WO1997030110A1

WO1997030110A1 - Model skin membrane

Info

Publication number: WO1997030110A1
Application number: PCT/JP1997/000314
Authority: WO
Inventors: Yu Nagase; Takao Aoyagi; Yasunori Morimoto; Kenji Sugibayashi; Hideshi Natsume
Original assignee: Sagami Chemical Research Center
Priority date: 1996-02-14
Filing date: 1997-02-07
Publication date: 1997-08-21
Also published as: JPH09221528A

Abstract

A cross-linked polymer obtained by mixing monomer compounds respectively represented by general formulae (I), (II), and (III) in amounts of 40 to 70 wt.%, 20 to 55 wt.%, and 5 to 40 wt.%, respectively, polymerizing the mixture and simultaneously forming the same into a film, and then treating the resultant polymer to replace the hydroxyl-protective groups represented by A in the formula with hydrogen atoms, and an artificial model skin membrane which comprises the cross-linked polymer and is similar to the human skin in permeability to various drugs.

Description

Description Skin model membrane Technical field

The present invention relates to a novel crosslinked polymer, and an artificial skin model membrane comprising the polymer and having properties similar to human skin in permeability of a drug. The membrane of the present invention is used as a model membrane in an in vitro skin permeation test of a drug for the transdermal administration of the drug, and is used for a standard test for quality control, function evaluation, and the like of a skin application formulation. It is especially useful. Background art

Originally, skin preparations were external preparations expected to have an effect on local areas such as inflammation and muscle pain. Over the last quarter century, the mechanism of drug permeation through the skin has been elucidated, and the development of skin permeation enhancers or the advancement of formulation system technology found in the Transdermal Therapeutic System (TTS) has resulted in sickness and angina. Drugs and other skin preparations that are expected to have systemic effects have been commercialized worldwide. There are more than a dozen transdermal preparations of TTS currently under development, including topical preparations, and it is expected that these preparations will be increasingly commercialized in response to social demands. Based on this situation, in the U.S. Pharmacopoeia, in the 22nd edition of the United States Pharmacopeia, each test method proposed by the Federal Food and Drug Administration, Ciba-Geigy, and Boehringer-Ingelheim in the Transdermal Therapeutic Systems of rDRUC RELEASE J Was pioneered soon before in the world. However, these three test methods are used to evaluate the quality of the drug product itself, such as drug release from the drug product, that is, the variation in release between lots and drug products. It does not evaluate the most important functions. On the other hand, in Japan, there is no test method described in the section of “DRUG RELEASEJ” in the United States. At present, each company takes its own method.

Generally, experimental animals such as heron rats are often used to evaluate the skin permeability of drugs.However, the permeability varies greatly depending on the animal species, gender, and age, and the measurement results vary. is there. Also, from the viewpoint of animal welfare, an evaluation method that does not use laboratory animals is desired.

Skin penetration of drugs varies greatly depending on animal species, gender, and age, and is evaluated using human skin because the designed drug product is ultimately applied to humans It is desirable. However, it is practically difficult to use human skin for evaluating a large number of samples. Therefore, if it is possible to prepare an artificial membrane for evaluation that exhibits the same permeability as that of human and is inexpensive, it can be used to evaluate the quality and functions such as release from the formulation, transfer to the skin, and permeation using the membrane. It may be possible to establish a unified test method. As a result, the social reliability of the increasingly important quality and functionality of dermatological preparations can be increased.

As an artificial membrane as described above, the present inventors have already proposed a skin model membrane comprising a copolymer having a hydroxyalkyl group and a polysiloxane chain in a side chain (see Japanese Patent Application Laid-Open No. 6-245991). That is, the membrane obtained by impregnating the porous membrane with the copolymer has very similar permeability of various drugs to that of human skin. However, since the copolymer has no self-supporting property and cannot form a film by itself, it is necessary to impregnate the porous film as described above, and as a result, reproducibility and permeation stability are low. There was a problem. Disclosure of the invention

The present inventors have made intensive studies to obtain a membrane material which exhibits properties similar to that of human skin in drug permeability and yet has self-supporting properties. As a result, a monomer component having a hydroxyalkyl group, a polyorganosiloxane component having a polymerizable group at one terminal, and In the range of a copolymer composition having a film made of a crosslinked polymer composed of a polyorganosiloxane component having a compatible group, the permeation behavior of various drugs is similar to that of human skin, and the self-supporting property is also high. The present inventors have found that the film becomes a durable film, and have completed the present invention.

That is, the present invention provides the following general formula (I)

(Wherein X ¹ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, A is a hydroxyl-protecting group, and p is an integer of 2 to 6). 40 to 70% by weight, and the following general formula (Π)

(In the formula, X ² is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, and R ¹ to R ⁷ are the same or different and may be an alkyl group having 1 to 6 carbon atoms, q is an integer of 2 to 6, m is an integer of 3 to 100.) 20 to 55% by weight of a polyorganosiloxane compound represented by the following general formula (m):

(In the formula, X ³ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, and R ⁸ to R ¹³ are an alkyl group having 1 to 6 carbon atoms which may be the same or different, X and y are integers of 2 to 6, and n is an integer of 3 to 100. 5 to 40% by weight of each of the polyorganosiloxane compounds represented by A cross-linked polymer obtained by removing the hydroxyl-protecting group represented by A and replacing it with a hydrogen atom, and a skin model comprising the polymer It concerns the membrane. BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph showing the relationship between the permeability coefficient (Log Pm) of each drug in the model membrane (1) and the permeability coefficient (Log Ph) of each drug in human skin. The drug names in the figure are LC = lidocaine, ΑΜΡ-aminopyrine, ANP = antipyrine, IPH = isoprenaline, DPH = dopamine hydrochloride.

FIG. 2 is a graph showing the relationship between the permeability coefficient (Log P m) of each drug in the model membrane (2) and the permeability coefficient (Log Ph) of each drug in human skin. The drug names in the figure are LC-lidocaine, ΑΜΡ-aminopyrine, ANP = antipyrine, IPH = isoprenaline, and DPH = dopamine hydrochloride. BEST MODE FOR CARRYING OUT THE INVENTION

Among the substituents represented by X ′ to X ³ in the above general formulas (I) to (DI), examples of the alkyl group having 1 to 6 carbon atoms include a methyl group, an ethyl group, a propyl group, an isopropyl group, and a butyl group. And the like are preferred in view of the polymerizability of the obtained monomer. However, considering the ease of synthesis, the substituent represented by X ^{1 to} X ³ is most preferably a hydrogen atom or a methyl group. Further, the substituent represented by the general formula (H) and (m) Medium R "to R ^{1 3} may be the same or different, for example, a methyl group, Echiru group, propyl group, isopropyl group, butyl group And linear or branched alkyl groups such as isobutyl group, t-butyl group, pentyl group, hexyl group, etc. However, ease of synthesis and skin model membrane derived from these compounds In view of the characteristics of the above, a methyl group is most preferable among the above substituents, and the methylene chain in the general formulas (I) to (! II) needs to have a certain length. Wherein the number of methylene groups represented by p, q, x, and y is in the range of 2 to 6. Further, the number of siloxane units represented by m in the above general formulas (Π) and (H) is In the range of 3 to 100, especially in the range of 3 to 20, It preferred in order to utilize the characteristics of ease your and obtained skin model membranes. o

As the hydroxyl-protecting group represented by A in the general formula (I), those which are stably present in the above polymerization reaction and can be removed without deteriorating other sites in the deprotection reaction are selected. Hydroxyl protecting groups satisfying this requirement include substituted alkyl groups such as methoxymethyl group and 2-methoxyethoxymethyl group, benzyl group, p-methoxybenzyl group, p-nitrobenzyl group, ο, Substituted or unsubstituted arylmethyl groups such as ρ-dimethoxybenzyl group, benzhydryl group, di- (Ρ-methoxyphenyl) methyl group, trityl group, tetrahydroviranyl group, tetrahydrofuryl group, 1.4-dioxane-2 Examples thereof include a cyclic ether residue such as a -yl group, and a silyl group such as a trimethylsilyl group, a t-butyldimethylsilyl group and a t-butyldiphenylsilyl group. A silyl group is preferably used.

In order for the skin model membrane of the present invention to exhibit a drug permeability similar to that of human skin, a 40-70% by weight of the compound represented by the general formula (I) should be used when preparing the polymer membrane. The polyorganosiloxane compound represented by the formula (D) is mixed and polymerized in the range of 20 to 55% by weight and the polyorganosiloxane compound represented by the general formula (m) in the range of 5 to 40% by weight. The optimum copolymer composition depends on the value of the degree of polymerization m of the polysiloxane chain in the repeating unit represented by the general formulas (H) and (1).

In mixing the above monomer compounds and then forming a film simultaneously with polymerization, the monomer compounds are sequentially dissolved in a polymerization solvent, and the solution is cast on a substrate such as a glass plate or a Teflon plate. It is preferable to carry out polymerization using a known addition polymerization method such as radical polymerization, anion polymerization, or cationic polymerization. In this case, the radical polymerization method is preferably used as the simplest method. The radical polymerization reaction is initiated simply by heating, irradiation of visible light or ultraviolet light, or addition of a radical initiator. Examples of the radical initiator suitably used in the reaction include organic peroxides such as dilauryl peroxide, di-t-butyl peroxide, benzoyl peroxide, t-butyl hydroperoxide, cumene hydroperoxide and the like. Or α, α '-azobisi An azo compound such as sobutyronitrile diazobiscyclohexanecarbonitrile and the like can be exemplified. Further, when the polymerization is started by irradiation with light such as visible light or ultraviolet light, the polymerization is suitably started by performing the polymerization in the presence of a generally used photopolymerization initiator and a photosensitive agent. The photopolymerization initiator used here includes benzoin, benzophenone, acetate phenone, dibenzyl, ρ, ρ'-dimethyloxydibenzyl, ρ, ρ'-dichlorodibenzyl, camphorquinone, α-naphthyl, Examples include acenaphthene, thioxanthene, 2-chlorothioxanthene, 2-methylthioxanthene, 2,4-diethoxythioxanthene, and trimethylbenzoyldiphenylphosphine oxide. Examples of the sensitizer include η-butylylamine, triethylamine, dimethylaminoethyl methacrylate, Ν, Ν-dimethylylaniline, Ν, Ν-dimethyltoluidine, triethyl-η-butylphosphine, and 4-dimethylaminobenzoic acid. Isoamil and the like are preferably used. On the other hand, any polymerization solvent may be used as long as the above monomer compound is soluble. Examples thereof include benzene, toluene, xylene, benzene, tetrahydrofuran, chloroform, methylethyl ketone, benzene, benzene, and methanol. , Ethanol, π- or i-propanol, Ν, Ν-dimethylformamide, Ν, Ν-dimethylacetamide and the like can be used alone or as a mixture, but are not limited thereto. The polymerization reaction usually proceeds smoothly from room temperature to 100.

The compound represented by the general formula (I) can be prepared by a method known in the art for protecting the above hydroxyl-protecting group (for example, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981, p. 10). -85), the following general formula (Ι \ Π

X ¹

OV)

0- <CH2) pOH (wherein, X ¹ is a hydrogen atom, a halogen atom, a cyano group, a carbon atom having 1 to 6 carbon atoms) A alkyl group, p is an integer of 2-6. The compound can be synthesized by introducing the compound having a hydroxyalkyl group represented by the formula (1). The removal of the protecting group after the polymerization is performed by a known method according to the type of the protecting group used here. (See, for example, "Protective Groups in Organic Synthesis", John Wiley & Sons, New York, 1981, p. 10-85.)

Examples of the compound having a hydroxyalkyl group represented by the general formula (IV) include 2-hydroxyethyl acrylate, 2-hydroxyethyl methacrylate, 3-hydroxypropyl acrylate, 3-hydroxypropyl methacrylate, 4-hydroxybutyl methacrylate, 5-hydroxypentyl methacrylate, 6-hydroxyhexyl methacrylate, 2-hydroxyethyl-α-chloroacrylate, 3-hydroxypropyl-α-chloroacrylate, 2-hydroxy Examples include ethyl-α-cyano acrylate, 2-hydroxyethyl-α-ethyl acrylate, 2-hydroxyxethyl-α-butyl acrylate, and 2-hydroxyethyl-α-hexyl acrylate. However, in terms of cost and ease of synthesis, 2-hydroxyethyl acrylate or 2-hydroxyethyl acrylate De Loki Chez chill meth click relay Bok are preferred.

Some of the polyorganosiloxane compounds represented by the general formula (Π) are commercially available (such as Silaplane FM-0711 manufactured by Chisso Corporation), but those not commercially available are shown below. It can be manufactured by a method. That is, the following general formula (V)

(Wherein, R ^{5 to} R ⁷ may be the same or different and are an alkyl group having 1 to 6 carbon atoms.) The silanol compound represented by the formula is reacted with a strong base to form a silanolate anion. After that, using this as an initiator, the following general formula (VI) ¾3 (VI)

(Wherein, R ³ and R ⁴ may be the same or different and each is an alkyl group having 1 to 6 carbon atoms), and further reacts with a cyclotrisiloxane compound represented by the following general formula (W)

(In the formula, X ² is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, R ¹ and R ² may be the same or different, and an alkyl group having 1 to 6 carbon atoms, q is 2 It is an integer of up to 6. The reaction can be stopped by using a chlorosilane compound represented by).

Strong bases used in the above reaction include organic lithium compounds such as methyllithium, n-butyllithium, sec-butyllithium, t-butyllithium, phenyllithium, lithium diisopropylamide, bistrimethylsilyllithium amide, hydrogenated Examples thereof include sodium, hydrogenated metal hydride such as hydrogenated hydride, and magnesium compounds such as methylmagnesium bromide, thimagnesium bromide, and phenylmagnesium bromide. These strong bases are generally used in an amount of about 1 equivalent to the starting material silanol compound represented by the general formula (V). The reaction is preferably carried out at a relatively low temperature from 180 to room temperature in order to suppress side reactions. This reaction is preferably carried out in an organic solvent, and as the solvent used, tetrahydrofuran, benzene, toluene, hexane, chloroform, carbon tetrachloride and the like are suitably used. Further, this reaction is desirably performed in an inert gas atmosphere such as argon or nitrogen.

On the other hand, alkyl lithium compounds such as methyllithium, n-butyllithium, sec-butyllithium, and t-butyllithium were started without using the silanol compound represented by the general formula (V) in the above reaction. _g

Similarly, the cyclosiloxane compound represented by the general formula (VI) and the chlorosilane compound represented by the general formula (W) are successively reacted to give the compound represented by the general formula (n). The resulting polyorganosiloxane compound can also be synthesized more easily. In this case, among the substituents represented by R ^{5 to} R ⁷ in the general formula (H), two are the same as R ³ and R ^{4 in the} general formula (Π), and one is It is the same as the alkyl group of the alkyl lithium compound used in the above.

Examples of the silanol compound represented by the general formula (V) include, for example, trimethylsilanol, triethylsilanol, tripropylsilanol, triisopropylsilanol, tributylsilanol, tripentylsilanol, trihexylsilanol, and methylethylsilanol. Dimethylethylsilanol, dimethylpropylsilanol, dimethylisopropylsilanol, dimethylbutylsilanol, dimethylisobutylsilanol, dimethyl-t-butylsilanol, dimethylhexylsilanol and the like.

The cyclotrisiloxane compound represented by the general formula (VI), which is a monomer for forming a polysiloxane skeleton in the above reaction, includes hexamethylcyclotrisiloxane, hexethylcyclotrisiloxane, and hexethylcyclotrisiloxane. Xaprovircyclotrisiloxane, hexisoisobutylvircyclotrisiloxane, hexabutyltrisiloxane, hexapentylcyclotrisiloxane, hexahexylcyclotrisiloxane, 1,3,5-trimethyl-1,3 1,5-triethylcyclotrisiloxane, 1,3,5-trimethyl-1,3,5-tri-1-butylbutyltrisiloxane, 1,3,5-trimethyl-1,3,5-tripropylcyclotrisiloxane Examples include siloxane, 1,3,5-trimethyl-1,3,5-trihexylcyclotrisiloxane, and the like. Cyclotrisiloxane is most preferred. In addition, these cyclotrisiloxane compounds may be used as a mixture of two or more kinds in this reaction. Examples of the chlorosilane compound represented by the general formula (W) used as a terminator include 2-acryloxyshethyldimethylchlorosilane, Methyl silane, 3-acryloxypropyl dimethyl chlorosilane, 3-methacryloxy propyl dimethyl chloro silane, 3-methacryloxy propyl methyl ethyl chloro silane, 3-methacryloxy propyl methyl phenyl chloro silane, 3- (α-chloroacrylic oxy) -propyldimethylchlorosilane, 3- (α-cyanoacrylic oxy) -propylmethylethylchlorosilane, 3- (hexylacrylic oxy) -propyldimethylchlorosilane, 3- ( -Hexylacryloxy) -propyldimethylchlorosilane, 4-methacryloxybutyldimethylchlorosilane, and the like.

Some of the polyorganosiloxane compounds represented by the general formula (III) are commercially available (such as Silaplane FM-7711 manufactured by Chisso Corporation), but those not marketed include, for example, It can be manufactured by the method shown below. That is, the cyclotrisiloxane represented by the general formula (VI) or the following general formula (邐)

(Wherein, R ′ ° and R ¹¹ may be the same or different and are an alkyl group having 1 to 6 carbon atoms.) A cyclotetrasiloxane represented by the following general formula (K)

(Wherein, X ³ represents a hydrogen atom, a halogen atom, Shiano group, § alkyl group having 1 to 6 carbon ^{^{atoms, R 8, R 9, R}} 'z and R' ³ is C 1 -C rather good be the same or different X and y are mixed with a disiloxane compound represented by _c which is an integer of 2 to 6, and an acid or a base is added thereto in a catalytic amount, followed by ring-opening equilibrium polymerization by a known method. This ring-opening equilibrium polymerization is described, for example, in the 4th edition of New Experimental Chemistry Course, Vol. 28, p.371-382 (1992). ₁ ^

Examples of the cyclotetrasiloxane compound represented by the general formula (VI) include octamethylcyclotetrasiloxane, octaethylcyclotetrasiloxane, octaprovir cyclotetrasiloxane, and octaisopropyl cyclotetrasiloxane. Octabutyltetrasiloxane, octapentylcyclotetrasiloxane, octahexylcyclotetrasiloxane, 1,3,5-tetramethyl-1,3,5-tetraethylcyclotetrasiloxane, 1,3,5 -Tetramethyl-1,3,5-tetra-1-butylbutyltetrasiloxane, 1,3,5-tetramethyl-1,3,5-tetrapropylcyclotetrasiloxane, 1,3,5 -The ability to exemplify tetramethyl 1,3,5-tetrahexylcyclotetrasiloxane etc. <, In terms of ease of synthesis, octamethylcyclotetrasiloxane is It is also preferred. In addition, a mixture of two or more of these cyclotetrasiloxane compounds may be used in this reaction. The disiloxane compound represented by the general formula (K) can be easily obtained by reacting the chlorosilane compound represented by the general formula (VH) with water. In the production method described above, by adjusting the amount of the cyclosiloxane compound represented by the general formula (VI) or 01), the amount of the polyorganosiloxane compound represented by the general formulas (I) and (m) is adjusted. The degree of polymerization m and n can be controlled. In order to set the degree of polymerization m and n to 3 or more, the amount of the cyclosiloxane compound represented by the general formula (VI) or () is used in an amount of at least 1 equivalent to the initiator or the disiloxane compound. It is necessary. However, in this case, the polyorganosiloxane chains in the general formulas (H) and (dish) are a mixture of polyorganosiloxane chains having different degrees of polymerization m and n, respectively. And n (each 3 or more real numbers).

The skin model membrane of the present invention shows good correlation with human skin in permeability of various drugs, as described later in Examples. Therefore, the skin model membrane of the present invention can be used as a model membrane in an in vitro skin permeation test of a drug for transdermal administration of the drug, _{l 2}

It is suitably used for standard tests for quality control and function evaluation of products. Drugs used in drug permeation experiments using the skin model membrane of the present invention as a standard sample include, for example, anti-inflammatory analgesics such as acetaminophenone, aspirin, methyl salicylate, choline salicylate, glycol salicylate, Menthol, camphor, mefenamic acid, flufenamic acid, aminobiline, antipyrine, indomethacin, diclofenac, alclofenac, ibuprofen, ketoprofen, naproxen, planobrofen, fenobrofen, fenprofen, fluprofen, indofen Thiazac, tolmetin, splofen, benzadak, bufexamac, piroxicam, fuirbutazone, oxifene butazone, clofiasone, pentazozine, Pyrazol, etc .; Steroid-type anti-inflammatory agents include hydrocortisone, prednisolone, dexamethasone, triamcinolone acetonide, fluocinolone acetonide, fluocinolone acetate, etc .; antihistamine or antiallergic agent Such as chlorfeniramine, glycyrrhizic acid, diphenylhydramine, and velactin; local anesthetics such as benzocaine, proforce, jib forcein, and lidocaine; antibacterial agents such as chlortetracycline and other tetracyclines; Penicillins such as ampicillin, cephalosporins such as cephalothin, aminoglycosides such as kanamycin, macrolides such as erythromycin, chloramphenicol, eodo compounds, nitrofurofin, Nice evening chin, amphotericin, fradiomycin, sulphonamides, pyrrolnitrin, clotrimazole, nitrofurazone, etc .; antihypertensive agents such as clonidine, na-methyldopa, reserpine, syrosingopine, recinamine, cinnarizine, hydrazine, prazosin Antihypertensive diuretics such as theophylline, trichloromethiazide, furosemide, torinocumide, methyclothiazide, penfluzide, hydrothiazide, spironolactone, metrazone, etc .; and cardiotonic agents such as digitalis, ubidecarenone and dopamidone Min, etc .; Coronary vasodilators such as ditroglycerin, isosorbitol-yl dinitrate, erythrose tetranitrate, pentaerythritol tetranitrate, dipyridamole, dilazeb, travigil, trimetazidine; etc .; Dihydroergomin, dihydroergotoxin, etc .; 3-blockers or antiarrhythmic agents such as pindol, probranolol, etc .; calcidium antagonists such as diltiazem, difudipine, dicardipine, verapamil, bensicran, dilazeb; Antiepileptic drugs such as nitrazepam, meprobamate, and phenytoin; anti-vertigo drugs such as isoprenaline, betahistine and scopolamine; psychiatric drugs such as diazeham, lorazepam, and fluni Tolazepam, flupanadine, etc .; hypnotic sedatives, such as phenobarbital, amobarbital, cyclobarbital; muscle relaxants, such as triperizon, nokuclophan, tantrolene sodium, cyclobenzapyrine, etc .; Respiratory agents such as codine, ephedrine, isoproterenol, dextromethorphan, oresiprenaline, iprat pium bromide, cromoglycic acid, etc .; Drugs include corticotropin, oxitosine, nokusopressin, testosterone, progesterone, estradiol, salivary gland hormone, thyroid hormone, adrenal hormone, kallikrein, insulin, oxendron, etc .; Vitamins A, B, C, D, E, K and their derivatives, calciprolol, mecobalamin, etc .; antitumor agents such as 5-fluorouracil and its derivatives, adriamycin, krestin, Picibanil, ancitabine, cytarabine, etc .; examples of enzymes include perokinase; other prostaglandins, antidiabetic agents and the like.

Hereinafter, the present invention will be described in more detail by reference examples, examples, and comparative examples. However, it goes without saying that the present invention is not limited to these. _{t 4}

Example Reference Example 1

HEMA HEMA-TMS Under an argon gas atmosphere, 60.Og of hexamethyldisilazane was dropped slowly to 48.0 g (360 mmol) of 2-hydroxyethyl methacrylate (HEM （) at 0. After the addition was completed, 0.5 ml of trimethylchlorosilane was added to the mixture, and the mixture was further stirred at room temperature for 12 hours. After separating the precipitated salt by filtration, vacuum distillation was performed to obtain 61.3 g of the desired 2- (trimethylsilyl) ethyl methacrylate (HEMA-TMS) as a colorless transparent liquid.

b. p. = 50/2 ramHg, yield: 84%.

H-NMR, δ (CDCls.pm): 0.05 (9H, s), 1.88 (3H, s), 3.74 (2H, t), 4.14 (2H, t), 5.51 (lH, d), 6.10 (lH , d). Examples 1 and 2 Preparation of skin model membrane

The HEMA TMS obtained in Reference Example 1, a polydimethylsiloxane having a 3-methacryloxypropyl group at one end and a trimethylsilyl group at the other end [Chiraso FM-0711 manufactured by Chisso Corporation, Lot No. 179589, Average polymerization degree of dimethylxanxane component m = 13.5, hereinafter abbreviated as PDMS-MA], polydimethylsiloxane having 3-methacryloxypropyl groups at both ends [Sylaplane FM-7711 manufactured by Chisso Corporation, Lot No. 279302, average polymerization degree of dimethyl siloxane component Η = 10 · 1, PDMS-DMA; camphorquinone (CQ) and Ν, Ν-dimethyltoluidine (DMT) And nitrogen replacement was performed. The obtained mixture was placed in a syringe, and poured between two glass plates (10 cm × 10 cm) sandwiching a 200 μin-thick Teflon spacer. This is irradiated with visible light uniformly at an intensity of about 0.5 niW / cni ² for 10 minutes. Polymerization was performed for each (

Table 1 Example number

HEMA-TMS 2.5g (50wt.¾) 3.Og (60wt.¾)

PDMS-MA 1.5g (30wt.¾) 1.5g (30wt.¾)

PDMS DMA L Og (20wt.¾) 0.5g (10wt.¾)

CQ 0.05g 0.05g

DMT 0.05 g 0.05% Next, in order to remove CQ and DMT, the glass plate was immersed in a 50 Vol.! Aqueous solution of aceton, and the polymer films were removed from between the glass plates and air-dried at room temperature. . Further, the obtained polymer film was immersed in a mixed solution of tetrahydrofuran / water / acetic acid (volume ratio: 14/3/3) overnight, and subjected to hydrolysis (removal of a protecting group, trimethylsilyl group). After the completion of the hydrolysis, it was further immersed in a 50% aqueous solution of acetone for washing, taken out, and air-dried at room temperature. The thickness of each of the two polymer films thus prepared was 180 to 200 wm. The characteristic absorption of hydroxyl groups in the IR spectrum (near 3400 cm— "), which was not observed before hydrolysis, was observed in the polymer film after hydrolysis. Example 3 It was confirmed that the group had been removed.

A polymer membrane prepared in Examples 1 and 2 [hereinafter referred to as model membranes (1) and (2)] or a heat exchanger between a two-chamber diffusion cell with a water jacket having an average effective diffusion area of 0.95 cm ^2. The skin exfoliated from the chest (hereinafter referred to as human skin) was sandwiched, and a water suspension of each drug was placed in the donor part, and 2.5 ml of water was placed in the receiver part. By circulating 37 waters in the jacket, the whole cell was kept at a constant temperature, ₁ g

The inside of the cell was stirred with a magnetic stirrer. Over time, lml was sampled from the receiver side, and the same volume of water was added each time to keep the volume in the cell constant. The drug concentration in the obtained sampling solution was quantified by liquid chromatography. The time variation of the concentration of the permeated drug was determined from the slope in the steady state of the permeation curve obtained by plotting the accumulated permeation amount of the drug in the receptor part at each sampling time with respect to time. Next, the permeation coefficient P of the drug permeating through the model membranes (1), (2) and human skin was calculated from the time-dependent changes in the drug concentration of each of the obtained drugs according to the following equation. About the drug of the nose (ϋ /

P = (VdC / dt) Z (ACv) (4)

V: Receptor volume

d C / d t: time change of drug concentration in receptor

A: Effective area

C V: Saturated drug concentration in the donor part

The drugs used were lidocaine (LC), aminovirine (AMP), antipyrine_ (ANP), isoprenaline (IPH), and dopamine hydrochloride (DPH). The molecular weight (MW) of each drug, its saturated solubility in water (Cw), and the partition coefficient of the octanol aqueous system (the ratio of the saturated solubility of the drug in octanol to the saturated solubility of the drug in water) Table 2 shows the log Kow values. Here, Log Kow is an indicator of drug polarity. That is, as shown in Table 2, drugs having substantially the same molecular weight and significantly different polarities were selected. In addition, Log Kow adds each drug to octanol or distilled water in excess of the drug, stirs it sufficiently, and then puts it on a membrane filter (manufactured by Advantec Toyo;

The concentration of the drug in the soluble part was quantified by liquid chromatography, and the saturation solubility was calculated and determined. Table 2 Drug LC AMP ANP I PH DPH .W. 234.33 231.29 188.23 247.70 189.64

Cw (mg / ml) 3.03 55.9 816 345 520 Log Kow 2.37 0.50 -1.55 -2.69 -3.40 Permeation coefficient of each drug through model skin (1) and (2) and human skin The correlation was examined. That is, the logarithm of the permeability coefficient Pm of each drug in the model membranes (1) and (2) is plotted on the vertical axis, and the logarithm of the permeability coefficient Ph of each drug in human skin is plotted on the horizontal axis, and the respective values are plotted. As a result, the results shown in Figs. 1 and 2 were obtained. As is clear from the figure, it became clear that the drug permeability of these model membranes showed a good correlation with the drug permeability of human skin for drugs having different polarities. [Relative number of correlation between model membrane (1) and human skin: r = 0.950, correlation coefficient between model membrane (2) and human skin: r = 0.936] Industrial applicability

The skin model membrane of the present invention shows a good correlation between the permeability of various drugs and that of human skin, and is a model for in vitro drug transdermal experiments for the transdermal administration of drugs. Suitable for use as a membrane and for standard tests for quality control and functional evaluation of skin-applied preparations _c

Claims

The scope of the claims

1. The following general formula (I)

(π)

(In the formula, X ² is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, and R '' to R ⁷ are an alkyl group having 1 to 6 carbon atoms which may be the same or different, Q is an integer of 2 to 6, m is an integer of 3 to 100.) 20 to 55% by weight of a polyorganosiloxane compound represented by the following general formula (m):

(In the formula, X ³ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, and R ^{8 to} R ¹³ are an alkyl group having 1 to 6 carbon atoms which may be the same or different, and X And y is an integer of 2 to 6, and n is an integer of 3 to 100.) 5 to 40% by weight of a polyorganosiloxane compound represented by A crosslinked polymer obtained by removing the hydroxyl-protecting group represented by A and replacing it with a hydrogen atom.

2. The following general formula (I)

(Wherein X ′ is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, A is a hydroxyl-protecting group, and p is an integer of 2 to 6). 40 to 70% by weight, and the following general formula (Π)

(In the formula, X ² is a hydrogen atom, a halogen atom, a cyano group, an alkyl group having 1 to 6 carbon atoms, and R ′ to R ⁷ are the same or different and may be an alkyl group having 1 to 6 carbon atoms, q is an integer of 2 to 6, m is an integer of 3 to 100.) 20 to 55% by weight of a polyorganosiloxane compound represented by the following formula (m):

")

(Wherein, X ³ represents a hydrogen atom, a halogen atom, a Shiano group, § alkyl group having 1 to 6 carbon atoms, R ^B ~ R ^{1 3} are the same or different connexion also well alkyl group having 1 to 6 carbon atoms, X and y are integers of 2 to 6, and n is an integer of 3 to 100. 5 to 40% by weight of a polyorganosiloxane compound represented by A skin model membrane comprising a crosslinked polymer obtained by removing the hydroxyl-protecting group represented by A and replacing it with a hydrogen atom.