mL Timely up to 24 hours Temperature: 37 °

HP L C measurement conditions

Column Hy p e r s i 1 OD S 1 00 X 4 mm, 3 μm

Mobile phase Water-acetonitrile 'Methanol mixture (65: 305) Detection UV 205 nm

Injection volume 20 μL

Column temperature 40 °

Under the conditions shown in Table 12, a change in blood concentration of the drug was evaluated for Example 13 and Comparative Example 14 to conduct an absorption test from the skin on the back of rats. Figure 5 shows the results.

Table 12 Sample weight: 1.0 g

Apply the sample to the back skin of WBN hairless rats at 40 cm ²

Sampling: 0.5 mL from the jugular vein Timely up to 24 hours

Sample preparation: Serum samples (0.2 mL), 2.0 M sodium carbonate buffer _(P H9.4) 1 m L

Add 6 mL of ethyl acetate and extract. Separate the organic layer, concentrate to dryness, and concentrate

Use the HP LC moving layer 0.2111 as the sample solution.

HP L C measurement conditions

Column L- column 0DS, 5 μ τη 25 0 X 4.6 mm

Mobile phase Acetonitrile. 1 O mM phosphate buffer (pH 3.5) mixed solution (1585)

Detection Electrochemical detection method

Injection volume 50 μL

Column temperature 40 ° Industrial potential

ADVANTAGE OF THE INVENTION According to this invention, in the form which does not depend on a patch form, the pharmaceutical preparation for external use on the skin which can control drug release can be provided. In addition, it is possible to provide a pharmaceutical preparation for external use on the skin which is also effective for an application target such as a hyperkeratosis site, a joint site or a site remote from a lesion.

Claims

The scope of the claims

1. A pharmaceutical composition comprising: 1) a film-forming agent; 2) a water-soluble plasticizer in the form of a solid or a paste at 20 ° C. at 1 atm; and 3) a drug.

2. The pharmaceutical composition according to claim 1, wherein the film-forming agent is hardly water-soluble or water-insoluble.

3. The water-insoluble or water-insoluble film forming agent is one or more selected from the group consisting of ethyl cellulose, hydroxypropylmethylcellulose phthalate and acryl resin emulsion. Pharmaceutical composition of

4. The pharmaceutical composition according to claim 2, wherein the poorly water-soluble or water-insoluble film-forming agent is ethyl cellulose.

5.1 The water-soluble plasticizer in the form of a solid or paste at a pressure of 20 ° C is a compound having a polyoxyethylene group and a Z or polyoxypropylene group.

The pharmaceutical composition according to any one of claims 1 to 4.

The pharmaceutical composition according to claim 5, wherein the water-soluble plasticizer in the form of a solid or paste at 6.1 atm. 20 ° C is an oxyethylene oxypropylene copolymer.

7. The drug is a steroid, steroidal anti-inflammatory, cardiovascular, antihistamine, antiviral, anti-inflammatory, local anesthetic, sulfa, antibacterial, humectant, vitamins, antibiotics, bactericide or The pharmaceutical composition according to any one of claims 1 to 6, which is a blood circulation promoter.

8. The pharmaceutical composition according to any one of claims 1 to 7, wherein the pharmaceutical composition is used as an external preparation for skin.

9. The pharmaceutical composition according to any one of claims 1 to 8, wherein the pharmaceutical composition is used as an object to be applied to skin at an area of hyperkeratosis, a joint or a lesion remote from a lesion. object.