JPH0441423A - Percutaneous absorbable pharmaceutical and method for percutaneous administration - Google Patents

Abstract

PURPOSE:To obtain a percutaneous absorbable pharmaceutical, responsive to a change in external temperatures and capable of on-off control over percutaneous administration of a drug with hardly any individual difference by using a temperature-responsive hydrogel membrane in a release control membrane. CONSTITUTION:A temperature-responsive hydrogel membrane capable of absorbing water and swelling below the phase transition temperature, releasing water and contracting above the phase transition temperature is used in a release control membrane of a percutaneous pharmaceutical containing 4 layers of a coating layer, a drug storing layer, the aforementioned release control layer and a tacky layer. A water-insoluble polymer prepared by using >=50 mol%, especially >=75 mol% compound (e.g. N-n-propylacrylamide) expressed by formula I (R1 is H or methyl; R2 and R3 are H or lower alkyl) and/or a compound (e.g. N-acryloylpyrrolidine) expressed by formula II [A is (CH2)n (n is 4-6) or (CH2)2-O-(CH2)2] is used as the temperature-responsive hydrogel membrane and the phase transition temperature thereof is preferably within the range of 0-50 deg.C, especially 20-32 deg.C.

Description

Detailed Description of the Invention [Industrial Field of Application] The present invention relates to a transdermal administration method for a drug and a transdermal absorption preparation used in the method, and particularly relates to a transdermal absorption preparation that reversibly changes shape in response to temperature changes. Using a temperature-responsive hydrogel membrane, the permeation or release of the drug is controlled by temperature, allowing the drug to be transdermally delivered to the blood circulation system when and for the required period of time, and to be administered transdermally for an unneeded period of time when it is not needed. The present invention relates to the method and the preparation, which are characterized in that they are paused.

BACKGROUND OF THE INVENTION Methods for delivering drugs at steady state flow rate through the skin to the blood circulation system are already known in the art.

For example, an overview of currently marketed transdermal drug administration products can be found in the literature ``Transdermal absorption preparations and their mechanisms'', Pharmacy,
Volume 39, No. 9, pp. 1293-1300, 19
It was written in 1988. As shown here,
Various types of transdermal formulations are commercially available and are capable of delivering drugs to the blood circulation at steady state flow rates for more than 24 hours. For example, TrangdermNitro (
A121-Cibt-Geig7) is a coating film.

It consists of four layers: a drug storage layer, a release control membrane, and an adhesive layer, and the release control membrane controls the release of nitroglycerin in the drug storage layer to a steady state flow rate. This Tr
When two sheets of Cyamarm-Nijto■1o are applied to the left chest, the average plasma nitroglycerin concentration remains constant at 200 to 300 pg/H1 over 24 hours.

Problems to be Solved by the Invention A fundamental limitation of these transdermal formulations is that they are designed only to deliver drug to the blood circulation system at a constant flow rate during the administration period.

That is, by continuing to administer a drug at a constant flow rate for a long period of time, side effects may occur.

For example, "How to use transdermal absorption drugs - development of resistance and its countermeasures", Pharmacia, Vol. 24, No. 7.

As described in 1988, pp. 699-702, the development of resistance due to long-term administration of nitroglycerin is a problem.

[Means for Solving the Problems] In order to solve the above problems, it is necessary to maintain the blood concentration at which the drug exerts its action for an arbitrary period of time (on-administration period).
Therefore, it is desirable to formulate an administration plan so as to recycle the administration period during which the blood concentration of the drug continues to disappear for an arbitrary period of time (off administration period).

As a result of intensive research to solve the above problems, the present inventors found that it is possible to achieve such an administration plan by using a temperature-responsive hydrogel membrane.

That is, the present inventors have discovered that a hydrogel, which is a water-insoluble polymer obtained by using, for example, a compound represented by formula (I) and/or a compound represented by formula (II) as a main component, is compatible. Focusing on the fact that they have a transition temperature and change their form by changing the temperature from below that temperature to above that temperature, or vice versa, that is, they have "temperature responsiveness", these As a result of intensive investigation into the use of hydrogel as an on-off drug administration control membrane, it was found that below the phase transition temperature of the hydrogel membrane, the drug permeates, and above the phase transition temperature, drug permeation is suppressed, and the repeated temperature It was found that the behavior did not change even with the change.

The present invention was completed based on this knowledge.

That is, the present invention provides: (1) A transdermal absorption preparation characterized by using a temperature-responsive hydrogel membrane as a release control membrane.

(2) Using the transdermal absorption preparation described in (1) above, the drug is administered on-off by changing temperature, with a steady-state flow rate during the on-administration period and a smaller steady-state flow rate or a substantially lower steady-state flow rate during the off-administration period. A transdermal administration method characterized in that the drug is delivered through the skin into the blood circulation system with zero flow rate.

Regarding.

In the present invention, "temperature-responsive hydrogel membrane" refers to
A membrane that absorbs water and swells below the phase transition temperature, and releases water and contracts above the phase transition temperature. This swelling and shrinking behavior occurs reversibly in the presence of water. Furthermore, since this reversible change is surface rate-determined, rapid change can be achieved.

The transdermal absorption preparations of the present invention may be of any of the various types conventionally known as described in the above-mentioned documents, and may include a controlled release membrane (different names) included as a component of these preparations. However, the temperature-responsive hydrogel membrane is included as a membrane that is substantially interposed between the drug storage layer and the skin, and through which the drug reaches the skin. It is fine as long as it is used.

The structure of the transdermal absorption preparation in the present invention usually includes four layers: a coating film, a drug storage layer, a temperature-responsive hydrogel film, and an adhesive layer. The coating membrane may be any membrane as long as it is impermeable to the drug or the contents in the drug storage layer, such as aluminum foil. The drug storage layer may be water or an aqueous system that can maintain the drug at a saturation concentration for a predetermined period of time; for example, if the drug has a saturation concentration or higher,
Alternatively, it is desirable to use a liquid or gel-like carrier in which a carrier containing a drug at a saturation concentration or higher is dispersed in water or an aqueous solvent.

As the temperature-responsive hydrogel membrane, for example, the following hydrogel membranes can be used. The adhesive layer is for adhering the hydrogel film to the skin, and includes, for example, a silicone-based pressure sensitive adhesive that is hypoallergenic to the skin.

Typical examples of the temperature-responsive hydrogel membrane include compounds represented by formula (I) and/or compounds represented by formula (II) (wherein R1 is a hydrogen atom or a methyl group, R2 and R3
represents a hydrogen atom or a lower alkyl group, preferably R
2 is a hydrogen atom, a methyl group or an ethyl group, R3 is a methyl group, an ethyl group or a propyl group, R and R3 may be the same or different, but at least one of them has a lower alkyl group. show. ) (wherein, R1 -(-CH2-)-.

+CH2+2 represents a hydrogen atom or a methyl group, and n represents 4 to 6 or 0+CH2+2. ) A can include water-insoluble polymers obtained using A as a main component.

Such a polymer comprises a compound represented by the above formula (I) and/or
Alternatively, it is a polymer of a compound represented by the formula (Il) or a copolymer of these compounds and another copolymerizable monomer, which is insoluble in water.

Specifically, the compound represented by formula (1) or formula (II) includes N-o-propylacrylamide, N-n-
Propylmethacrylamide, N-isopropylacrylamide, N-isopropylmethacrylamide, N
-ethyl acrylamide.

N,N-diethylacrylamide, N-ethylmethacrylamide, N,N-dimethylacrylamide.

N,N-dimethylmethacrylamide, N-acryloylpyrrolidine, N-methacryloylpyrrolidine.

Examples include N-acryloylpiperidine, N-methacryloylpiperidine, and N-acryloylmorpholine.

In addition, monomers that can be copolymerized with the above monomers include:
Examples include hydrophilic monomers and hydrophobic monomers, and one or more of these monomers can be used. Specifically, hydrophilic monomers include, for example, acrylamide, methacrylamide, N-methylacrylamide, diacetone acrylamide, hydroxyethyl methacrylate, hydroxyethyl acrylate, hydroxypropyl methacrylate, hydroxypropyl acrylate, and various methoxypolyethylene glycol methacrylates.

Various methoxypolyethylene glycol acrylates,
N-vinyl-2-pyrrolidone, acrylic acid.

Methacrylic acid, vinyl sulfonic acid, allyl sulfonic acid,
Methacrylsulfonic acid, styrenesulfonic acid, 2-acrylamido-2-phenylpropanesulfonic acid, 2
Acids and their salts such as -acrylamido-2-methyl-propanesulfonic acid, N,N-dimethylaminoethyl methacrylate, N,N-diethylaminoethyl methacrylate, N,N-dimethylaminoethyl acrylate, N,N-dimethylamino Examples include amines and their salts such as propyl methacrylamide, N,N-dimethylaminopropylacrylamide, various acrylates, methacrylates, acrylamide, methacrylamide, acrylonitrile, vinyl acetate, glycidyl methacrylate, etc., and these can be introduced by copolymerization. If necessary, it can be hydrolyzed to impart hydrophilicity. Examples of the hydrophobic monomer include N-n-butylacrylamide, N-butylmethacrylamidylamide, N-tett,-butylmethacrylamide, N-n-hexylacrylamide, N-a-
Hexyl methacrylamide, N-n-octyl acrylamide, N-n-octyl methacrylamide, N-1s
t+. - N-alkyl (meth)acrylamide derivatives such as octylacrylamide, N-n-dodecyl acrylamide, N-n-dodecylmethacrylamide, N,
N-diglycidyl acrylamide, N,N-diglycidyl methacrylamide.

H-(4-glycidoxybutyl)acrylamide.

H-(4-glycidoxybutyl)methacrylamide.

N-(5-glycidoxypentyl)acrylamide.

N-(ω-glycidoxyalkyl)(meth)acrylamide derivatives such as N-(6-gelicidoxyhexyl)acrylamide. (Meth)acrylate derivatives such as ethyl acrylate, methyl methacrylate, butyl methacrylate, butyl acrylate, lauryl acrylate, 2-ethylhexyl methacrylate, glycidyl methacrylate. acrylonitrile, methacrylonitrile,
Vinyl acetate, vinyl chloride, olefins such as ethylene, propylene, butene, styrene, α-methylstyrene,
Butadiene, isoprene, etc. can be mentioned.

Methods for obtaining water-insoluble polymers of the above-mentioned monomers include a method in which the polymer is made insoluble during polymerization and a method in which it is made insolubilized in a post-polymerization treatment. Specifically, a method of copolymerizing with a crosslinkable monomer having at least two or more double bonds in the molecule (first method), a method of copolymerizing with an N-alkoxymethyl (meth)acrylamide derivative (Second method),
When a hydroxyl group or an amino group is present in the polymer, a method of crosslinking by reacting them with a polyfunctional compound such as epichlorohydrin (third method) can be mentioned. Any method may be used as long as the ultimately obtained polymer is insoluble in water.

More specifically, in the first method, as a crosslinkable monomer,
For example, H+-methylenebisacrylamide, N, N'
- diallylacrylamide, triacryl formal,
N,N'-diacryloimide.

N,N'-dimethacryloimide, ethylene glycol diacrylate, ethylene glycol dimethacrylate, various polyethylene glycol diacrylates, various polyethylene glycol dimethacrylates, propylene glycol diacrylate.

Propylene glycol dimethacrylate, various propylene glycol diacrylates, various propylene glycol dimethacrylates, 1,3-butylene glycol diacrylate, 1,3-butylene glycol dimethacrylate, 1,4-butylene glycol dimethacrylate,
Glycerol dimethacrylate, neopentyl glycol dimethacrylate, trimethylolpropane triacrylate.

Trimethylolpropane trimethacrylate, trimethylolethane trimethacrylate, trimethylolethane triacrylate, tetramethylolmethanetetramethacrylate, tetramethylolmethane triacrylate, divinylbenzene.

Diaryl phthalate, etc. can be used.

As the N-alkoxymethyl (meth)acrylamide derivative in the second method, for example, N-methylol (meth)
Acrylamide, N-methoxymethyl (meth)acrylamide, N-ethoxymethyl (meth)acrylamide, N-n-butoxymethyl (meth)acrylamide,
N-terj, -butoxymethyl(meth)acrylamide, etc. can be used.

In the third method, amino groups can be easily introduced by copolymerization, but in the case of hydroxyl groups, they are introduced by copolymerization with hydroxyethyl methacrylate or vinyl acetate, followed by hydrolysis. These amino groups or hydroxyl groups are reacted with a polyfunctional compound such as epichlorohydrin in the presence of a basic substance to make them insolubilized.

The compound represented by formula (I) and/or the compound represented by formula (II) is preferably used in an amount of 50 mol% or more, particularly preferably 75 mol% or more, based on the total monomers to be polymerized.

Specific polymerization methods for obtaining a gel film that can be used in the present invention according to the above-described method include a method in which the monomer is directly poured into a template without being diluted with a solvent, and a method in which the monomer is polymerized using a solvent in which the monomer is dissolved. Method of polymerizing by pouring into a template,
Examples include a method of impregnating a monomer or a film-like substance insoluble in a solvent containing the monomer and polymerizing it, or a method of graft polymerization. At that time, the method of initiating polymerization is usually by heating alone.
Better results can be obtained by using a polymerization initiator. The polymerization initiator is not limited as long as it has the ability to initiate radical polymerization, and examples thereof include inorganic peroxides, organic peroxides, combinations of these peroxides and reducing agents, and azo compounds. be. Specifically, ammonium persulfate, potassium persulfate, hydrogen peroxide,! er1. -butyl peroxide, benzoyl peroxide, tet
Examples include j-butylperoxy-2-ethylhexanoate, butyl perbenzoate, etc. Reducing agents used in combination with these include sulfites, hydrogen sulfites, salts of iron, copper, cobalt, etc., and organic amines such as aniline. etc. can be given.

A,zo compounds include azobisisobutyronitrile,
2.2'-azobis-2-amidinopropane hydrochloride, 2
．． 2'-Azobis-2,4-dimethylvaleronitrile and the like can be used.

The amount of these polymerization initiators added is sufficient within the range adopted in normal radical polymerization, for example, 0.01 per monomer.
-5% by weight, preferably 0.05-2% by weight.

The gel film obtained in this way is washed with a solvent that dissolves unreacted substances and is compatible with water, and then the cap is sufficiently replaced with water to obtain a hydrogel film. The thickness of the hydrogel membrane used in the present invention is preferably O,0f-1
, 0 m, particularly preferably in the range of 0.05 to 0.5 m. The amount of water contained in 1 g of the hydrogel film at a temperature equal to or higher than the phase transition temperature is preferably 0.1 to 0.6 g.

Further, the drug used in the present invention may be any drug that can penetrate the skin, such as nitroglycerin, isosorbide nitrate, and nifedipine.

Examples include salbutamol.

When using the transdermal absorption preparation of the present invention, if the temperature is too high, it will cause skin burns, and if it is too low, it will cause frostbite. Therefore, the phase transition temperature of the hydrogel film is the temperature at which skin burns occur. The temperature must be below and above the temperature that causes frostbite on the skin. That is, the phase transition temperature of the hydrogel membrane used in the present invention is specifically in the range of 0°C to 50°C, preferably IO°C to 37°C.
°C, more preferably in the range of 20 °C to 32 °C.

The phase transition temperature of the hydrogel membrane used in the present invention is
It can be freely changed depending on the type of compound represented by formula (I) or formula (II), the type or composition ratio of monomers to be copolymerized, and the type or composition ratio of the crosslinking agent. for example,
The phase transition temperature of the hydrogel film of Example 1 shown below is 2
6°C, and the phase transition temperature of the hydrogel membrane of Example 2 is 23°C.

Furthermore, the drug permeability at a certain temperature below the phase transition temperature of the hydrogel membrane used in the present invention is determined by the formula (I
) or the compound represented by formula (If), the type or composition ratio of monomers to be copolymerized, and the type or composition ratio of the crosslinking agent. For example, in the hydrogel membrane of Example 1, the permeability coefficient of nitroglycerin at 22°C is 4. llx 108aa/+ec
In the hydrogel membrane of Example 2, the permeability coefficient of nitroglycerin was 3.5 at 22°C. lx io 8
There was am/secte. Furthermore, at temperatures above the phase transition temperature of these hydrogel membranes (32° C.), the amount of drug permeation was substantially zero.

The permeability coefficient of drugs to the skin varies depending on the animal species, age, site, etc., so if a drug is delivered to the blood circulation system through the skin from a membrane that is not controlled in a certain way, there will be individual differences in the blood concentration of the drug. will occur.

That is, the permeability coefficient of the drug to the membrane is P (membrane),
If the permeability coefficient to the skin of the animal species to which the drug is to be administered is P (skin), and the net permeability coefficient for release from the membrane through the skin is P (net), then the following relational expression holds true. When using this method, the blood concentration of the drug is affected by the permeability coefficient of the skin, which results in individual differences.

In order to reduce or eliminate the above-mentioned individual differences during the on-dermal administration period or the oll transdermal administration period using the transdermal absorption preparation of the present invention, it is necessary to add specific controls to the design so as to satisfy the following conditions. is preferred.

That is, in order to make a transdermal administration system with membrane rate control in order to reduce individual differences, it is desirable to set the condition of formula (2) to 50 to 1 (10%, preferably 70 to 90%).

The conditions of formula (2) include the type of compound represented by formula (I) or formula (II), the type or composition ratio of monomers to be copolymerized,
This can be achieved by appropriately selecting the type or composition ratio of the crosslinking agent.

In the present invention, drugs can be administered transdermally using a transdermal absorption preparation having a hydrogel membrane designed according to the above conditions.
When olj administration was attempted, it was found that a certain blood drug concentration was achieved during the on administration period, and the blood drug concentration disappeared during the o++ administration period, with little individual variation.

The transdermal absorption preparation of the present invention is a transdermal absorption preparation (for example, one in which a coating film, a drug storage layer, a temperature-responsive hydrogel film, and an adhesive layer are provided in this order) on the skin. It is used by adhering it by contacting it. ■-on administration of drugs due to temperature changes, for example, using a cooling device, etc.
This can be done by externally controlling the temperature for the required period of time.

[Effects of the Invention] The transdermal absorption preparation of the present invention and the method using the same enable transdermal administration of drugs in response to external temperature changes with little individual variation (o
N-off control becomes possible, and it can be used for automated formulations for drug administration periods and intelligent formulations that respond to external stimuli.

[Example] Next, the present invention will be explained in detail by way of examples.

Example I N-isopropylacrylamide 3. Og and butyl methacrylate 0.158 g and ethylene glycol dimethacrylate 0.021111 g and terj, -butyl-peroxy-2-ethylhexanoate 0.00
9 g was dissolved in 1.4-dioxane 3d, and after bubbling with N2 gas for 10 minutes, it was poured between glass plates sandwiching a spacer of θ, 05 to 0.5-゛, and reacted in an oven at 80 ° C. for 12 hours. A gel film was obtained. This was washed with methanol, water-methanol (1:1), and water for 2 days each to obtain a hydrocarbon copolymer with a composition of 5% by weight of butyl methacrylate, 1% by weight of ethylene glycol dimethacrylate, and 94% by weight of N-isopropylacrylamide. Got the gel. This hydrogel membrane was sandwiched between a two-chamber cell with a jacket, and a phosphate buffer solution was placed in each chamber, and then nitroglycerin was placed in one chamber and suspended. The other chamber was sampled over time and the concentration of nitroglycerin was measured by HPLC. Figure 1 shows the change in cumulative permeation amount of nitroglycerin over time when the temperature was changed stepwise between 32°C and 22°C. Japanese white rabbit (male, 14 weeks regression 2.4
The animal (~2.5 kg) was fixed in the dorsal position under bendoparbital anesthesia, and the abdomen was sectioned with clippers and then carefully shaved with a razor. A jacketed glass cell containing a nitroglycerin suspension was attached thereto via the hydrogel membrane. From the femoral artery where the catheter was inserted 1-3II!
Blood was collected over time, and plasma nitroglycerin concentration was measured by HPLC or ECD gas chromatography.

Figure 2 shows the plasma nitroglycerin concentration profile when the temperature was maintained at 22°C for 6 hours and at 32°C for 6 hours.

Example 2 30 g of N-isopropylacrylamide, 0.2433 g of butyl methacrylate, 0.0293 g of ethylene glycol dimethacrylate, 0.0 g of jerl,-butyl-peroxy-2-ethylhexanoate
Example 1
Polymerize in the same manner as above, form a film, and wash to obtain 7.5% by weight of butyl methacrylate and ethylene glycol dimethacrylate.
1% by weight, N-isopropylacrylamide 91,5
A copolymer hydrogel film having a composition of % by weight was obtained. This was evaluated in the same manner as in Example 1, and the results are shown in FIGS. 1 and 2.

Examples 3 to 4 N-acryloylpiperidine was used instead of N-isopropylacrylamide in Example 1 (Example 3)
A test was conducted in the same manner as in Example 1 except that H-acrylo, ylmorpholine (Example 4) was used, and the resulting gel film was temperature-responsive in all cases.
In either case, it was confirmed that on-off control of the drug was possible.

[Brief explanation of drawings]

FIG. 1 shows the change over time in the cumulative permeation amount of nitroglycerin, and FIG. 2 shows the change over time in the plasma nitroglycerin concentration.

Claims (3)

[Claims] (1) A transdermal absorption preparation characterized by using a temperature-responsive hydrogel membrane as a release control membrane. (2) The temperature-responsive hydrogel film is made of a compound represented by formula (I) and/or a compound represented by formula (II) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (I) (where R_1 is A hydrogen atom or a methyl group, R_2 and R_3 represent a hydrogen atom or a lower alkyl group, and R_2 and R_3 may be the same or different, but at least one of them represents a lower alkyl group.) ▲Formula , chemical formulas, tables, etc. ▼ (II) (In the formula, R_1 is a hydrogen atom or methyl group, A is ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ and n is 4 to 6 or ▲ Numerical formulas, chemical formulas, tables, etc. 2. The transdermal absorption preparation according to claim 1, which is a water-insoluble polymer obtained using as a main component a water-insoluble polymer. (3) Using the transdermal absorption preparation according to claim 1 or 2, the drug is administered on-off by changing temperature, and the on-administration period is a steady-state flow rate, and the off-administration period is a smaller steady-state flow rate or a substantially lower steady-state flow rate. A method of transdermal administration characterized in that the drug is delivered through the skin into the blood circulation system at zero flow rate.