JP3240496B2 - Transdermal formulation - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a system for gradually releasing a drug into the body through the skin (TTS; Transdermal).
Therapeutic System).

[0002]

2. Description of the Related Art In general, drugs are administered by transmucosal (digestive, respiratory, intranasal, buccal, sublingual, ocular, anal),
It is divided into injection (vascular, subcutaneous, muscle) and transdermal.
Of these, the skin has long been used as a site to which the drug is applied, and there are many dosage forms such as ointments, pastes, liniments, and lotions. However, they are mainly expected to have a local topical effect.

[0003] In recent years, a transdermal therapeutic system (TTS), which is a DDS (Drug Delivery System) for the purpose of drug delivery to the systemic circulation, has recently been developed.
m) Development was done.

The percutaneous absorption preparation of this system has the following advantages as compared with injections and oral preparations. The blood concentration can be maintained for a certain period of time and can be maintained. First-pass metabolism in the digestive tract and liver can be avoided. It is possible to avoid gastrointestinal disorders due to oral preparations, pain and tissue disorders due to injections, and to perform home treatment without going to hospital.
Reducing the number of doses improves compliance.
It can be peeled off at any time, the absorption is easily interrupted after administration, and side effects and overdose are easily avoided. Continuous administration of short half-life drugs is possible.

For many of these advantages, at one time
TTS conversion to any drug is technically possible and seems to be significant, and research has been actively conducted. However, the conditions for TTS formation are that the molecular weight of the drug is small and the melting point is low, the action is time-dependent, the effective plasma concentration is low, and the problems that injections and oral preparations actually have To find the significance of changing the dosage form that can solve the problem.

[0006] In addition, on the skin side as an administration site, the penetration and absorption of water-soluble drugs among the drugs are poor.
Differences in release and absorption of drugs are likely to occur depending on the skin site, damage situation, individual differences, etc., danger of rash due to repeated application to the same site, drug ineffective due to drug metabolizing enzymes in skin There is a problem that there is a possibility of becoming. In addition, there are also problems such as difficulty in producing a preparation capable of stably storing a drug having a short half-life and being easily decomposed, which is an obstacle to the progress of TTS thereafter.

[0007] At present, drugs used in transdermal preparations for practical use to reach the systemic circulatory system are scopolamine for preventing motion sickness, nitroglycerin for angina pectoris, and isonitrate. Limited, such as sorbitol, clonidine for hypertension, estradiol for estrogen lowering, nicotine for smoking prevention.

[0008] In addition, the drug storage layer of a transdermal preparation which has been put into practical use has the following characteristics in view of the type of drug storage / release.
Reservoir type, matrix type, pressure-sensitive adhesive (adhesive)
Tape agents, multilayer adhesive tape agents, and others can be broadly classified. Each drug storage layer is made of a silicone oil as a base material, a hydrophilic polymer such as polyvinyl alcohol (PVA) or polyvinylpyrrolidone (PVP) or a silicone elastomer as a base material, and an acrylate-based pressure-sensitive adhesive (PSA) as a base material. ).
In addition, there is a type in which adhesive layers having different affinities with a drug are stacked in multiple layers to control release properties. In addition, natural rubber
Transdermal preparations using various polymers such as synthetic rubbers, celluloses, and synthetic resins as bases for drug storage layers have been studied.

[0009] Among the above-mentioned percutaneous absorption preparations, the drug storage layer, which belongs to the category, is generally coated with a drug release control membrane (drug permeable membrane) for controlling the release of the drug. As the drug release control film, a polymer film such as an ethylene-vinyl acetate copolymer, an acrylic resin, polyethylene, and ethyl cellulose, and a porous film thereof are used. In particular, the gelatin film examined by the present inventors in JP-A-63-146812 is superior to the above-mentioned polymer film in this respect because it does not cause irritation to the skin and does not cause rash.

[0010]

A conventional transdermal absorption preparation does not depend on a method of externally applying energy such as electricity or ultrasonic waves, but simply sticks the preparation on the surface of the skin, and the drug is not absorbed. The concentration gradient is used as a driving force for diffusion and release.It is intended to diffuse naturally in the base material, distribute and migrate to the skin side, and be absorbed into the body. is there. To this end, it is essential that the base of the drug storage layer has at least the following chemical and morphological properties.

(A) Base and drug have moderate affinity (compatibility)
It is necessary to have Moderate means that the drug has an affinity that is strong enough to release the base and transfer to the skin. This greatly affects the drug release rate. Also, it is possible to release in the zero order.

(B) The base is liquid at room temperature or apparently looks like a swollen gel containing liquid so that the drug (especially a solid drug) can diffuse through the base. Must be in the form between a solid and a liquid. In practical use reservoir type, silicone oil which is liquid is used, and in matrix type, hydrogel by water-soluble polymer is used. When using a silicone elastomer, which is a rubbery polymer,
The drug is dispersed therein with the solvent. In the case of the pressure-sensitive adhesive tape, the tackifier in the pressure-sensitive adhesive is dispersed as a liquid, and the pressure-sensitive adhesive itself is a gel in an intermediate region between the solid and the liquid. These facts satisfy the above conditions as a base.

[0013] However, in general, in a type in which a drug is carried in an adhesive, a very high drug release rate cannot be obtained. In the case of an oily or aqueous swelling gel, a gel with a slightly higher release rate can be obtained, but some drugs have a problem in storage stability when used as a preparation. In other words, there is a risk that the initial amount of drug input changes due to the temporal release of the solvent or water that is the swelling medium, and that there is a risk of deterioration due to the reaction with these dispersing media. Furthermore, in the case of a reservoir type in which a liquid drug is mixed with a powder in a liquid, such as an emulsion base, or a solid drug is dispersed together with a liquid cosolvent, these are transferred to the surface during storage. Therefore, it is inevitable that the drug is stored at a high concentration in the drug release control membrane (drug permeable membrane) covering the surface, and explosive release of the drug at the initial stage of application may be a problem.

(C) It is necessary that there is little or no skin irritation. Since the transdermal preparation is repeatedly replaced, skin irritation becomes a major problem. Advantageously, the size of the formulation can be reduced.

(D) Even an unstable drug which exhibits a medicinal effect with a small amount of about several μg and is easily deteriorated by air, moisture, heat, etc., can be stably stored and has a high release rate. Must be able to be released at Drugs of particular significance for making transdermal preparations are those that have a high rate of degradation in the gastrointestinal tract, liver, etc., a short half-life, and low effective plasma concentrations. Since most of such drugs have the above-mentioned properties, countermeasures are required.

(E) It is necessary that even a water-soluble drug having poor permeation and absorption from the skin can be sustainedly released into the body with high efficiency. It is particularly desirable that this is possible without the use of an absorption enhancer. In recent years, studies on absorption enhancers have been actively conducted, but there is a challenge that it is necessary to examine the toxicity of the absorption enhancer itself.

As a solution to the above problems, the present inventors have developed a transdermal absorption preparation described in JP-A-63-146812. This percutaneous absorption preparation, as a base of the drug storage layer,
A heat-sensitive and water-sensitive amphiphilic polymer, in which the degree of hydrophilicity increases nearer to one end of the polymer molecule, and the connection of blocks is increased so that the degree of hydrophobicity or lipophilicity increases nearer to the other end of the polymer molecule. It uses a conditioned segmented polyurethane.

The hydrophilicity / hydrophobic balance of the molecules and the molecular weight of the constituent molecules of the segment are adjusted so that the amphiphilic segmented polyurethane is dissolved or melted in response to water and heat. When dissolved and melted, the hydrophilic segment solubilizes the hydrophilic drug, and the hydrophobic (lipophilic) segment solubilizes the hydrophobic (lipophilic) drug. Generally, a drug also has a structure having a polar group and a non-polar group,
It has hydrophilic, lipophilic or amphiphilic properties and dissolves in the same kind of medium. Even if the drug is exceptionally insoluble, the drug exerts its efficacy even in a very small amount of dissolution, so it is only necessary to speak at an extremely low solubility level,
It belongs to any of the above categories. In addition, since the solubilization by the polymer enables dissolution at the molecular level, that is, molecular dispersion, it is extremely effective for the sustained release of a physiologically active substance that exerts a medicinal effect even in a minute amount of several μg / dose. It is. In other words, for storage and release of a drug having a low effective plasma concentration that exerts a medicinal effect in a minute amount, dispersion at the molecular level is indispensable. Many of these physiologically active substances are easily decomposed by oxygen, water, heat, and the like. However, as the nature of heat sensitivity implies, room temperature below the temperature of natural skin, ie, 30
Since the drug remains in a solid state at a normal temperature of less than ° C., the drug can be stably held in the solid. However, when attached to the body surface, it is easily transformed from a solid to a liquid in response to the temperature of the body surface. It is also sensitive to water, as implied by its amphipathic nature, so that it is dissolved by a small amount of water from the body surface. Then, the drug diffuses and migrates in this, passes through the drug permeable membrane on the surface, and is absorbed by the skin. Some drugs are liquid at room temperature, but most are solid. To diffuse a solid drug through the base and release it, and to absorb it into the skin,
The base must be a liquid or gel-like substance, but the polymer satisfies the conditions and was a base polymer for a transdermal formulation effective for many drugs. .

However, according to the subsequent studies by the present inventors, among drugs, a water-soluble drug which is difficult to pass through the skin requires a heat-sensitive polymer having higher hydrophilicity. I understand that. In order to release such a drug with high efficiency in a short period of time, for example, within 24 to 48 hours, it is necessary to create an environment in which the melted and melted polymer has a lower viscosity and is more easily diffused. It has been found that it is necessary.

Further, in the above-mentioned polymer membrane conventionally used as a drug release control membrane (drug permeable membrane) covering the drug storage layer, the speed and permeation of a certain trace amount of drug when it moves through the membrane. It is difficult to control the amount, and it is difficult to use it in transdermal preparations that require strict control of the amount of a small amount of drug absorbed into the skin. It has also turned out that a membrane is needed.

The present invention has been made to provide a transdermal preparation which satisfies these requirements.

[0022]

In order to achieve the above object, the present invention relates to a transdermal absorption preparation comprising a drug release surface of a drug storage layer containing a drug coated with a drug release control film. The storage layer is a compound of the general formula RA- (U) -F- (U) -BR '(where A and B are polymers of ethylene oxide, propylene oxide, tetramethylene oxide, 1,2-butylene oxide, or These are random or block copolymers, where R, R 'are H, CH ₃ ,
C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , A = B or A ≠ B, R
ＲR ′ or R ≠ R ′, and F represents a skeleton of a portion of the diisocyanate compound excluding two isocyanate groups,
(U represents a urethane bond), and at least one of A and B is hydrophilic, and at least one of them has a property of melting near human skin temperature (30 to 40 ° C.). Based on a heat-sensitive segmented polyurethane, and a drug release control membrane,
It is a phase separation membrane in which a crosslinked gelatin phase and an uncrosslinked segmented polyurethane phase are mixed.

In a preferred embodiment of the transdermal absorption preparation of the present invention, at least one of A and B in the above general formula is an ethylene oxide polymer, one of A and B is an ethylene oxide polymer, and the other is a tetramethylene oxide polymer. Wherein one of A and B is an ethylene oxide polymer and the other is a butylene oxide polymer, both of A and B are ethylene oxide polymers, and at least one of A and B is a random mixture of ethylene oxide and propylene oxide. Or a block copolymer, one of A and B is an ethylene oxide polymer and the other is a random or block copolymer of ethylene oxide and propylene oxide, and each of the above ethylene oxide polymers has a number average molecular weight of 800 to 1200. And those in which the total molecular weight of the segmented polyurethane serving as a base of the drug storage layer has a number average molecular weight of 1,000 to 6,000, and those in which glycerin and / or polyglycerin is contained in the drug release control membrane. .

FIG. 1 is a cross-sectional view illustrating the basic structure of the percutaneous absorption preparation of the present invention, and FIG. 2 is a plan view thereof, wherein 1 is a skin layer, and 2 is a pressure-sensitive adhesive layer applied to the skin layer. Reference numeral 3 denotes a hard base material, 4 denotes a drug storage layer, 5 denotes a drug release control film (phase separation film), and 6 denotes a liner.

The skin layer 1 and the hard substrate 3 adhered thereto
Is a support for a transdermal absorption preparation, which prevents moisture absorption during storage and prevents the drug from exuding to the side opposite to the skin. For the skin layer 1, a synthetic resin film such as polyethylene, polypropylene, soft polyvinyl chloride, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, polyethylene terephthalate, etc. is used. Low modulus material with good elasticity, softness and texture, for example 100
% Polyurethane having a modulus of about 5 kg / cm ² or less, a flexible polyvinyl chloride foam, an ethylene-vinyl acetate foam, a 1,2-polybutadiene foam, or a nonwoven fabric which has been subjected to moisture barrier and gas barrier treatment with a polymer film. used. Among them, those which do not cause blocking, those which are thin and have no bleeding of the plasticizer and have high safety are 1,2-polybutadiene foams, which is one of the most desirable ones. The thickness is suitably about 0.15 to 1.0 mm in consideration of ease of handling. Also, in some cases, apply a surface treatment agent to the front or back surface to prevent the patch from peeling off even if it touches the clothing, and to prevent the drug or adhesive from seeping into the epidermis layer. Can be.

The hard base material 3 adhered to the skin layer 1 via the pressure-sensitive adhesive layer 2 prevents the drug and the base as a storage layer from migrating to the skin layer 1 and has flexibility. The object is to make the movement of the drug to the skin side effective by the epidermis layer 1 pressing the hard base material 3 against the skin side according to the movement of the skin and making it more closely adhered to the skin side. It is. This includes polyvinyl chloride, polyethylene terephthalate, polypropylene, polyethylene, polystyrene,
A hard sheet or film such as polymethyl methacrylate is used.

The pressure-sensitive adhesive layer 2 is composed of a skin layer 1, a hard base material 3, and a mutual adhesion between a phase separation film 5 as a drug release control film,
And for bringing the preparation into close contact with human skin. At this time, if a hydrophilic or lipophilic substance opposite to the properties of the base and the drug is used, the polymer and the drug in the drug storage layer 4 can be prevented from flowing out to the pressure-sensitive adhesive layer 2. Further, only the portion that is in close contact with the skin may be replaced with one having good affinity for the skin. Generally, an acrylic or rubber pressure-sensitive adhesive can be used, but a polysaccharide-based vegetable adhesive or an animal adhesive such as gelatin can also be used as appropriate. The thickness of the adhesive layer 2 is suitably about 20 to 500 μm.

The liner 6 can be made of ordinary silicone-treated release paper or release film. The liner 6 is peeled off before the transdermal absorption preparation is applied to the skin.

The transdermal preparation of the present invention comprises a drug storage layer 4
And the drug release control membrane 5 (drug permeable membrane) covering the drug release surface has a great feature.

The drug storage layer 4 is based on the novel segmented polyurethane represented by the above-mentioned general formula. Specific examples of the structure include those shown in Table 1 below.

[Table 1]

In the segmented polyurethane of the above general formula, it is necessary that at least one of A and B is hydrophilic, although the hydrophilic drug is required to be at a low concentration level enough to exhibit its medicinal effect, but relatively high. This is for dissolving. Here, the hydrophilic drug is compared with a lipophilic drug, and has an affinity for water. Basically, it has some solubility in water, specifically, prostaglandins, nitroglycerin, atropine, etc., which will be described later. In addition, strophantin, isoproterenol hydrochloride, oxpreno hydrochloride Rolls and captopril. In addition, this segment gives a hygroscopic (water) property and is a factor of water sensitivity that the polymer is easily dissolved by a trace amount of water on the body surface. Here, the water sensitivity means that the substance itself has hygroscopicity, absorbs and dissolves a small amount of water (moisture), and further transforms from a solid to a liquid containing water by absorbing water by itself. At this time, the property that the sensitivity to water is sensitive, that is, the melting temperature also decreases. The hydrophilic roots are ether oxygen (-O-) in the molecular chain and -OH at the terminal of the molecular chain. —CH ₃ , —C ₂ H ₅ attached to the methylene chain (—CH ₂ —) does not have these side chains because it hinders the access of water to the ether oxygen. Ethylene oxide (EO) bound at the rate of one ether oxygen
Is the most hydrophilic of these. Some with side chains are more hydrophobic, and those with larger alkyl side chains are more hydrophobic. Although terminal is hydrophilic if _{-OH, -OCH 3, -OC 2 H} 5, -OC 3 H 7, -O
If an alkoxy terminal such as C ₄ H ₉ is formed, the alkyl group becomes hydrophobic in the order of the size of the alkyl group shown here. Therefore, when the segments on both sides of the urethane bond are EO, the degree of hydrophilicity can be finely adjusted by making the alkoxy terminal hydrophobic.

If the alkyl chain length at the alkoxy terminal is too long, it affects the hydrophilicity of the whole molecule, and the melting temperature is also different from that of the segment itself. Therefore, it is not preferable to utilize the original properties of the segment. One method is to form an ester bond at the end with a long-chain alkyl or aromatic carboxylic acid like a conventionally used nonionic surfactant. Since the interaction with the ester bond other than the interaction between the ether bond and the drug therein enters, the control of sustained release becomes more difficult. In addition, similarly to the case where the alkoxy terminal is terminated with a long-chain alkyl alcohol, it is considered that the influence on the freezing point and the amphiphilicity is large, so that the alkoxy terminal with an alcohol having a short alkyl chain such as the region of the present invention is used. That's good.

Further, by segmenting the above-mentioned copolymer containing EO into hydrophilic segments (hydrophobic) depending on the ratio of EO.
Can be adjusted. From this viewpoint, combinations of segments on both sides of the diisocyanate compound can be listed as shown in Table 1.

On the other hand, near the surface temperature of living human skin, the heat sensitivity of melting from a solid at room temperature and transforming it into a viscous liquid is expressed by EO or tetramethylene oxide (T
MO) can be adjusted by the molecular weight. However, in consideration of the low viscosity at the time of melting, it is particularly preferable to adjust by EO. Here, the vicinity of the surface temperature of human skin is 30 to 4
A temperature range of 0 ° C. is shown, and ordinary temperature indicates a temperature range of 0 ° C. or more and less than 30 ° C. The human skin temperature has a temperature range of 30 to 37 ° C. Other alkylene oxides are liquid at room temperature and do not contribute to heat sensitivity. Rather, it is expected to act as a segment for imparting amphipathic hydrophobicity, and acts as a factor for increasing the affinity with hydrophobic drugs. In the case of a copolymer containing EO, there is a demand for heat-induced transformation depending on the ratio of EO and its molecular weight, the type of copolymer (whether block or random) and the molecular weight of EO therein. There are some that satisfy, but many have solidification and melting temperatures that are not as clear as EO homopolymers.
In addition, since it is not a crystalline hard solid, there is some concern that it can be used as a stable solid phase for storing a drug for a long period of time.
Further, such a copolymer has a relatively large molecular weight due to the necessity of its chemical structure, and therefore has a relatively high viscosity when melted, which is not preferable in terms of drug diffusion. (E.g., more hydrophobic drugs).

Here, at least one segment has E
An example with an O homopolymer is described. Among polyethylene glycols, which are EO homopolymers, the number average molecular weight at which the solid / liquid transformation takes place at a temperature of 30 to 40 ° C. around the temperature of the skin surface is about 800 to 1200. For example, the freezing point of the number average molecular weight of 1,000 is 37. Since the temperature is 1 ° C. (Japanese Pharmacopoeia, standard value: 35 to 39 ° C.), the number average molecular weight is preferably selected.

In the case of Table 1, if an EO segment having a number average molecular weight of 1,000 is used for one of them, the other EO segment having a number average molecular weight of 200 to 1,000 may be used. At least one of the terminals may be an alkyl ether, and at least one other may remain -OH. Both ends are -OH
Alternatively, it may be an alkyl ether. These may be selected according to the properties of the drug. What should be noted here is, for example, the freezing point when a segment having a number average molecular weight of 1000 and a freezing point of 37.1 ° C. is used for both segments. When polyethylene glycol having a number average molecular weight of 1,000 is simply joined, the solidification point of a sample having a number average molecular weight of 2,000 is about 45 ° C., but the solidification point in the above case is almost the same as that of a number average molecular weight of 1,000.
In addition, depending on the terminal alkyl group, the temperature is reduced by about 1 to 2 ° C. This is because the segments of the diisocyanate that exist between the two segments through the urethane bond between them serve as a spacer, and the movement of the EO chain of polyethylene glycol, the length of the molecule, and the intermolecular This is because the influence of the intramolecular cohesive force on the freezing point is canceled out, and the intrinsic intermolecular and intramolecular motions of the segments are made independent.
The freezing point of 0 appears almost as it is. This fact is the basis for designing a molecule for the purpose of the present invention. That is, even if the total molecular weight increases, the freezing point is at a temperature close to that of the constituent segments, so that one segment can have another function.

The structure shown in Table 1 is an example in which a propylene oxide (PO) chain is introduced into one segment, and the PO chain is considerably hydrophobic due to —CH _{3 in} the side chain. However, if the molecular weight is several hundreds or less and the terminal remains -OH, a considerable amount of hydrophilic property remains due to the influence of the hydroxyl group. Therefore, if one is an EO segment, the molecular weight of the PO segment is used up to about 1000. This is also a limitation on the length in consideration of the melt viscosity.

In Table 1,,,,,,,, and, successively indicate cases having more hydrophobic segments on one side. In this case, they are useful for hydrophobic drugs, and the molecular weight of those segments is also affected by the same factors. Considering the number average molecular weight 150
Up to about 0, preferably about 300 to about 1500
Is appropriate.

Table 1 shows the case where an EO / PO copolymer was used for one of the two. Depending on the ratio of EO and its molecular weight, the type of copolymer, the degree of hydrophilicity and hydrophobicity varies, but both segments can be adjusted to be more hydrophobic than when EO polymer,
Can be adjusted to be more hydrophilic than in the case of Also, the melt viscosity is between. Copolymers are commonly less crystalline than homopolymers, so their thermal sensitivity changes more sensitively when crystalline segments of EO polymers are used. In the case of a random copolymer, the property of actively moving in small units of molecular motion gives a desirable result for diffusion and release of a drug.

The ratio of the subsequent copolymer of EO and other alkylene oxide is such that the molar ratio of EO is 10 to 90%.
%, Preferably 30 to 70%.

The same is true for the following combinations in Table 1, and these combinations may be selected in consideration of the properties of the drug and the required release pattern. In addition, the type of the terminal group may be similarly selected.

The total molecular weight of the polymer represented by these structural formulas varies depending on the combination of the respective segments, but is approximately 1000 to 6000, preferably 1200 to 6000.
It is about 2500.

Next, diisocyanates having an F skeleton in the middle of the above general formula include p-phenylene diisocyanate and 2,4-toluylene diisocyanate (TD
I), 4,4'-diphenylmethane diisocyanate (MDI), naphthalene 1,5-diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, lysine diisocyanate, xylylene diisocyanate, TDI with water, hydrogenated MDI, dicyclohexyl dimethyl methane p, p '-Diisocyanate,
What is necessary is just to select from isophorone diisocyanate etc. However, a structure in which both segments spread on a straight line is more sensitive to heat sensitivity and tends to have a lower melt viscosity. Aliphatic is more preferable than cyclic in view of ease of molecular movement. Although more polyfunctional ones such as triisocyanate may be used, they are not preferred because the melt viscosity generally increases.

A urethane bond (-NHCO) formed by the reaction of such a diisocyanate with an alkylene glycol.
The cohesive force of O-) is 8.74 (kcal / mol), and the structural unit molecule of alkylene glycol, -CH _{2
-; 0.68, -CH (CH 3} ) -; 1.36, -CH
₃ ; 1.77, -O-; 1.00, etc., so that they act in the direction of increasing the melt viscosity, which is convenient for obtaining a good melt viscosity for the drug storage layer. In fact, the polymer of the present invention having these urethane bonds interposed therebetween has a slightly higher melt viscosity than an alkylene glycol having the same molecular weight, and is effective for finely controlling the release of a drug. Incidentally, if the melt viscosity is too low, the polymer flows down from the skin, which is not preferable. In addition, it has an appropriate molecular length as a spacer between the segments on both sides, and each segment has a convenient action for performing independent molecular motion.

The segmented polyurethane having the above structure is synthesized, for example, by the following method. First, the polyalkylene glycol having segments A and B of the above general formula is dehydrated and dried at 60 ° C. under reduced pressure using a vacuum dryer or the like. After measuring the OH value of these polyalkylene glycols and the NCO value of the diisocyanate having the skeleton of F in the general formula by a conventional method, a catalyst such as di-n-butyltin dilaurate is used without a catalyst. The above-mentioned polyalkylene glycols A and B and the diisocyanate F are mixed in a molar ratio of 1: 1: 1 using an inert gas atmosphere such as N _2.
React at ° C. This reaction was carried out by dropping the diisocyanate of F into the polyalkylene glycols of A and B, and the point at which the absorption wave number (2250 cm ^-1 ) of the isocyanate group disappeared from the IR absorption spectrum was regarded as the end point of the reaction.

In order to make the segmented polyurethane contain a drug, a predetermined amount of the drug may be mixed and stirred to dissolve and disperse in the polymer melted by heating to 40 to 60 ° C. In the case of a polymer having a high melt viscosity, complete dissolution can be achieved in a short time by adding a common solvent for the drug and the polymer. After that, the solvent may be removed by evaporating the solvent under vacuum.

Next, the drug release controlling film 5 will be described. As schematically shown in FIG. 3, the drug release control membrane 5 is a phase separation membrane (phase-separated membrane) in which a crosslinked gelatin phase 5a and an uncrosslinked segmented polyurethane phase 5b are mixed.

In general, a phase separation film is a film in which two or more different phases are mixed in the film, and the interface between the phases is physically weak, and it is considered that transmission occurs from this. ing. The phase transition of the polymer mixture system proceeds slowly over a wide temperature range, and tends to cause phase separation from those having a high crystallization temperature (Tc).

[0049] Polymer alloys, which are multi-component polymer systems that combine chemically different polymers, have a micro phase-separated structure of blocks or graft copolymers in which different polymers are connected by covalent bonds. And a polymer blend group in which heterogeneous polymers are mixed macroscopically and have a phase-separated structure. The phase separation membrane used as the drug release control membrane 5 in the present invention belongs to the latter polymer blend. The film is cast from a solution of water, the common solvent for gelatin and segmented polyurethane, and is a solution-cast blend.
s).

Generally, in an amorphous polymer blend system, an LCST type (Lower Critical Solution Temperatur) is used.
e; Lower critical solubility temperature and UCST type (Upper Critical)
Solution temperature (upper critical solution temperature) occurs. In this case, the binary phase diagram of the liquid / liquid phase separation is represented by a binodal curve connecting the cloud points and a spinodal curve connecting the changes in the free energy curve of mixing. Divided. Here, the inside of the spinodal curve is an unstable region, and even if there is a slight fluctuation of the concentration, the free energy is reduced and the phase separation proceeds. This phase separation is called spinodal decomposition (SD).

In the case of physical blends such as the solution cast blends described above, the components are rarely mixed uniformly and the adhesion between the components is poor. Therefore, if both components are not blended as uniformly as possible, good quality is obtained. Material (film)
Can not be obtained. Therefore, for both components, polymers having some degree of miscibility are selected. The aqueous solution of the gelatin and the amphiphilic (hydrophilic) segmented polyurethane in the present invention forms a metastable compatible region between the binodal curve and the spinodal curve, which indicates that both components in the process of water evaporation. An increase in the concentration of N leads to a certain degree of nucleation and growth (NG). The metastable phase separation structure that appears due to the NG mechanism or SD decomposition in such a process depends on the evaporation rate and cooling rate of water, and changes in the viscosity of the system, and cannot be determined only by the thermodynamic properties of the system. In short, the formation process of the phase separation membrane used in the present invention can be basically formed by spinodal decomposition by a solution cast blending method.

More specifically, the gelatin phase 5a of this phase separation membrane forms the skeleton of the membrane, and accounts for at least 40% or more, preferably 60 to 80% of the weight of the whole membrane. To create a continuous phase. On the other hand, the segmented polyurethane phase 5b serves as a passage for preferentially permeating the drug, and accounts for 60% or less, preferably 20 to 40% of the weight of the entire membrane, and is continuous at least in the thickness direction of the membrane. We are making a phase.

It is necessary that the above-mentioned gelatin phase 5a is cross-linked and water-insoluble. If not cross-linked,
When the liner 6 of the transdermal absorption preparation was peeled off and applied to the skin, water coming out of the skin dissolved the gelatin phase 5a,
This is because the shape of the film cannot be maintained. However, the segmented polyurethane phase 5b must be uncrosslinked and remain fluid. This is because, when crosslinked, the segmented polyurethane phase 5b becomes a gel or a solid, cannot move by its own melting and flow, and impedes penetration, permeation and movement of a drug or the like. Here "crosslinked"
Indicates a state where the molecular chain is three-dimensionalized to such an extent that it becomes insoluble in water, and "uncrosslinked" indicates a state where the molecular chain is linear and not three-dimensionally.

The segmented polyurethane phase 5b must be solid at room temperature. This is because if it is liquid at normal temperature, the segmented polyurethane bleeds out from the phase-separated membrane. However, when the segmented polyurethane phase 5b is in a solid state when the phase separation membrane is brought into contact with the skin, the segmented polyurethane phase 5b is fixed in the phase separation membrane and does not bleed out. And it hardly functions as a drug release controlling film for a trace amount of drug. Therefore, this segmented polyurethane phase 5
It is necessary that b melts and becomes liquid at a temperature of 30 to 40 ° C., which is around the temperature of human skin. As described above, the liquid segmented polyurethane phase 5b which is solid at room temperature and melts at 30 to 40 ° C can be prepared by adjusting the molecular weight of the used segmented polyurethane, the type and molecular weight of the segment, as described above. It is.

A suitable thickness of the phase separation membrane is about 5 to 50 μm, preferably about 10 to 30 μm. 5 μm
As the thickness becomes thinner, the film strength becomes extremely weak, and film formation becomes difficult. On the other hand, when the thickness is more than 50 μm, the permeability of a drug or the like decreases.

Such a phase separation membrane is produced, for example, by the following method. That is, the segmented polyurethane heated and melted, an aqueous solution of gelatin and a cross-linking agent are mixed and stirred at a predetermined ratio, and after defoaming, the mixture is developed to a constant thickness on a base film having good releasability, and at room temperature. It may be dried for about two days. The heating and melting temperature varies depending on the segmented polyurethane, gelatin and crosslinking agent used, but is usually from 50 to 80 ° C, preferably from 55 to 70 ° C. The defoaming method is not particularly limited, and is usually performed by a method such as ultrasonic irradiation or defoaming under reduced pressure. The substrate film having good releasability is not particularly limited, but a synthetic resin film such as polyethylene terephthalate (PET) and polymethyl methacrylate (PMMA) is used. The method of drying is not particularly limited, and even when the drying is performed at normal pressure,
Although it may be carried out under reduced pressure, it is preferable to carry out the treatment in a clean room at a constant temperature of 23 ° C. and a constant humidity of 65% in order to guarantee the quality of the produced phase separation membrane. In the above production method, the blending ratio of gelatin to segmented polyurethane is 4: 6 to 8: 2, preferably 6: 4 to 8: 2, and the blending amount of the crosslinking agent is 2 to 100 parts by weight of gelatin. To 5 parts by weight, preferably about 3 parts by weight.

In some cases, glycerin or polyglycerin (di, tri, tetra, hexaglycerin, etc.) may be dissolved in an aqueous solution of gelatin. When these are blended, they have a relatively dry feel when dried, but act as a hygroscopic agent due to moisture to obtain a sticky phase separation membrane having a moisturizing property. The amount of glycerin or polyglycerin is 20 parts per 100 parts by weight of gelatin.
The appropriate amount is 60 parts by weight, preferably 30 to 50 parts by weight. The glycerin and polyglycerin are dissolved in the gelatin and the segmented polyurethane during mixing and stirring, and after phase separation, are contained in both the segment phase 5a and the segmented polyurethane phase 5b.

As a raw material gelatin, desalted alkali gelatin which has been subjected to alkali treatment is preferably used. Gelatin is a polypeptide obtained by decomposing and purifying collagen derived from animal skin and bone. The term "alkali treatment" refers to decomposing collagen by immersion in an alkali such as lime. Some gelatins are acid-treated, but acid-treated gelatins are unsuitable because of their low strength and brittleness.

The crosslinking agent for gelatin is formalin,
Glutaraldehyde and the like are conventionally known, but are less toxic, can enlarge the crosslinked network chain of gelatin, and can easily form a flexible film. Crosslinking agents are preferably used. For example, polyethylene glycol diglycidyl ether, polypropylene glycol diglycidyl ether, neopentyl glycol diglycidyl ether,
Examples thereof include 1,6-hexanediol diglycidyl ether, glycerol polyglycidyl ether, trimethylolpropane polyglycidyl ether, diglycerol polyglycidyl ether, and polyglycerol polyglycidyl ether. Crosslinking of gelatin is carried out by reacting an epoxy group of these crosslinking agents with a constituent molecule of gelatin, for example, an amino group.

On the other hand, as the segmented polyurethane, a heat-sensitive and water-sensitive polymer represented by the above general formula is suitably used as it is. According to such a polymer, as described above, the type of alkylene oxide constituting the segment, the molecular weight, the type of the copolymer, the ratio occupied by EO in the copolymer, the type of the terminal group, the type of the diisocyanate, The total molecular weight and the like of the polymer can be adjusted and selected. Then, the viscosity at the time of melting, the degree of hydrophilicity, the degree of hydrophobicity (degree of lipophilicity), the interaction, and the like according to the properties of the drug can be adjusted, and the diffusion / transfer rate and the amount of permeation of the drug can be strictly controlled.

The above-mentioned phase separation membrane may be reinforced with a fiber net or the like, if necessary. Examples of the fiber net include synthetic resin fibers such as polyamide fibers and polyester fibers. When reinforcing with a fiber net or the like, after immersing the fiber net in a preparation liquid containing segmented polyurethane, gelatin and a cross-linking agent, and squeezing it lightly enough to fill the net even when drying the mesh between the nets, What is necessary is just to spread on a base film with good releasability and to dry it. The drying method is as described above. The thickness of the reinforced membrane is 100 to 250 μm for the fiber net portion and 5 to 50 μm for the phase separation membrane portion.

Next, the drug contained in the drug storage layer of the present invention is not particularly limited as long as it can be transdermally absorbed. The object of the present invention can be achieved regardless of whether it is a hydrophilic drug or a lipophilic drug, or a liquid as well as a solid. For example, the following compounds may be mentioned. a) Prostaglandins (PG) (for example, PGA,
PGD, PGE, PGF, PGI, 6-keto-PGE,
6,9-nitrilo-PGI1,6,9-methano-PGI
_2, and their derivatives etc.), b) vasodilators (e.g., nitroglycerin, etc.) c) corticosteroids (e.g., hydro Corti chromatography Zon, betamethasone, etc.) d) anti-inflammatory agents (e.g., indomethacin, ibuprofen, etc. E) antibiotics (eg, penicillin, erythromycin, etc.) f) hypnotic sedatives (eg, phenobarbital, etc.) g) anesthetics (eg, benzocaine, etc.) h) antibacterial substances (eg, pentamycin, etc.) i) vitamins (E.g., vitamin A) j) Anticonvulsants (e.g., atropine) k) Hormones (e.g., testosterone)

The content of these drugs with respect to the base is appropriately determined according to the potency of the drug, the age and symptoms of the patient, the intended therapeutic effect, the site of application, and the intended duration of release.

[0064]

The percutaneous absorption preparation of the present invention uses the above-mentioned segmented polyurethane as the base of the drug storage layer 4 and the above-mentioned phase separation membrane as the drug release controlling membrane 5 (drug permeable membrane). The following operations and effects are produced due to use.

(1) At room temperature of less than 30 ° C., the polymer is a crystalline or pasty solid, and is a biologically active agent (for example, a prostaglandin such as a prostaglandin) which is easily denatured by air, moisture, heat or the like. , Antibiotics, vitamins, abortions, hypnotics, sedatives, tranquilizers, antispasmodics, muscle relaxants, anti-Parkinson's agents, analgesics, antipyretics, anti-inflammatory agents,
Local anesthetics, anti-ulcer agents, bactericides, hormonal agents, androgenic steroids, estrogens, sympathomimetics, cardiovascular agents, diuretics, anti- (cancer) cancer agents, hypoglycemic agents and nutrients) It can be stably stored in the drug storage layer 4.
In particular, drugs that are solid at room temperature do not migrate during storage.

(2) The base polymer of the drug storage layer 4 easily becomes a low-viscosity liquid near the skin temperature of the body. And
Since it becomes an amphipathic liquid in which water-soluble or hydrophilic and hydrophobic segments are present simultaneously, it is perfect if a relatively small amount of the drug is in a range of relatively small enough to exhibit the efficacy at room temperature. And the molecules can be uniformly dispersed in the high affinity portion of the segment. Therefore, it is often unnecessary to use a solvent for dissolving the polymer in the polymer, no complicated means for completely evaporating the solvent is required, and the danger of the residual solvent being toxic can be avoided.

(3) When the liner 6 is peeled off and the transdermal absorption preparation is applied to the skin, the segmented polyurethane phase of the phase separation film (drug release control film 5) becomes liquid at the temperature of the skin,
It is easily dissolved by a small amount of water coming out of the skin. The gelatin phase of the phase separation membrane swells with water. Similarly, the segmented polyurethane, which is the base of the drug storage layer 4, is melted and dissolved by the skin temperature and water to become a liquid. If the drug in the base is solid and the drug is dispersed in a system where the base is also solid, no drug distribution to the membrane will occur. However, when one or both of the drug and the base are liquid, the drug is distributed to both in a state where they are in contact with each other. That is, when the base and the phase separation membrane are in contact with each other, the drug concentrations in the base and the membrane are not the same, and a concentration gradient occurs due to the distribution between the base and the membrane. However, in the system of the present invention in which both the stability of the drug during storage and the migration to the surface are prevented, the polymer is transformed into a liquid by application of skin temperature or moisture at the time of application. For the first time, the drug migrates to the membrane.
In this system, the partition coefficient from the base material to the membrane is a major factor for membrane permeation. That is, the distribution coefficient Km to the film, the difference in concentration between the film front and back surfaces are ΔC, the concentration in the base is Cv, and the diffusion coefficient D
m and film thickness hm, the transmission amount Jm is

(Equation 1) Becomes That is, the permeation amount is determined by the drug concentration in the base and the distribution coefficient. Since the phase-separated membrane is obtained by embedding the same segmented polyurethane as the base as a microphase in the membrane, it becomes a liquid and fluidizes, exits the membrane, and moves to the skin. This fact greatly increases the distribution coefficient, that is, the transmission coefficient.

The viscosity of the segmented polyurethane after melting is about 2000 centipoise or less,
This is described in JP-A-63-108019 and JP-A-63-108019.
No. 146812 has a viscosity of about 5,000 to 1
This is a low value compared to 0000 centipoise. Therefore, the ratio of the dissolved drug that diffuses into the skin and migrates to the skin side is high. Then, the segmented polyurethane in the liquid state escapes from the phase separation membrane and migrates to the skin, so that the efficiency of the drug reaching the skin is improved. This means that a transdermal preparation having a high release rate of a physiologically active substance such that a drug is contained only in a low concentration in a base or a very small amount of several μg to several hundreds μg / dose is required. It is effective for making. Here, the viscosity was measured with a Brookfield-type rotational viscometer at 60 / min using a No. 4 rotor.
The values measured by rotating are shown.

T. Higuchi (J. Soc. Cosmetic Chemist
According to s, 11, 85 (1960)), in the case of release from a solution state, if only the release process from the base is rate-determining,
The amount of drug released during the initial process

(Equation 2) Is established. That is, the amount of release is proportional to the initial concentration, diffusion coefficient, and time. Assuming that CO, t is constant, the emission rate depends on the diffusion coefficient. Thus, it is understood that the present invention is significant in reducing the viscosity of the base polymer after melting in order to increase the diffusion coefficient.

The equation of Wilke [Wilke: Chem. Eng. P
rogr., 45,218 (1949)], the liquid phase diffusion coefficient is

(Equation 3) Indicated by Therefore, this equation shows that the diffusion coefficient increases as the viscosity of the solvent decreases. That is,
It is supported that the lower the viscosity of the base polymer after melting, the larger the diffusion coefficient of the drug and the more the low concentration side moves to the skin side.

(4) In the segmented polyurethane serving as the base of the drug storage phase 4, the EO polymer is selected for the hydrophilic segment, and the crystals are sensitive to heat and liquefy. Further, it is easily dissolved in water emitted from a living body, and is sensitive to water. That is, the hydrophilic drug is easily dissolved. However, by making the hydrophobic segment or the terminal group an alkoxy group of an alkyl chain on the other hand, it can be made amphiphilic, so that the degree of affinity with the hydrophilic drug can be controlled. This is advantageous for improving the release rate of hydrophilic drugs that are poorly absorbed into the skin.

(5) In the percutaneous absorption preparation of the present invention in which the base segmented polyurethane is melted, escapes from the drug release controlling film 5 and reaches the skin surface to come into contact with the skin, the segmented polyurethane is amphiphilic. Because of this, it shows a good affinity for skin lipids, so that even poorly absorbable drugs can be relatively efficiently absorbed from the skin. Therefore, it is not necessary to use a new absorption promoter.

(6) The base segmented polyurethane is
It has a molecular structure similar to that of polyalkylene glycol, which is a conventionally used drug or cosmetic additive. Therefore, it was safe without any skin irritation or toxicity. Also, unlike acrylic polymers, it is safe because there is no residual monomer.

(7) The segmented polyurethane of the base has a viscosity at the time of melting that is low enough to be efficiently diffused, but not enough to flow and fall down at the time of application, but to an extent that it spreads appropriately on the surface of the skin. It is convenient for absorption of the drug from the skin. Such adjustment of the melt viscosity is performed by adjusting the urethane bond, the type of the segment, its molecular weight and the total molecular weight.

[0075]

Embodiments of the present invention will be described below.

[Example 1]

Embedded image A wax-like polymer (melting point: 35.0-35.6 ° C.) that is soft at normal temperature and represented by the above structural formula is heated to 60 ° C. to obtain a transparent low-viscosity (about 1000 cps) liquid polymer. Prostaglandin E1 (PGE1
) Was added and stirred to dissolve uniformly to obtain a transparent liquid. Although the melting point of this drug was 120 ° C., it was completely dissolved in the polymer. Next, this was cooled to room temperature of less than 30 ° C. and solidified, and used for the drug storage layer. The composition of the preparation was as shown in FIGS. That is, 1,2-polybutadiene foam (expansion ratio 5
Acrylic pressure-sensitive adhesive was applied to a thickness of about 50 μm on one side of a 400 μm thick, 3.5 cm square), and a polyester film of a hard base material (100 μm
(Thickness, 2 cm square). Then, a polymer containing PGE1 was spread as a drug storage layer on the film surface. Next, a phase separation membrane of the above-mentioned gelatin and the above-mentioned segmented polyurethane (polymer / gelatin: 30/70 wt%, 20 μm) so as to cover the drug storage layer from above.
(2.5 cm square). Further, a release paper treated with silicone as a liner was adhered from above to complete the preparation. The drug content of this formulation is 200
μg / sheet.

This preparation was placed in a moisture-proof aluminum-evaporated packaging film bag, sealed in a vacuum in the presence of silica gel, and sealed. After this was stored at a temperature of 25 ° C. or lower for one year, it was taken out of the bag again and examined for drug stability.
Little change was observed, and storage stability was confirmed. Then, the liner of the preparation was peeled off and applied to the skin inside the upper arm of a human, and the amount of the drug that was absorbed percutaneously over time was calculated by measuring the amount remaining in the preparation and on the surface of the skin did. As a result, the amount of drug absorbed into the body through the skin was 20 μg after 6 hours and 40 μg after 12 hours.
g, 60 μg after 18 hours and 80 μg after 24 hours, and were gradually released in almost zero order. In this case, an absorption enhancer (enhancer) is not used, but it is clear that the preparation with a small content will be absorbed transdermally at a high absorption rate, and there will be no irritation to the skin, making it sufficiently practical. There was a formulation.

[Example 2]

Embedded image Prostaglandin E1 was dissolved in a waxy polymer (melting point: 36 to 37 ° C.) at room temperature represented by the above structural formula in the same manner as in Example 1. However, for quick dissolution,
A method was used in which a small amount of ethanol was added and dissolved, and then ethanol was removed by evaporation under vacuum.

Next, a preparation was prepared in the same manner as in Example 1, and the percutaneous absorption of the drug after application was traced. The amount of skin absorbed was about 75 μg. Again,
Although no absorption enhancer was used, the formulation with a small content had a relatively high absorption rate and was sufficiently practical.

[Embodiment 3]

Embedded image Prostaglandin E1 methyl ester (PGE1 methyl ester) was added to the polymer having the above structural formula in the same manner as in Example 1.
r) was dissolved and a phase separation membrane was similarly adhered to obtain a preparation. This preparation also had good results in the patch test, with a zero-order release and a transdermal absorption rate of about 50%.

[Embodiment 4]

Embedded image A waxy crystalline polymer having the above structural formula
After heating to 0 ° C. to obtain a transparent, low-viscosity liquid polymer, testosterone was added as a drug in an amount of 0.5% by weight and stirred well. The melting point of this drug is 153-157 ° C
However, as a result of observation with a microscope, complete dissolution was confirmed. In the same manner as in Example 1, a percutaneously absorbable preparation was obtained. This preparation was applied to human skin and the release rate of the drug 48 hours later was measured to be about 40%.

[Embodiment 5]

Embedded image A waxy crystalline polymer having the above structural formula
After heating to ℃ to obtain a transparent, low-viscosity liquid polymer, 1.0 wt% of betamethasone sodium phosphate (dexamethasone sodium phosphate) was added as a drug to the polymer, and the mixture was stirred well. In the same manner as in Example 1, a percutaneously absorbable preparation was obtained. When this preparation was applied to the abdomen of rats and the release of betamethasone sodium phosphate was examined, it was found that the preparation had good release performance.

Example 6 Using the polymer represented by the above formula [1], adding 2.4 wt% of PGE1 to Example 1,
A drug storage layer was obtained in the same manner as described above. As a phase separation membrane, polymer / gelatin / glycerin = 25/55/20 (wt.
%) And adhered to the drug storage layer in the same manner as in Example 1 to obtain a preparation. When this preparation was applied to human skin and the amount of transdermal absorption was measured, almost the same amount of drug as in Example 1 was released.

[Comparative Example 1]

Embedded image The polymer having the above structural formula is the polymer of Example 2 in the specification of JP-A-63-146812, and has a melting point of 36.
~ 37 ° C. A percutaneous absorption preparation was prepared by dissolving the same drug in the same amount as in Example 1 of the present invention in the same manner as in Example 1 of the present invention, and was similarly applied to human skin. After 24 hours, the percutaneous absorption was 30 μg. The following small amounts were relatively small. One of the major reasons is considered to be that the viscosity at the time of melting is high and the diffusion and movement of the drug are poor.

[Comparative Example 2]

Embedded image The polymer having the above structural formula is the polymer of Example 3 in the specification of JP-A-63-146812. The same drug as in Example 1 of the present invention was dissolved in the polymer in the same amount in the same manner. Next, this was cooled to room temperature of less than 30 ° C. and solidified to form a drug storage layer. The composition of the preparation is the same as in Example 1 of the present invention.
The release control film is the same as that described in JP-A-63-1468.
12, the reactivated gelatin film of Example 3 (20 μm).
m thickness). This preparation was applied to the skin inside the upper arm of a human, and the amount of drug absorbed into the body through the skin was measured.
g, the amount was as small as 20 μg after 18 hours and 24 μg after 24 hours, and the absorption rate was low. The reason for this is that, when compared with the preparation of the present invention, the viscosity of the polymer in the drug storage layer of the comparative example at the time of melting is high and the diffusion and migration of the drug are unlikely to occur. This is considered to be due to the low permeability.

Therefore, the polymer of Example 1 of the present invention is
The viscosities of the polymers of Examples 2 and 3 in the specification of JP-A-63-146812 when melted were measured and are shown in FIG.
The polymers of Examples 2 and 3 of JP-A-63-146812 have a high melt viscosity near the melting point of about 7000 cps, and the viscosity gradually decreases with increasing temperature. On the other hand, the polymer of Example 1 of the present invention has about 2000 cps even near the melting point.
At around 60 ° C., which is even lower at 1000 cps. It is 100 ° C that the three have the same viscosity
It is above high temperature. This fact supports the fact that the low viscosity of the polymer of the present invention facilitates drug diffusion and migration, and increases transdermal absorption.

[0087]

As is clear from the above description, in the transdermal preparation of the present invention, the segmented polyurethane, which is the base of the drug storage layer, is solid at room temperature and becomes liquid near the temperature of human skin. In addition, it has heat-sensitive and water-sensitive properties such that it has a hydrophilic segment, has a low viscosity at the time of melting, and has properties convenient for dissolution and diffusion of a drug. And it has properties that are convenient to spread on the skin surface. Moreover, the phase separation membrane used as the drug release control membrane can control the diffusion, permeation rate and permeation amount of the drug. Therefore, the percutaneously absorbable preparation of the present invention is a drug which has heretofore been difficult to prepare a preparation for percutaneous administration, that is, it is solid at ordinary temperature, water-soluble and hardly absorbable into the skin, and has a small amount of medicinal effect. When a drug that is expressed, has a short half-life and is easily degraded is stored stably for a long time and applied to the skin, it can be transdermally administered at a high release rate, with sustained release, with little irritation to the skin, Has a remarkable effect.

[Brief description of the drawings]

FIG. 1 is a cross-sectional view showing an example of a basic structure of a transdermal preparation of the present invention.

FIG. 2 is a plan view showing an example of the basic structure of the transdermal absorption preparation of the present invention.

FIG. 3 is a partial plan view schematically showing a phase separation membrane used as a drug release control membrane.

FIG. 4 is a graph showing the relationship between the respective melt viscosities and temperatures of the base polymer used in the present invention (the polymer of Example 1) and the polymers of Examples 2 and 3 of JP-A-63-146812. It is.

[Explanation of symbols]

 Reference Signs List 1 skin layer 2 pressure-sensitive adhesive layer 3 hard base material 4 drug storage layer 5 drug release control film (phase separation film) 5a gelatin phase 5b segmented polyurethane phase 6 liner.

Continued on the front page (72) Inventor Haruhide Sasaya 3-1-1, Sakurai, Shimamoto-cho, Mishima-gun, Osaka Prefecture Ono Pharmaceutical Co., Ltd. Inside the Minase Formulation Research Laboratory (72) Inventor Mao Sudo 3-chome Sakurai, Shimamoto-cho, Mishima-gun, Osaka No. 1-1 Ono Pharmaceutical Co., Ltd. Minase Formulation Laboratory (56) References JP-A-7-51555 (JP, A) JP-A-4-13620 (JP, A) JP-A-4-13618 (JP, A JP-A-63-146812 (JP, A) (58) Fields investigated (Int. Cl. ⁷ , DB name) A61K 9/70 A61K 47/34 A61K 47/42

Claims (10)

(57) [Claims] In a percutaneous absorption preparation comprising a drug-releasing surface coated with a drug-releasing control film, the drug-storing layer has a general formula RA- (U) -F. -(U) -B-R '(where A and B are polymers of ethylene oxide, propylene oxide, tetramethylene oxide, 1,2-butylene oxide, or a random or block copolymer thereof, and R and R' are H, CH ₃ ,
C ₂ H ₅ , C ₃ H ₇ , C ₄ H ₉ , A = B or A ≠ B, R
ＲR ′ or R ≠ R ′, and F represents a skeleton of a portion of the diisocyanate compound excluding two isocyanate groups,
(U represents a urethane bond), and at least one of A and B is hydrophilic, and at least one of them has a property of melting near human skin temperature (30 to 40 ° C.). Based on a heat-sensitive segmented polyurethane, the above-mentioned drug release control membrane,
A percutaneous absorption preparation comprising a phase separation membrane in which a crosslinked gelatin phase and an uncrosslinked segmented polyurethane phase are mixed. 2. The percutaneous absorption preparation according to claim 1, wherein at least one of A and B in the general formula is an ethylene oxide polymer. 3. The transdermal preparation according to claim 1, wherein one of A and B in the general formula is an ethylene oxide polymer and the other is a tetramethylene oxide polymer. 4. The percutaneous absorption preparation according to claim 1, wherein one of A and B in the general formula is an ethylene oxide polymer and the other is a butylene oxide polymer. 5. The percutaneous absorption preparation according to claim 1, wherein both A and B in the general formula are ethylene oxide polymers. 6. The percutaneous absorption preparation according to claim 1, wherein at least one of A and B in the general formula is a random or block copolymer of ethylene oxide and propylene oxide. 7. The transdermal preparation according to claim 1, wherein one of A and B in the general formula is an ethylene oxide polymer and the other is a random or block copolymer of ethylene oxide and propylene oxide. 8. The transdermal preparation according to claim 2, wherein the ethylene oxide polymer has a number average molecular weight of 800 to 1200. 9. The total molecular weight of the segmented polyurethane serving as the base of the drug storage layer has a number average molecular weight of 1,000 to 600.
The percutaneous absorption preparation according to claim 1, which is 0. 10. The percutaneous absorption preparation according to claim 1, wherein the drug release controlling membrane contains glycerin and / or polyglycerin.