JPH0725666B2 - Patch for transdermal administration - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a controlled release preparation for transdermal administration, which comprises a universal technology applicable to a wide variety of drugs. More specifically, the main base of the drug storage layer is composed of a multi-block copolymer of amphiphilic segmented polyurethane, which is a solid state at room temperature and has thermal and water sensitivities. Have,
It is possible to control the high drug utilization efficiency and appropriate release pattern,
Moreover, the present invention provides a patch for transdermal administration, which is excellent in storage stability. In particular, it enables transdermal administration of even minute amounts of highly biodegradable highly physiologically active substances, which have hitherto been most difficult to administer transdermally.

[Prior art]

Traditionally, transdermal agents include ointments (creams, gels),
There are plasters, tapes, poultices, liniments, lotions, aerosols and other dosage forms, and for the purpose of local action, antihistamines, steroids, non-steroidal anti-inflammatory agents, antipruritic agents, sulfa agents, antibiotics, etc. Drugs such as purulent skin disease agents, parasitic skin disease agents, emollients, and agents for treating vitiligo vulgaris are used.

Recently, TTS (Transdermal Thera
peutic system) is being actively researched. This is aimed at improving the therapeutic effect by maintaining the blood concentration of the drug, reducing side effects by the route or improving compliance, and formulations such as nitroglycerin, isosorbite nitrate, clonidine and scopolamine have been developed. There is.

In addition, recently, further research has been conducted, and a drug (eg, digoxin, lidocaine, quinidine, theophylline, etc.) that requires controlled release due to a small amount of strong activity, poor stability in vivo, and narrow safety margin has been passed. Considered as a drug for dermal administration.

Conventionally, as a base material for these transdermal administrations, natural rubber type,
Synthetic rubber-based, acrylic-based, cellulose, polysaccharide, silicon, oil-based gel made of synthetic rubber-mineral oil, etc., or water-soluble polymer made of water-soluble polymer such as sodium acrylate or polyvinyl alcohol-water is used. It had been.

The purpose of using these polymer compounds as a base or an additive is because they serve as a structural material having physical / mechanical properties such as self-restoration and adhesiveness as a drug support, and also as a polymer compound. This is because it has the chemical properties of the monomer unit, the segment structure of the chain structure, or the chemical properties of the main chain and side chains of the polymer unit. Furthermore, as an aggregate of polymer molecules, the interaction between the polymers and the interaction with the drug This is because it becomes a mechanical material that can utilize the chemical properties of action.

In most of the conventional formulations, a polymer compound is mainly used. In other words, although the target drug is often used as a matrix, the interaction between the true molecular structure of the polymer and the low-molecular compound (drug) (In
Considering the teraction), the design of the system mainly focusing on is not done. The present invention has been made by molecularly designing a base extremely useful as a percutaneous absorption agent.

By the way, there are very few examples for the purpose of sustained release of highly physiologically active substances, and one example is found in Japanese Examined Patent Publication No. 61-9922. There are some similarities such that the highly physiologically active substance is a prostaglandin derivative (fluprostenol sodium) and the base is a hydrophilic linear polyoxyalkylene / polyurethane block copolymer. The above-mentioned base is not heat-sensitive, and the present invention is a patch for transdermal administration, whereas it is related to transmucosal administration, which is also a big difference. And the polymer of the above patent is one in which a drug is mixed and dispersed in a state of being dissolved in a solvent, and in use, a body fluid permeates the dispersion composition, and a diffusion path to a body tissue in contact with the dispersion composition is formed, The result is a sustained release of the biologically active agent.

In this example, the polymer is provided with hydrophilic and hydrophobic moieties, but like other conventional controlled release formulations with other polymer bases as the matrix, the interaction between the polymer and drug or the polymer required for transdermal administration is required. It is not a drug product that includes a new and universal technology that expresses the special function of the drug based on molecular design.

Recently, drug / polymer mixed systems are not only approaches from the field of pharmacy but also Polymer Science.
Has been deeply studied from the standpoint of. While the development of polymers for specific drugs and the principle of release by them, the development of universal release control system using polymers that can subtly and precisely change the molecular structure depending on the drug is strongly demanded. .

[Problems to be solved by the invention]

Most of the above-mentioned base materials that have been widely used in the past were those in which the drug was simply carried in the adhesive, and the release of the drug mixed and dispersed in the adhesive was extremely poor. . Further, when the pressure-sensitive adhesive of this type has poor adhesion due to sweat or the like, even a drug near the surface of the pressure-sensitive adhesive hardly reaches the skin, and it is difficult to expect a sufficient drug effect. In addition, although oily gels and aqueous gels are somewhat better than those mentioned above in terms of drug release, there are problems with drug stability, and the shape retention and drug retention of thin films There was a problem with solubility and dispersibility.

Conventional developments relating to transdermal agents can be broadly divided into the processes from the diffusion process of the drug in the preparation to the release to the stratum corneum and the processes of distribution of the drug to the stratum corneum and diffusion process. If any one of these has a fatal defect, it cannot be a practical formulation, and it can be said that the above-mentioned conventional formulations were extremely defective.

Here, one condition of an ideal transdermal administration system is presented. First, the drug is dissolved and dispersed in the base as uniformly as possible. However, if the solubility is too high, that is, the base and the drug form a relatively strong binding state and the activity coefficient is low, the degree of drug release is strongly suppressed, which is not desirable. Rather, it is desirable that the drug and the base have a relatively low affinity and exhibit a high activity coefficient in order to enhance the release rate. However, the affinity between the drug and the base is loose, the drug freely moves in the base during storage of the drug, and is unevenly distributed on the surface, or bleeding out causes the expensive drug to be wasted. Can't control the release of the drug. Therefore, a more desirable form for the preparation is such that the base and drug are uniformly dispersed in the molecule during storage to form a strong binding state or a state similar thereto, and the binding state of both is relaxed during use. If the drug has a low affinity and is uniformly dissolved in a base having the minimum solubility, the release rate is high and it is economical. In addition, many systems in which the drug is not dissolved in the base but are uniformly dispersed have been studied.
It is a matrix type drug delivery system, and it is divided into a microseal type and a micro reservoir type. In the former, a drug, which is usually a liquid, is dispersed in a polymer matrix as a microsphere as a mixture with a powder. In the latter, a mixture of drug and liquid cosolvent is dispersed in a polymer matrix as a microreservoir. When liquid particles are dispersed in a liquid such as an emulsion base, it is said that the fat-soluble drug should be added to the oil phase which is a continuous phase of the W / O base. There is also an example in which a W / O / W type composite emulsion was investigated as an emulsion base with high sealing properties. However, in spite of such a large amount of research, no method has been found so far that always promises high-efficiency release, even if there is some improvement in drug release efficiency.

By the way, whether it is a drug that has been conventionally injected or orally administered, or a new drug, the nature and efficacy of the drug itself,
The route of administration needs to be selected depending on the therapeutic purpose.
Up to now, transdermal administration has been expected to have a local effect, but recently systemically applied preparations have been receiving much attention. In other words, the number of types of drugs that are expected to be administered transdermally has increased, and there is great expectation for the development of a universal base and a new sustained-release mechanism accordingly.

[Means for solving problems]

The present inventors have conducted extensive studies to solve the above-mentioned problems, and as a result, by using an amphipathic polymer compound having heat sensitivity and water sensitivity as the base of the drug storage layer, the conventional base Diffusion, release of drugs with universality completely different from
They have found that a distribution mechanism can be obtained, and completed the present invention.

That is, the present invention provides a patch for transdermal administration, characterized in that the drug storage layer has a heat-sensitive and water-sensitive amphipathic polymer compound as a main base, and the drug is contained in the base. Is.

Drugs are generally classified into lipophilic (hydrophobic), hydrophilic, or solid and liquid at room temperature. Also, depending on the drug effect, mg / dos
There is a large difference in the applied amount from the order of e ~ μg / dose. And some are unstable to heat, water and air.

The present invention provides a polymer base that is widely applicable to these drugs, and a patch having a novel release mechanism therefor.

In general, a compound that dissolves in both polar and non-polar solvents at the same time is called an amphiphilic substace, but it reversibly aggregates in water to form micelles and reversely in oil. Form micelles.

Similarly, when a block copolymer consisting of a succession of blocks of different types of molecules is dissolved in a liquid that becomes a solvent only for one of the blocks when it is composed of a hydrophilic block and a hydrophobic (lipophilic) block, It has recently been shown to form stable colloidal particles. That is, such a block copolymer is called an amphipathic polymer compound because it forms a micelle similar to a low molecular weight surfactant.

The amphipathic polymer compound used in the present invention also means a polymer compound having a hydrophilic block and a hydrophobic block at the same time in one molecule as described above. Each block has slightly different hydrophilicity or hydrophobicity (lipophilicity), and the hydrophilicity (hydrophobicity) has a gradient from one end to the other of all molecules. Is preferably connected to.

Further, the thermal sensitivity in the present invention means a solid polymer which exhibits a crystalline state or an amorphous state when stored at room temperature, and sensitively melts at a certain temperature or higher. Is suitable for dissolving or dispersing in suspension when the solid state polymer in the form of a frame or paste is dissolved at a skin surface temperature of 30 to 37 ° C at room temperature and the drug is in a solid state. It means that it has a viscosity of centipoise. This 30-37
An amphipathic polymer compound which has become a liquid at a relatively mild temperature of ° C has a large solubilizing power, and any of the affinity blocks dissolves many kinds of drugs, not only liquid but also solid. Therefore, it is advantageous to uniformly knead a prescribed amount of the drug into the base polymer to prepare a formulation.

Further, the water-sensitivity means that the hydrophilic block is hydrated when the amphiphilic polymer compound is brought into contact with water, but the polymer melted by heat-sensitivity is more sensitive to water. To be sensitive. For example, the phenomenon of water sensitivity can be classified as follows depending on the properties of the polymer.

A) For polymers with a relatively low total molecular weight and low melt viscosity.

 Hydrophobicity is dominant for all molecules.

It spontaneously emulsifies at the interface between water and polymer to form particles of about 0.1 to 100 μm, forming microspheres and naturally migrating to the water phase.

 Hydrophilicity is dominant for all molecules.

Emulsifies when in contact with water but dissolves immediately thereafter. Or it dissolves from the contact surface with water.

B) When the total molecular weight is relatively large and the melt viscosity is high.

 Hydrophobicity is dominant for all molecules.

Upon contact with water, the hydrophilic block of polymer at the interface hydrates at a slow rate. Although the entire base polymer is hydrated over a relatively long period of time, the whole does not flow in an emulsified state and remains as a viscous liquid. However, hydration lowers the apparent melting temperature, making it more heat sensitive. Such polymers are advantageous for releasing and delivering lipophilic drugs directly to the skin without a control membrane.

 Hydrophilicity is dominant for all molecules.

Upon contact with water, the hydrophilic segment is immediately hydrated, and further hydration proceeds in the direction in which all the polymer is dissolved. As a result, the apparent melting point decreases, and the melting and dissolution proceed in an antagonistic state. The polymer does not have the fluidity as in A), but gradually migrates to the skin surface and spreads.

In any case, the polymer heats up and melts,
It is a viscous liquid with some or considerable fluidity when dissolved in response to water, and is solubilized in a more uniformly molecularly dispersed state than when the drug was mixed. At the contact surface with the skin, the drug molecule is released from weak interaction with the high affinity segment and gradually distributed and supplied into the skin.

The balance and molecular weight of the constituent molecules of this amphiphilic polymer compound are controlled so that it dissolves or melts in response to water and heat. When dissolved and melted, the hydrophilic block acts to solubilize the hydrophilic low molecular weight compound and the hydrophobic block acts to solubilize the hydrophobic low molecular weight compound. In general, drugs are also classified into those that dissolve in polar solvents and those that dissolve in non-polar solvents. Although the meanings are slightly different, they can be roughly divided into hydrophilic drugs and hydrophobic drugs. Therefore, having slightly different blocks of hydrophilicity or hydrophobicity (lipophilicity) is correspondingly advantageous in dissolving different drugs. In fact, we have confirmed that the polymers of the present invention solubilize, whether the drug is lipophilic or hydrophilic, and that it can be liquid as well as solid. In particular, it is extremely significant to use a patch that can be transdermally administered even with a minute amount of a solid physiologically active substance that is easily decomposed, which has been considered to be quite difficult.

As the base of the present invention, any amphipathic polymer compound having heat and water sensitivities can be used, but the heat and water sensitive amphiphiles are preferable. A block polymer in which the block linkage is adjusted so that the hydrophilic polymer compound has a greater hydrophilicity as it approaches one end of the polymer molecule and has a greater hydrophobicity or lipophilicity as it approaches the other end of the polymer. It is desirable that the melting point of the polymer of the present invention is in the range of 30 to 37 ° C., in order to maintain stable in stock and to melt at around body temperature during application. More preferably, the amphipathic polymer compound is a polymer represented by the following general formula.

[In the formula, (S) is (I): a polyalkylene oxide segment of R ₁ -O-R ₁ -Ol, or Aliphatic polyester segment of, or Is a polyester segment.

Here, in the case of (I), R _{1 to} Rx are polymethylene groups having 7 to 2 carbon atoms and having or not having a side chain, and R _{1 to} Rx have carbon atoms in the order of R _{1 to} Rx. Less (however,
The number of carbon atoms in R _{1 to} Rx of adjacent segments is partly the same or / and a part of the segment consisting of R _{1 to} Rx is also included. ).

(II) is a polyester composed of a dibasic acid and a dihydric alcohol, and each methylene group R ₁ , R ₁ ′ has a carbon number of R ₁ + R ₁ ′> R ₂ . (III) is an ester compound of a ring-opening polymer of a cyclic ester of R ₁ ′ and R ₁ ″ having 5 carbon atoms and a dihydric alcohol (provided that R ₁ ′ and R ₁ ″ or l and l ′ are the same. May be).

In the case of (II) and (III), R ₁ represents a methylene group of a dihydric alcohol forming a polyester, and R _{2 to} Rx are methylene groups having 4,3,2 carbon atoms and R _{2 to} Rx. The carbon number decreases in the order of. (However, the number of carbon atoms of R _{2 to} Rx of adjacent segments is partly the same, and / or a part of the segment consisting of R _{2 to} Rx is also included.).

X is RO when (1) (S) is (I) or (II)
−, RCOO−, R-NHCOO-, R-OOCHN--NHCOO-, wherein R represents an alkyl group or a vinyl group having 1 to 18 carbon atoms, is a skeleton of isocyanate, and (2) (S) is (III)
In the case of, R-, RCO-, R-NHCO- and R-OOCHN--NHCO- (R, has the same meaning as above). In addition, l, l ', m, n, p are positive integers representing the degree of polymerization. (A), (B) and (C) show the skeleton of an isocyanate compound. ] It is comprised by the base polymer which consists of two or more multiblock polymers shown by these.

The polyester segment in the formula is lipophilic
In addition, the polyalkylene oxide segment has a lipophilicity when it has 5 or more carbon atoms. Polymers consisting of 4 or 3 alkylene oxides are hydrophobic (Hydrophobi
c), those with 3 or 2 carbon atoms are hydrophilic (Hydrophol
ic). The hydrophilicity (hydrophobicity) of polypropylene glycol having 3 carbon atoms largely depends on the size of the molecular weight. This amphiphilic polymer compound is designed so that the hydrophobicity (hydrophilicity) has a gradient from one end of the molecule to the other end (Hydrophobicity-Hydrophilicity Tapered Blo
ckpolymer). For example, a polyester segment (polyalkylene oxide consisting of alkylene oxide having 5 to 7 carbon atoms) consisting of a dibasic acid and a dihydric alcohol (or a ring-opening polymer of a cyclic ester) in order from the hydrophobic direction.
It is composed of polytetramethylene glycol segment-polypropylene glycol segment-polyethylene glycol segment. Each of these segments is linked by a diisocyanate. Then, a multi-element block polymer of binary to hexa-element consisting of heterogeneous segments having a sequence having a hydrophilic-hydrophobic gradient is constituted. Further, it may be a multi-element block polymer in which different kinds of segments are connected to a polymer which is connected by the same kind of segment, and / or some of these segments may be missing without being continuous.

Next, the amphipathic segmented polyurethane of the present invention having a heat-sensitive and water-sensitive hydrophilic-hydrophobic gradient will be described in more detail.

The polymer of the present invention preferably has a melting point in the range of 30 to 37 ° C. so that the drug can be stably stored in stock and melted at the body surface temperature during application. The apparent melting point of the segmented polymer depends on the melting point of each segment. The polymer of each segment constituting the polymer of the present invention does not matter whether it is a liquid or solid at room temperature as polyester glycol or polyether glycol, but only a liquid polymer or only a solid polymer having a melting point of 37 ° C. or higher is connected as a segment. In that case, a segmented polyurethane that melts at 30 to 37 ° C cannot be obtained. A polymer that melts at 30 to 37 ° C is preferably linked, but a liquid polymer and a solid polymer may be linked. When a liquid polymer is used as a segment, its interaction with the drug is different from that of the solid polymer due to its thermal motion, which is interesting from the viewpoint of drug release. When a liquid segment is included, a solid polymer having a considerably high melting point can be linked, although it depends on the ratio of the segment of the liquid polymer to that of the fixed polymer. Experience has shown that polymers with melting points of about 50 ° C. can be used as some segments. This seems to be because the molecular motion of the liquid segment lowers the apparent melting point or the water sensitivity causes the melting point to decrease. However, it is generally preferable to connect a solid polymer having a Tm of about 30 to 37 ° C. and a liquid polymer with a diisocyanate. However, the polymer forming each segment is a compound having a relatively low degree of polymerization because the polymer needs to be melted into a liquid having low viscosity and fluidity.

Now, the polyester glycol as the lipophilic segment will be described. The polyester glycol of the present invention is selected from aliphatic polyesters because it needs to have a low melting point as described above and a low melt viscosity.
The sum of carbon numbers of each methylene group R ₁ and R ₁ ′ is larger than that of R ₂ and smaller than 30. There are many types of aliphatic polyester depending on the combination of aliphatic dicarboxylic acid and glycol. However, in general, low molecular weight ones are brittle waxy and high molecular weight ones are tough keratin. Therefore, in the present invention, a low-molecular wax is selected. The melting point rises with an increase in the molecular weight, but reaches almost constant at a relatively low molecular weight. Naturally, the melting point is a value specific to each polyester composed of a combination of dicarboxylic acid and dihydric alcohol. However, if roughly limited by the molecular weight, about 500 to 3,000 polymers can be used. Further, in general, a polyester having a side chain introduced therein, which increases the intermolecular distance and lowers the symmetry of the molecule, has a low melting point and is often in a liquid state, so that it is easy to use as a segment. However, as a whole polymer, hydrophilic-hydrophobic balance, melting temperature, viscosity,
Naturally, it is selected based on the relationship with the drug and the like. Examples of the polyester having a melting point in the vicinity of 30 to 37 ° C. or being liquid are as follows.

-Ethylene glycol and glutaric acid, pimelic acid, azelaic acid-Propylene glycol and succinic acid, glutaric acid, adipic acid, pimelic acid, suberic acid, azelaic acid, sebacic acid-Butanediol and glutaric acid, pimelic acid-Hexanediol and amber Acid, glutaric acid, adipic acid, pimelic acid, suberic acid ・ Eicosane diol and azelaic acid ・ Diethylene glycol and suberic acid, sebacic acid ・ Triethylene glycol and sebacic acid ・ Neopentyl glycol and succinic acid, adipic acid, suberic acid, azelaine Acid, sebacic acid, etc. polyester polyols, other poly 3-
Methyl-pentane-1,5-diol adipate is also a low-viscosity liquid, and 1,000 to 3,000 can be used.

Of the polyesters that are combined with the glycols and dicarboxylic acids listed above, the low molecular weight (about 500-3,000, preferably
You can choose one from 500 to 1,000). However, the number of methylene groups is preferably 5 or more because it is more hydrophobic than the adjacent polytetramethylene glycol segment. Here, there is doubt about the influence on hydrophilicity and hydrophobicity due to the difference between the ester bond of polyester and the ether bond of polyether, but according to the experience of the present inventors, the ester bond has a strong intermolecular cohesive force in the solid state. ,
It has been confirmed that polyester has a stronger affinity for a more hydrophilic solvent than polyether. Then, due to the intermolecular force caused by the ester bond, it has a hard waxy state in the solid state even with a low molecular weight, but when melted, it changes into a low viscosity liquid. That is, a polymer having a clear melting point and a clear change in viscosity is easily obtained. This fact is a property different from the amphiphilic segment polyurethane which is composed of only alkylene oxides having a polyalkylene oxide having 5 to 7 carbon atoms in the lipophilic segment, and this polymer is harder in the solid state and has an apparent Tm. Is clear and it is easy to obtain a melt having a low viscosity. Further, there are many types of polyester, and since liquid polyester can also be used, a large number of types having different hydrophobic-hydrophilic balances can be obtained.

Similarly, a ring-opening polymer of a cyclic ester having 5 carbon atoms can be used for the same purpose. For example, a ring-opening polymer of ε-caprolactone and a polyester glycol such as diethylene glycol have a molecular weight of 500 to 2,000, preferably
500 to 1,000 items are selected. In addition, poly β-methyl-δ
Valerolactone glycol can also be used as a low viscosity liquid polyester up to a molecular weight of 1,000 to 3,000.

Next, the polyether glycol forming the polyalkylene oxide segment will be described. Polyalkylene oxide is generally synthesized by ring-opening polymerization of a cyclic ether compound. In this polymer, the smaller the number of alkylene oxide methylene groups, the higher the proportion of ether oxygen, and thus the higher the hydrophilicity, and the larger the number of alkylene oxide methylene groups, the lower the proportion of ether oxygen. Therefore, there is a property that the degree of hydrophobicity increases. However, although an alkylene oxide having a large number of methylene groups is expressed as hydrophobic, its ether oxygen has an affinity for water (Affinity), and the ether oxygen and water are associated with each other due to the structural obstacle of the methylene group chain. It is hydrophobic because it is suppressed. In other words, the reason why the alkylene oxide becomes hydrophobic as the number of methylene groups increases is explained as follows.

Due to the lack of affinity between the methylene group and water when the alkylene oxide contacts water, it seeks to minimize contact with water. This is because such a state has the smallest hydration sphere and is the most stable. This phenomenon of self-association is called Hydrophobic Interactio
n). Molecules increase in volume to reduce hydrophobic contact with water. And the number of CH ₂ units of the methylene group greatly contributes to the volume increase. In other words, it can be said that the alkylene oxide having a larger number of CH ₂ is more hydrophobic. Further, in the case of polyalkylene oxide, the polymer effect is added to the hydrophobic effect of the monomer unit. Therefore, the polyalkylene oxide segment having 5 or more carbon atoms has a property that it can be said that it is lipophilic rather than hydrophobic.

The alkylene oxide polymer used in the present invention is selected from those having a low degree of polymerization in order to form a segment.
It is selected in consideration of hydrophilic-hydrophobic balance, melting temperature / viscosity, affinity with drugs, etc., but the molecular weight is 500
It can be roughly limited to 3,000, preferably 500 to 1,000.

The lipophilic polyalkylene glycol that can be used in the present invention may be any one that can be obtained by ring-opening polymerization, and examples thereof include polypentamethylene glycol, polyhexamethylene glycol, and polyheptamethylene glycol.
Polypentamethylene glycol, which is difficult to synthesize by ring-opening polymerization of a four-membered tetrahydropyran, is not practical. Generally, when these polyalkylene oxides are used for the lipophilic segment, the melt viscosity is higher than when the polyester segment is used. Therefore, it is suitable for use as a melted adhesive in which a drug is dissolved for the purpose of directly sticking to the skin without going through a control film. The hydrophobic and hydrophilic alkylene oxide polymers will be described below.

Polytetramethylene glycol is a hydrophobic segment that is insoluble in water and well soluble in ethanol. Since those having a molecular weight of 500 to 3,000 satisfy the melting point, they can be used. Mw650, 1,000, 2,000, 3,000 Tm (℃) is 11 ~
19, 25-33, 28-40, 30-43. Polypropylene glycol is still a liquid with a molecular weight of about 40,000 and is used as a liquid segment. However, if the molecular weight is
Since it is water-soluble at 750 or less and hardly soluble or insoluble at 750 or less, it is selected in consideration of the hydrophilic-hydrophobic balance, the effect of lowering the melting point due to the liquid-solid segment balance, and the melt viscosity. Polypropylene glycol
The molecular weight effect on the hydrophobicity is large because the CH ₃ group is in the side chain. Therefore, it is necessary to pay attention to the interaction with the drug.

Polyethylene glycol also forms a water-soluble segment. It has a molecular weight of 600 or less and is liquid at room temperature. A solid segment having a molecular weight of 800 to 1,000 (Tm: 30 to 38 ° C) can be used. However, depending on the balance with other liquid segments, up to 2,000 (Tm: 48 ° C) molecular weight can be used. As the molecular weight increases, the polymer effect increases the hydrophobicity. Polyethylene glycol is a polymer with high crystallinity, and has a very low melt viscosity after being melted, especially when it is contained in water. It also has a sharp melting point. for that reason,
It is the most important determinant of the melting point and melt viscosity of the amphiphilic polyurethane of the present invention. In addition, since polyethylene glycol has an exclusion effect on non-polar substances, it seems to have a great influence on the mechanism of release of non-polar drugs. Further, since the ether oxygen of alkylene oxide shows only a weak bond with the drug, there is little risk of decomposition of the drug by the reaction.

By linking each segment with diisocyanate so that the number of carbons in the monomer unit is in the order of 2,3,4,5 ..., the desired amphiphilic segment polyurethane having a hydrophilic-hydrophobic taper is obtained. can get. At this time, heat sensitivity and water sensitivity depend on the type of segment, molecular weight, molecular weight balance, total molecular weight, and the like. However, depending on the purpose, it is not necessary to be composed of all the segments, and some may be missing. Alternatively, from the relationship of hydrophilic-hydrophobic balance, melting point and melt viscosity, several segments of the same kind may be linked by diisocyanate. Particularly, a method of linking polyethylene glycol is useful in the sense that the melting point is clarified by maintaining hydrophilicity and the temperature is maintained at 30 to 37 ° C.

Similarly, a method in which polyester glycol is also linked by diisocyanate is conceivable, but the hydrophobic effect is remarkable, the melt viscosity increases as the number of urethane bonds increases, the melt viscosity increases as the molecular weight increases, Also, it is not desirable to extend the same type of segment with diisocyanate more than necessary considering the complexity due to the increase in the number of polymerizations.

Also, the total molecular weight is approximately 1,500 to 10,000 considering the melt viscosity.
It is selected in the range of 0, preferably 2,000 to 5,000.

The -OH at the terminal of the hydrophobic segment is blocked with various alkyl groups having hydrophobicity by a conventional method. However, when the alkyl group is too large, the melting point is high and the melting point of the entire polymer is increased, so that the one having 1 to 18 carbon atoms is preferably selected. For example, in the case of a monoisocyanate represented by RNCOO at the end, CH ₃ (CH ₂ ) ₁₇ NCOO has a freezing point of 19 ° C. and is an effective hydrophobic end-capping agent. On the other hand, the terminal on the hydrophilic side is easy to synthesize and a non-toxic -OH group is most useful.

On the other hand, as the isocyanate compound for connecting the segments of the multi-block copolymer, p-phenylene diisocyanate, 2,4-toluylene diisocyanate TDI, 4,
4'-diphenylmethane diisocyanate MDI, naphthalene 1,5-diisocyanate, hexamethylene diisocyanate, tetramethylene diisocyanate, lysine diisocyanate, xylene diisocyanate, water-added TD
I, hydrogenated MDI, dicyclohexyldimethylmethane p, p ′
-Diisocyanates such as diisocyanate, diethyl fumarate diisocyanate, isophorone diisocyanate, etc. are employed. These isocyanates may have the same or different (A), (B) and (C) in the general formula. However, it is desirable that the polymer has a conformation in which the methylene group or ether oxygen (a part of the carbonyl group of polyester) easily interacts with the drug. Therefore, the diisocyanate is more likely to form a linearly linked polymer when the isocyanate is located on a straight line than when the isocyanate is present at an angled position. A polymer composed of a linear aliphatic segment and an aliphatic diisocyanate is a waxy solid which is relatively brittle in the molecular weight range of the present invention, has a clear melting point, and has a low melt viscosity, which is preferable. That is, tetramethylene diisocyanate, hexamethylene diisocyanate and the like are preferably used.

Thus, the hydrophilic-hydrophobic (lipophilic) gradient is controlled to reach the end of the molecule, and a polymer having a heat-sensitive property and a water-sensitive function is molecularly designed.
In addition, as an auxiliary agent for the heat and water sensitivities of the amphiphilic polymer compound of the present invention, polyethylene glycol, polypropylene glycol, a copolymer of both of them having a molecular weight which should satisfy the conditions of the present invention, or a surfactant of these systems The agent may be optionally added.

Next, Table 2 exemplifies a preferable combination of segments of the present invention, but the combination of segments used in the present invention is not limited thereto. Table 2 is followed by a general flowsheet for polymer synthesis.

Now, the mixing of the synthesized polymer and the drug is generally performed by the following method. First, a solid polymer is weighed at a temperature below the melting point of the polymer. 30-37 by weighing or polymerizing the drug
Add to the polymer which became a viscous liquid by heating above ℃ and knead well. It is safer to carry out the kneading under vacuum or in an inert gas such as N ₂ in a dry state. The kneading temperature may be a little higher than the melting point of the polymer, and extremely mild conditions can be selected.

According to this method, no solvent or auxiliary agent for mixing is required, so that it is not necessary to pay attention to the complexity of scattering the solvent later and the safety of the residual solvent. Since the polymer consists of a hydrophobic part and a hydrophilic part, the polymer surfactant (Polymer
It functions as a Surfactant and has a large solubilizing power. The magnitude of the solubilizing power is supported by the fact that even the drug included in cyclodextrin and the like is gradually extracted. It therefore dissolves many types of drugs. The ability to dissolve a solid drug in a low temperature molten state is convenient for handling the drug in a stable state. Once mixed (dissolved) in the polymer, it is stored in the polymer in a solid state, so that it has good storage stability, no bleed-out of the drug during storage, and no change in content.

Generally, the toxicity, mucosal irritation, primary skin irritation, etc. of surfactants are in the order of cationic>anionic>zwitterionic> nonionic. The safety is high. The fact that the polyurethane resin with alkylene oxide as a segment is being considered as an artificial organ also supports this. We have indeed confirmed that the polymer is almost non-irritating.

Finally, the effects that occur because the polymer has a hydrophilic-hydrophobic gradient are summarized as follows. That is, many drugs are present in the vicinity of the segment having the highest affinity and are dissolved in a molecularly dispersed state. In other words, the hydrophilic (hydrophobic) drug is present in a large amount in the hydrophilic (hydrophobic) segment and is rarely present in the hydrophobic (hydrophilic) segment, and is dissolved so as to have a concentration gradient at the molecular level. It can be estimated that When the polymer melts and dissolves and the drug is gradually absorbed from the skin surface, the dispersion concentration of the drug molecule changes, but the drug moves from the side with high affinity while moving from the direction of one molecular end of the polymer. Is released.
The gradient is then considered to be involved in smooth movement and controlled release. Such gradient-bound polymers provide a "field" in which the release direction is always open, whether for hydrophilic or hydrophobic drugs.

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, a lipophilic drug, a liquid or a solid. For example, the following compound groups can be mentioned.

a) Prostaglandins (PGs) (eg PGA, PGD,
PGE, PGF, PGI, 6-keto-PGE, 6,9-nitrilo-PG
I ₁ , 6,9-methano-PGI ₂ and derivatives thereof) b) Vasodilator (eg, nitroglycerin) c) Corticosteroids (eg, hydrocortisone, betamethasone) d) Anti-inflammatory Agent (eg, indomethacin, ibuprofen, etc.) e) Antibiotic (eg, penicillin, erythromycin, etc.) f) Hypnotic sedative (eg, phenobarbital, etc.) g) Anesthetic (eg, benzocaine, etc.) h) Antibacterial substance (eg,) Pentamycin, etc.) i) vitamin agents (eg, vitamin A etc.) j) anticonvulsants (eg, atropine etc.) k) hormonal agents (eg, testosterone etc.) The content of these drugs in the base is the potency of the drug. Depending on the patient's age, symptoms, intended therapeutic effect, location of application, and intended duration of release

Next, the patch of the present invention has a drug storage layer consisting of an amphipathic polymer compound having heat sensitivity and water sensitivity and a drug as an essential constituent requirement, but is easy as a patch. , Other optional layers may be provided in consideration of the stability, release property, release sustainability of the contained drug and adhesion to the skin. Examples of these layers include a skin layer, a pressure-sensitive adhesive layer, a hard substrate, a release controlling layer, and a liner, which are used in the structure illustrated in the drawings. However, the examples are merely for specifically explaining the features of the present invention and the mechanism of diffusion and release, and the present invention is not limited to these examples. Following the drawings,
The functions of various layers, hard substrates and liners will be described.

FIG. 1 is a cross-sectional view and a plane view of the patch A of the present invention, which comprises a skin layer (1), a pressure-sensitive adhesive layer (2), a release controlling layer (4) and a liner (5) in addition to the drug storage layer (3). FIG. 2nd
The figure is a cross-sectional view and a plan view of a patch B of the present invention comprising a skin layer (1), a pressure-sensitive adhesive layer (2) and a liner (5) in addition to the drug storage layer (3), and FIG. FIG. 3 is a cross-sectional view of a patch C obtained by providing a hard substrate (6) on the patch A of FIG.
FIG. 4 is a sectional view of a patch D in which the patch B shown in FIG. 2 is provided with a hard substrate (6).

The epidermal layer (1) not only functions as a support for the patch, but also prevents the drug from seeping out to the side opposite to the skin side and preventing moisture absorption during storage.

The pressure-sensitive adhesive layer (2) fixes the drug storage layer (3) to the epidermis layer and pressure-sensitively adheres the entire patch to the skin. It also prevents the drug from seeping out to the epidermis side.

The controlled release layer (4) controls the release of the drug, reduces irritation to the skin, and controls the release rate and duration. However, when the base polymer has a sufficient matrix control function by the interaction with the drug, the release controlling layer (4) is not necessary.

The liner (5) prevents moisture absorption during storage. Remove just before use.

The rigid substrate (6) is a drug storage layer (3) or a controlled release layer (4)
Is pressed against the skin to improve adhesion to the skin and to prevent slippage. It also prevents the drug from migrating to the epidermal layer (1) side.

The above layers are made of the following materials.

For the skin layer of (1), synthetic resin films such as polyethylene, polypropylene, soft polyvinyl chloride, ethylene-vinyl acetate copolymer, ethylene-vinyl alcohol copolymer, and polyethylene terephthalate can generally be used. However, one of the causes of skin irritation of the patch is discomfort during application. In other words, the sticking of the skin leaves a feeling of sticking at all times. If the material is a low-modulus material that is soft, stretchable, soft to the touch, and feels good, it follows the skin well and forgets the sticking feeling. It is a material with a 100% modulus of approximately 5 kg / cm ² or less, such as flexible polyurethane film, flexible polyvinyl chloride foam, ethylene-vinyl acetate foam, 1,2-
Examples thereof include polybutadiene foam. Of these, 1,2-polybutadiene foam is most preferable because it does not cause blocking in the material, and is thin and highly safe without bleeding of the plasticizer additive. Considering the ease of handling, the thickness is preferably 0.15 to 1.0 mm. This material may be provided with a surface treatment agent on the inside or outside (in the case of the outside, it also has the meaning of giving lubricity when touching clothes) in order to prevent the drug from seeping out to the base side. This low-modulus skin material is adapted to the modulus of the pressure-sensitive adhesive (adhesive material) on the inner side to form a unity structure.

The pressure-sensitive adhesive (adhesive) of (2) may be converted into a lipophilic or hydrophilic one depending on the properties of the drug, and sometimes only the part which is in close contact with the skin is replaced with one having a good affinity with the skin. May be. Generally, acrylic or rubber-based adhesives can be used, but polysaccharide-based plant-based adhesives or animal-based adhesives such as gelatin can be used as appropriate. A suitable thickness is 20 to 30 μm.

The release controlling layer of (4) is an ethylene-vinyl acetate copolymer,
A polymer film of silicon, acrylic resin, polyethylene, ethyl cellulose or the like or a porous film thereof can be arbitrarily used. However, in view of the gist of the present invention and the characteristics of the base polymer, a film that is inactive during storage of the preparation and active during application is more preferable. That is, it does not function as a membrane before application, and after application it reactivates due to the temperature and moisture on the body surface to remarkably exhibit the function of permeation and diffusion. Moreover, since adhesion to the body surface is a basic condition for quantitative absorption into the skin, reactivation also means development of (stronger) tackiness.

Since the matrix control by the base polymer also works in the present invention, the release control may be required or the release promotion may be required for the membrane.

Also, since the membrane is in direct contact with human skin, the less stimulant the better. For the above reasons, the gelatin film is preferably used in the present invention. Examples of the gelatin film are as follows.

A) A diepoxy compound is added to a gelatin aqueous solution and a dextran aqueous solution as a crosslinking agent. This is formed into a film and then dried. Then, it heats at 60 degreeC and completes bridge | crosslinking. This film is a phase separation film of gelatin and dextran. Next, this membrane is immersed in water to remove dextran and dried again to obtain a porous gelatin membrane. If the membrane is fragile, it is reinforced by immersing a cloth such as nylon tricot with thin fibers and a small basis weight (coarse mesh) in an aqueous solution of gelatin-dextran-crosslinking agent, pulling it up, and then performing the same operation. A film is obtained.

B) Gelatin / water, glycerin and a cross-linking agent are mixed in a predetermined amount, and then dried and cross-linked in the same manner as in A) to have a thickness of 30-40.
Obtain a μm film. This belongs to the liquid film because it contains 20 to 50% glycerin. The film has a relatively hard and dry feel at room temperature and in a dry state due to the characteristics of gelatin, but is activated by temperature and humidity on the body surface and changes into a wet and sticky film. At the time of application, glycerin moisturizes the skin to keep the skin in a certain state, and the adhesiveness of the film adheres to the skin, thus forming a basic foundation for quantitative absorption of the drug. Primarily A) appears to function as a drug / polymer diffusion control and B) as a drug diffusion control or promotion.

As the liner (5), a release paper, a release film or the like which is usually used can be used.

For the hard substrate of (6), polyester, polypropylene,
Rigid polyethylene, polycarbonate, polystyrene,
A synthetic resin plate such as is preferable, but other plate-like materials can be used. This hard substrate must be inert to the drug in the drug storage layer (3), have appropriate rigidity, and should not be broken by impact. The thickness of the substrate (6) is preferably about 100 to 500 μm.

The shape of the patch of the present invention is not particularly limited, and may be a desired shape such as a round shape or a square shape, and the size and thickness may be drug titer, patient age, symptoms, purpose. It is appropriately determined depending on the therapeutic effect, the application site, the intended duration of release, etc.

In the present invention, the diffusion, release, and distribution of the drug are presumed to occur as follows.

1. The drug is mixed with the dissolved base polymer (however,
Under mild conditions not much higher than the melting point). The drug in the drug storage layer (3) is dissolved or dispersed in a solid polymer in a crystalline or non-crystalline state when stored at room temperature below about 30 ° C. When the drug is dissolved, it is molecularly dispersed in the vicinity of the affinity segment of the amphipathic polymer compound. If the drug is encapsulated or coated with molecules that are insoluble in the base polymer, it is dispersed.

2. Remove the patch from the liner (5) and apply it to the skin.

3. The amphipathic polymer compound of the present invention constituting the drug storage layer (3) first melts at body temperature due to its heat sensitivity. When there is a heat-sensitive or moisture-sensitive reactive adhesive film, it is preceded that the film becomes sticky due to body temperature and adheres to the skin.

4. After a while after application, when a certain amount of water emanating from the skin surface reaches the molten polymer in the drug storage layer, the polymer starts to hydrate. In reality, melting and hydration proceed in an antagonistic state, and the melting point is lowered, so that it becomes easier to melt and melt, and finally the whole becomes a viscous liquid that flows to the membrane side or the skin surface and gradually Spread to. As described in the definition of water sensitivity, the state during this period is: A) In the case of a polymer having a relatively small total molecular weight and a low melt viscosity, hydrophobicity is dominant as the total molecular weight, and hydrophilic stars are dominant as the total molecular weight. B) In the case of a polymer having a relatively large total molecular weight and a high melt viscosity, hydrophobicity is dominant as a total molecular weight, and hydrophilicity is dominant as a total molecular weight. The process is different.

It also differs depending on whether or not there is a film.

But the common fact is that it has hydrophilic and hydrophobic moieties,
Amphiphiles that have some solubility (affinity) in water increase in volume so as to minimize the contact area between the hydrophobic part and water. And it has a tendency to migrate to the interface. That is, it tends to gather on the surface of the skin where the water content is high, and the molecule tends to be elongated.

5. On the skin surface, the drug is distributed / absorbed with its own permeation rate into the skin, but at this time, the weak interaction between the amphipathic segments and the drug and the gradient of affinity act as an appropriate release suppressing force. Here, the extended state of the polymer due to its hydrophobic effect is advantageous for releasing a trace amount of drug with high efficiency.

Here, the drug is absorbed by the skin, but the polymer has large molecules and remains unabsorbed by the skin. Generally, enhancers such as dimethylsulfoxide (DMSO)
It is said that large molecules with a molecular weight of 3,000 or more are difficult to be absorbed even by skin stripped with a solvent that acts as an er). In the present invention, the block polymer satisfying the above-mentioned conditions is preferably 2,000 to 5,000, and since it is hardly absorbed from normal skin, it is extremely safe.

More specifically, a low molecular weight compound excluding hydrocarbons having no polar group generally has a polar group and a non-polar group in the molecule, and the molecular structure is established by taking a certain variation. The same applies to the molecular structure of drugs. The drug used in transdermal drug delivery has a relatively loose affinity with the polymer, which is the base, and the state of being uniformly dispersed with a high activity coefficient is considered when considering the release efficiency. desirable. However, the desired release pattern should be selected for each controlled release, depending on the potency of the drug, the age of the patient, the symptoms, the desired therapeutic effect, the application site, the intended duration of release, etc. is there. Such control of drug release is affected by the cohesive strength of the base polymer of the drug, that is, weak intermolecular interactions, morphology of dispersion at the molecular level, and thermal / physicochemical behavior of the polymer and drug. It is a thing.

When the bond between the drug and the polymer is too strong, for example, in the case of coordination bond, covalent bond, ionic bond, etc., it is considered that the drug reacts with the polymer and undergoes a chemical change. Moreover, a high activity coefficient cannot be obtained. On the other hand, a hydrogen bond or a bond having a weak Van der Waals force is unlikely to cause a drug reaction, and arbitrarily high activity can be obtained.

The relationship between the amphipathic alkylene oxide segment polyurethane used in the present invention and the drug is characterized as follows.

It is well known that alkylene oxide has ether oxygen, and this oxygen acts as hydrophilicity because of its affinity with water. It is well known that this oxygen solubilizes by forming a hydrogen bond with active hydrogen of alkylcarboxylic acid (for example, oleic acid) which is a hydrocarbon having polarity, or higher alcohols.
Similar weak bonds are formed for drugs.

Therefore, in the present invention, it is also possible to transdermally administer a minute amount of prostaglandins (PG), which are highly physiologically active substances that are extremely easily decomposed. PGs are unsaturated fatty acids having 20 carbon atoms and having a hydroxyl group, and show a fairly strong polarity. In general, it is well soluble in polar organic solvents such as alcohol, acetone, chloroform, ethyl acetate, etc., but hardly soluble in low polarity solvents such as hexane and petroleum ether. It is also sparingly soluble in water. PG is structurally composed of a lipophilic part and a hydrophilic part. From the above characteristics, it is easily presumed that the weak interaction described above is established between the PGs and the polyalkylene oxide segment.

On the other hand, the degree of hydrophobicity of alkylene oxide changes depending on the carbon number of methylene. However, in the monomer unit, the effect of hydrophobicity is not so remarkable. By linearly connecting the monomer units and using them as polymer segments, the effect is remarkably exhibited.
Furthermore, a continuous gradient from hydrophilicity to hydrophobicity is formed by adjoining and continuing a segment having a monomer unit in which the methylene number is gradually increased or decreased. If the number of drugs saturated with ether oxygen is molecularly dispersed in a weakly bound state with this oxygen, a concentration gradient is formed along the segment in the dispersed state of the drugs. When the drug exhibits strong lipophilicity, methylenes effectively act on the molecular dispersion, and thus a concentration gradient is similarly formed in the molecularly dispersed state. Such a smooth gradient of hydrophilicity or hydrophobicity allows the position having the highest concentration of affinity to exist in the vicinity of the segment that matches the solubility constant of the drug. This polymer is called an amphipathic polymer compound because either segment allows lipophilicity and hydrophilicity. In the case of a lipophilic drug, the molecular structure is always open so as to shift toward the lipophilic segment and toward the hydrophilic segment in the case of a hydrophilic drug.

Here, there remains concern about the interaction between the ester bond of the polyester segment as the lipophilic segment and the drug. However, the intermolecular force does not appear so strongly due to the fact that it is an aliphatic polyester, it occupies only one block of the multi-block polymer, and the copolymerization effect of being interfered with by other blocks. That is, the reactivity with the drug is extremely low and causes no problem in practical use.

Each segment of the polymer is cut by a urethane bond, but each segment has its own thermal motion depending on its molecular bonding force, molecular weight and intermolecular force. Therefore, the migration of the drug existing in the vicinity of the active segment of thermal motion is preferentially initiated. Further, the total melting temperature is determined by the interaction between the segments, but there is a difference in the thermal motion of each segment even at such a melting temperature.

As described above, the interaction between molecules makes it possible to release a wide variety of drugs, and their behaviors are so-called sustained release processes that are delicately controlled.

The present invention will be described in more detail by the following examples, but the present invention is not limited to these examples.

[Example 1] (However, polytetramethylene glycol has an average molecular weight of 650, polypropylene glycol has an average molecular weight of 400, and polyethylene glycol has an average molecular weight of 1000, which represents the skeleton of hexamethylene diisocyanate.) A waxy crystalline polymer having the above structural formula was used at 40 ° C.
After heating to a transparent low-viscosity liquid polymer,
To this, 0.1 wt% of prostaglandin and 17S, 20-dimethyl-trans-Δ ² -PGE ₁ as a drug were added and stirred well. The drug had a melting point of 97-100 ° C, but was completely dissolved in this polymer. This was applied to release paper in a layer thickness of 100μ. Then, further cool it to below 5 ° C to solidify the polymer more completely and punch it out with a 2.0 cm x 2.0 cm dumbbell to give about 40 mg.
A drug-containing polymer base was prepared. Separately, a low modulus 1,2-polybutadiene foam (expansion ratio 3 times, 200 μm thickness, 3 cm × 3 cm) is used as a skin material, and an acrylic adhesive is coated on one surface to a thickness of about 30 μm. The polymer side of the polymer base containing the drug was attached to the adhesive surface. Next, this was put in a moisture-proof aluminum-deposited packaging film bag and vacuumed and sealed.

After storing this at 25 ° C or lower for 6 months, it was taken out from the pack again and the stability of the drug was examined, but almost no change was observed. This is because the drug was uniformly dissolved and immobilized in the crystal of the polymer and was stably stored, and no bleeding of the drug on the surface was observed.

The release paper of the drug-containing polymer was peeled off and attached to the skin surface. The polymer base that came into contact with the skin began to change in response to body temperature and water released from the skin surface. The drug-containing polymer was a white solid at about 30 ° C or lower, but gradually changed to a paste at 30 ° C or higher, and rapidly melted into a transparent fluid liquid as the body temperature was approached. However, it does not have such a low viscosity that it flows down from the surface of the skin, and maintains a state in which it adheres well to the skin.

The remaining amount of the drug in the polymer base was measured 48 hours after application. The remaining amount was 15 to 20%. Since the residual amount of the transdermal agent of the conventional transdermal agent is 70 to 80%, the transdermal patch of the present invention shows a very high efficiency in releasing the drug into the skin. I understood.

Further, the behavior of the drug-containing polymer of the present invention was followed using an optical microscope. The white polymer has a temperature of 36
It melted rapidly at around ℃ and became a transparent liquid. When water of 1 to ² mg / cm ² · hr, which is similar to human sweating, is given to this, the polymer forms a large number of microspheres at the interface with water at a certain amount of water and vigorously in the water phase. Was drawn into and dispersed. This is because the polymer was self-dispersed by encapsulating the drug by the interfacial energy, and it is speculated that this phenomenon also occurs on the skin surface.

It is believed that the microspheres have their hydrophilic polymer segment on the water side. When it comes into contact with the skin, the microspheres are destroyed by the lipids present on the skin surface, causing a phase transition, and the water-insoluble lipid-rich medicinal agent with a large partition coefficient is gradually absorbed through the stratum corneum of the skin. It is presumed that it was done.

[Example 2] (However, the average molecular weight of poly ε-caprolactone is 530, the average molecular weight of polypropylene glycol is 400, and the average molecular weight of polyethylene glycol is 1,000 indicates the skeleton of hexamethylene diisocyanate.) The melting point of the polymer having the above structural formula by visual observation was 36 to 37 ° C. . This polymer was melted in the same manner as in Example 1 and included with α-CD (α-cyclodextrin) as a drug 17
S, 20-Dimethyl-trans-Δ ² -PGE ₁ (OP-1206 ・ α
-CD) was mixed and dispersed. This drug-containing polymer base
As a result of vacuum-sealing in a cool dark place below 25 ° C for 6 months,
No special changes were seen. After application on the skin surface in the same manner as in Example 1, the residual ratio of the drug in the polymer base after 72 hours was 20 to 30%, which was a good result.

In order to control the release pattern of this preparation, the polymer surface was covered with a porous membrane in which a gelatin-dextran phase-separated crosslinked material was network-reinforced with a nylon tricot cloth. The residual rate 72 hours after applying this was 30 to 40%, and although the release rate slightly decreased, the release pattern had a relatively uniform gradient.

[Example 3] (However, polytetramethylene glycol average molecular weight 650 polypropylene glycol average molecular weight 400 polyethylene glycol average molecular weight 1,000 indicates the skeleton of hexamethylene diisocyanate.) Wax-like crystalline polymer having the above structural formula at 40 ° C.
After heating to the above to form a transparent, low-viscosity liquid polymer, prostaglandin E ₁ methyl ester (PGE ₁ methyl ester) was added as a drug to this, and the mixture was stirred well.
The drug was in liquid form and dissolved easily. Then, the drug polymer was used in the drug storage layer of the formulation having the constitution shown in FIG. 3 in a state where it was cooled and solidified. However, PGE ₁ per patch
The amount of methyl ester, the amount of the base of the present invention, and the area of the drug storage layer are 10 μm / 20 mg / 4 cm ² . As the release controlling film, a reactivated gelatin film prepared as follows was used.

That is, normal temperature drying after film formation of alkali gelatin 100 parts by weight of crosslinking agent ^{* 3} parts by weight of glycerin 40 parts by weight of water 100 parts by weight of the formulation. After that, crosslinking is performed at 60 ° C. for 72 hours to obtain a dry film. A film having a thickness of 40 μm was used.

When this preparation was applied to human skin and the drug release rate after 72 hours was measured, it was 50 to 55%.

* Glycerol polyglycidyl ether [Example 4] (However, MPA is a polyester of 3-methylpentane-1,5-diol and adipic acid, and the average molecular weight of the polymer constituting the segment is 1,000, the average molecular weight of polypropylene glycol is 750, and the average molecular weight of polyethylene glycol is 1,000 is hexamethylene diisocyanate. The solid-state polymer of the above structural formula had a visual melting point of about 35 ° C. When this polymer was heated, it became a transparent and low-viscosity liquid, and 0.5 wt% of testosterone was added as a drug in a state of being heated at 40 to 50 ° C. and well stirred. The melting point of this drug is 153-157 ° C, but it was confirmed by microscopic observation that it was completely dissolved. This drug / polymer was then used in the solidified state in the cooled state in the drug reservoir of the formulation of the construction shown in FIG. However, the amount of testosterone per patch, the base amount of the present invention, the area of the drug storage layer is 100 μg
/ 20mg / 4cm ² .

When this preparation was applied to human skin and the drug release rate was measured 48 hours later, it was about 35-40%, which was a relatively high value.

[Example 5] Formulation similar to [Example 2] (OP-1206 / α-CD patch)
The drop in blood pressure when OP-1206 1 mg / kg was applied to hypertensive rats (SHR) was as shown in the graph in FIG.

PEG-polyethylene glycol) ointment under the same conditions shows an initial hypotension, but its persistence is almost non-existent.
On the other hand, in the case of Example 2, the sustainability of blood pressure reduction was observed even after 24 hours, and the superiority of the sustained release of this preparation is clearly confirmed.

〔The invention's effect〕

Since the patch of the present invention uses an amphipathic polymer compound having heat sensitivity and water sensitivity as a base of the drug storage layer, it controls the release and distribution of the drug with long-term stability and high efficiency. It is a patch that can be used.

More specifically, the polymer compound is a solid substance that is stable at room temperature and has a skin surface temperature or body temperature (30 to 70 ° C).
It is a heat-sensitive polymer compound that melts sharply with. Therefore, at the temperature at which the preparation is stored, the polymer is in a solid state, the drug is dissolved or dispersed in the crystalline or non-crystalline state of the limer, and the drug is kept stable and other drugs are stored during storage. Since the sustained release is started only after application without being diffused into the layer or being released, the transient release (initial release) immediately after application as in the conventional base is suppressed. Also, since the base polymer is an amphipathic polymer, it dissolves many drugs in liquid, solid, lipophilic or hydrophilic form. Therefore, it becomes a universal transdermal administration system applicable to a wide range of drugs as in the examples. It is particularly suitable for transdermal administration of highly physiologically active substances (eg, prostaglandins) that are extremely easily decomposed by heat and water and are unstable. That is, even a small amount of highly physiologically active drug is uniformly dissolved and dispersed at the molecular level by the block having a high affinity of the base polymer, and it is devised so that it is gradually released at a high utilization rate. Further, since the base polymer is extremely less irritating, it is highly safe and side effects can be minimized. The drug effect duration can be freely controlled by controlling the interaction between the polymer and the drug at the molecular level or through an appropriate membrane.

[Brief description of drawings]

1 to 4 show an example of the patch according to the present invention. FIG. 5 is a graph showing changes in sustained release between this preparation and the comparative preparation. 1 ... skin layer, 2 ... pressure-sensitive adhesive layer, 3 ... drug storage layer,
4 ... Release control layer, 5 ... Liner, 6 ... Hard substrate.

Claims (12)

[Claims] 1. A patch for transdermal administration in which a drug storage layer contains a heat-sensitive and water-sensitive amphipathic polymer compound as a main base, and the drug is contained in the base. The high-molecular compound is a polyether polyol composed of alkylene oxide, or a multi-element block copolymer composed of a reaction product of an aliphatic polyester polyol / the polyether polyol and diisocyanate, [Wherein (S) is (I): a polyalkylene oxide segment of R ₁ -O-R ₁ -Ol, or Aliphatic polyester segment of, or Is a polyester segment. Here, in the case of (I), R _{1 to} Rx are polymethylene groups having 7 to 2 carbon atoms and having or not having a side chain, and R _{1 to} Rx have carbon atoms in the order of R _{1 to} Rx. Less (however,
The number of carbon atoms in R _{1 to} Rx of adjacent segments is partly the same or / and a part of the segment consisting of R _{1 to} Rx is also included. ). (II) is a polyester composed of a dibasic acid and a dihydric alcohol, and each methylene group R ₁ , R ₁ ′ has a carbon number of R ₁ + R ₁ ′> R ₂ . (III) is an ester compound of a ring-opening polymer of a cyclic ester of R ₁ ′ and R ₁ ″ having 5 carbon atoms and a dihydric alcohol (provided that R ₁ ′ and R ₁ ″ or l and l ′ are the same. May be). In the cases of (II) and (III), R ₁ represents the methylene group of the dihydric alcohol forming the polyester. Further, R _{2 to} Rx are methylene groups having 4,3,2 carbon atoms, and the number of carbon atoms decreases in the order of R _{2 to} Rx. (However, the number of carbon atoms of R _{2 to} Rx of adjacent segments is partly the same, and / or a part of the segment consisting of R _{2 to} Rx is also included.). X is (1)
When (S) is (I) or (II), RO-, RCOO-, R-NHCOO-, R-OOCHN--NHCOO-, wherein R is an alkyl group or a vinyl group having 1 to 18 carbon atoms, is an isocyanate skeleton, and (2) (S) is (III)
In the case of, R-, RCO-, R-NHCO- and R-OOCHN--NHCO- (R, has the same meaning as above). Also, l, l ', m, n,
p is a positive integer representing the degree of polymerization. (A), (B),
(C) shows the skeleton of an isocyanate compound. ] A patch for transdermal administration, which is composed of a base polymer composed of two or more binary multi-block polymers represented by 2. The patch according to claim 1, which comprises an amphipathic polymer compound that melts at 30 to 37 ° C. 3. The polyalkylene oxide segment in the case where (S) in the general formula is (I) is polyethylene glycol, polypropylene glycol, polytetramethylene glycol, polypentamethylene glycol, polyhexamethylene glycol or polyheptamethylene glycol. And (II) is a polyester composed of a reaction product of a dibasic acid having a carbon number of 5 or more per polyester unit and 5 or more, and (III) is poly ε-caprolactone or poly β-methyl-δ. A polyester comprising a reaction product of valerolactone and an alkylene glycol, wherein the polyalkylene oxide in the case of (II) or (III) is polyethylene glycol, polypropylene glycol or polytetramethylene glycol. Patch described . 4. A heat-sensitive and water-sensitive amphipathic polymer compound has a higher hydrophilicity as it is closer to one end of the polymer molecule and has a higher hydrophobicity or lipophilicity as it is closer to the other end of the polymer molecule. The patch according to claim 1, which is a block polymer in which the block connection is controlled. 5. The polyester segment or polyalkylene oxide segment at one end of the amphipathic polymer compound is lipophilic or hydrophobic, and the polyalkylene oxide segment closer to the other end is adjusted to have a higher hydrophilicity. The patch according to claim 3, wherein 6. The patch according to any one of claims 1 to 4, wherein the drug contained in the drug storage layer is a prostaglandin. 7. The drug is 17S, 20-dimethyl-trans-Δ.
^The patch according to claim 5, which is ^2- PGE ₁ , its methyl ester, or its cyclodextrin inclusion compound. 8. The patch has at least a skin layer, a pressure-sensitive adhesive layer and a liner in addition to the drug storage layer, and the skin layer is bonded to the drug storage layer by the pressure-sensitive adhesive layer. The patch according to any one of claims 1 to 6. 9. The patch according to claim 8, wherein the skin layer is 1,2-polybutadiene foam. 10. The patch according to any one of claims 1 to 7, wherein the patch has a release controlling layer. 11. The adhesive patch according to claim 10, wherein the release controlling layer is a heat-sensitive and moisture-sensitive reactive adhesive film. 12. The patch according to claim 11, wherein the reactive adhesive film is a gelatin film.