JPH01149721A - Drug release controller - Google Patents

Abstract

PURPOSE:To obtain a drug-release controller which can freely control the release of the drug, and release it in the most suitable pattern according to its characteristics, by using a drug release-controlling layer which is formed by fixing a nonionic liquid crystal-forming compound to a hydrophobic high molecular weight film, and a heating material layer. CONSTITUTION:A liquid crystal compound such as polyoxyethylene glycerol monostearyl ether is adsorbed to, dispersed in or bound covalently to a hydrophobic high-molecular compound. The product is combined with a heating material such as a cloth coated with a paint containing carbon black. The combination of the drug release-controlling high-molecular compound with the heating material can change effectively the drug diffusion in the molecules, because the alkyl chains in the liquid crystals fluctuate, when they are heated over the gel-liquid crystal transition point of the liquid crystal molecules.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention relates to a device for controlling drug release that can freely control the release of drugs and thereby release drugs in a pattern according to the characteristics of each drug. It is something.

(Prior Art) Conventional drugs are administered in dosage forms such as oral preparations, external preparations, suppositories, injections, and inhalants, depending on the symptoms to be treated, pharmacological action, and pharmacodynamic properties.

However, oral preparations have limited availability due to stimulation of the gastrointestinal system and the so-called "early pass effect" in the liver.
There were problems such as a decrease in the biological drug utilization rate. When a drug is used as an external preparation, there are problems in that it is difficult to absorb the drug and it is also difficult to control the drug dosage. On the other hand, when drugs are used as suppositories, the amount absorbed varies depending on the amount of feces remaining in the rectum, and injections cause extreme pain to patients, making long-term use difficult.

In response to this, the development of DDS has been active in recent years, and the DDS that have been put into practical use include nitroglycerin and nitrite ester drugs for the treatment of angina pectoris, and scopolamine for motion sickness prevention. Transdermal absorption type external preparations such as

However, most of these are simply aimed at slow release of drugs, and are not close to the original DDS, which controls the amount of drug released according to the severity of symptoms.

Recently, it has been reported that in a membrane in which dialkyldimethylammonium bromide is supported on a polymer, the diffusion coefficient of the substance in the membrane changes in response to temperature changes. For example, the Journal on American Chemical Society (J.
American, Chem, Soc, ) 105,
N115.4855-4859 (1983) and Chemistry Letters
s, ) 645-648 (1979).

However, these films were not capable of responding to minute temperature changes, and it was difficult to say that the changes in the diffusion coefficient at that time were large. Furthermore, the objects whose diffusion can be controlled by temperature are limited to small ones such as sodium ions and chloride ions, and it has not yet been possible to control the diffusion of large molecules that have a pharmacological effect on -i. Furthermore, the dialkyldimethylammonium bromide supported on these polymer membranes has ionic properties and is not suitable for controlling the release of many ionic drug molecules.

(Problems to be Solved by the Invention) Therefore, the present invention is capable of sensitively responding to minute temperature changes, and is capable of sufficiently controlling the diffusion of drug molecules. By combining a temperature-sensitive drug release control polymer and a heating exothermic system that can control the release of ionic drugs and have no adverse effect on ionic drugs, each drug can be released through minute temperature changes in the heating exothermic system that is controlled in advance. An object of the present invention is to provide a drug administration system capable of controlling drug release in accordance with the physiological demand pattern of the human body.

(Means for solving the problems) The present invention fixes a liquid-forming compound to a specific polymer membrane,
This was done based on the knowledge that the above problems could be effectively solved by combining this with a heating member.

That is, the present invention provides a drug release control device characterized by having a drug release control membrane formed by fixing a nonionic liquid crystal-forming compound to a hydrophobic polymer membrane, and a heating member.

The polymer film for supporting liquid crystal-forming molecules of the present invention has a surface free energy or critical surface tension of 45.0 dyn/
Intrinsically hydrophobic polymers are used, such as those having a diameter of less than cm. In other words, when a hydrophilic polymer is used, the so-called -ater-Channe that exists in large numbers in the substance of the polymer
This is because drug molecules leak through the liquid crystal-forming compound, making it impossible to control the release of the microaggregated portion of the liquid crystal-forming compound.Specifically, as the polymer compound used in the present invention, polyhexafluoro Propylene, polytetrafluoroethylene, polytrifluoroethylene, polyvinylidene fluoride, polyvinyl fluoride, polyethylene, polytrifluorochloroethylene, polystyrene, polyurethane, polypropylene, polyvinyl chloride, polyvinylidene chloride, polyethylene terephthalate, nylon, polydimethylsiloxane , polycarbonate, cellulose acetate, polyethylene vinyl acetate, polyethylene vinyl alcohol, polymethyl (meth)acrylate, polyethyl (meth)acrylate, polybutyl (meth)acrylate, polyhexyl (meth)acrylate, polyoctyl (meth)acrylate, polylauryl (meth)acrylate, Examples include polystearyl (meth)acrylate, polybutadiene, polybutene, polyisoprene, natural rubber, etc. Among these, polymer compounds with a surface free energy or critical surface tension of less than 40 dyn/cm are preferred, and more preferred are polymer compounds with a surface free energy or critical surface tension of less than 40 dyn/cm. energy or critical surface tension] is less than 35 dyn/cm.

Among these, a polymer membrane having pores with a diameter of 3 μm or less and a porosity of 10 to 90% is preferred.

Here, the polymer membrane having a pore diameter of 3 μm or less means that it contains 30% or less of pores with a diameter exceeding 3 μm, and has an average diameter of 0.001 to 3 μm, more preferably It is preferable to use one with a diameter of 0.01 to 1 μm. The porosity can be easily measured by a method such as a mercury porosimeter, and it is preferable to use a porosity of 20 to 80%. In addition, the polymer membrane has a thickness of 1 to 3000 μm,
Preferably, one having a diameter of 10 to 500 μm is used.

As the liquid crystal-forming compound of the present invention, various liquid crystal-forming compounds having a gel-liquid crystal transition temperature in the range of 35 to 45°C are used. Among these, nonionic compounds, particularly nonionic compounds in which at least one terminal hydrogen of polyalkylene glycol is capped with a hydrocarbon, are preferred. Among these, those represented by the following general formula (1) or (II) are preferred.

R1-CH-0-+CH2CH2O-)-r-R.

Rz C-(CHz), 0-(CHzCtl□0-
h-R5・・・R3-Cl+-04CI2CH! O
→τ R6R? -0(CH2Cl, 0÷-rl?s
・ ・ ・ ・ (II) (wherein, R+, Rz and R3
is hydrogen or an alkyl group having 1 to 6 carbon atoms, R4, R5 and R6 are hydrogen, an alkyl group having 6 to 30 carbon atoms, or -C
OR9, -COR,. , COR++ (R? to R11 are each hydrogen or an alkyl group having 6 to 30 carbon atoms). However, at least one of R4-R6 has 6 or more carbon atoms. a, b, c are O~
20, n is O or 1. R1 is hydrogen, carbon number 1-3
0 alkyl group or a group represented by -0 OR+ t (
RI2 is hydrogen or an alkyl group having 1 to 30 carbon atoms), Ra
is hydrogen, an alkyl group having 1 to 30 carbon atoms, or -0 OR+
A group represented by s (RI 2 is hydrogen or has 1 to 3 carbon atoms)
0 alkyl group), but at least one terminal of the compound of formula (II) is an alkyl ether or alkyl ester having 6 or more carbon atoms. Or d is 1-20. ) In the above formula, R1-R3 are preferably hydrogen or an alkyl group having 2 to 3 carbon atoms, and the alkyl groups in R4-R6 and R1-R11 are preferably those having 12 to 18 carbon atoms. The sum of a, b, and c is 0 to 60, preferably 1 to 4.
0, more preferably 3-20. Also, R? , Rs.
, RI2, RI3 have 12 to 12 carbon atoms.
18 is preferable, and d is preferably 3 to 12.

Among these, liquid crystal forming compounds in which one or more of R4, R5, and R6 is an alkyl group having 6 to 24 carbon atoms in the compound represented by the structural formula (1) include polyoxyethylene glyceryl monoster, polyoxyethylene glyceryl distearyl ether, polyoxyethylene glyceryl tristearyl ether,
Examples include polyoxyethylene glyceryl monomyristyl ether, polyoxyethylene glyceryl dimyristyl ether, and polyoxyethylene glyceryl trimyristyl ether.

In addition, examples of liquid crystal-forming compounds in which one or more of R4, R3, and R6 are -COR (R is an alkyl group having 6 to 24 carbon atoms) include polyoxyethylene glyceryl monostearate, polyoxyethylene glyceryl Examples include distearate, polyoxyethylene glyceryl tristearate, polyoxyethylene trimethylolpropane monostearate, polyoxyethylene trimethylolpropane distearate, and polyoxyethylene trimethylolpropane tristearate.

Among the compounds represented by structural formula (II), R1, R6
Examples of compounds in which one of these is hydrogen include polyoxyethylene 2-hexyldecyl ether, polyoxyethylene 2-hebutyl undecyl ether, and polyoxyethylene 2-decyl pentadecyl ether.

Also, R? , Re are both not hydrogen,
Examples include polyethylene glycol distearate, polyoxyethylene lauryl ether stearate, polyoxyethylene cetyl ether stearate, and polyoxyethylene stearyl ether stearate.

Among these, liquid crystal forming molecules having a gel-liquid crystal transition temperature in the range of 35 to 43°C are preferred, and more preferably 35°C to 43°C.
It is a liquid crystal-forming molecule having a gel-liquid crystal transition temperature in the range of 7 to 42°C. That is, since the diffusion controllability of liquid crystal-forming molecules is expressed near the gel-liquid crystal transition temperature, it is advantageous for this gel-liquid crystal transition temperature to exist at a temperature higher than body temperature.

Various methods can be used to immobilize the liquid crystal-forming compound on the hydrophobic polymer compound. Specifically, immobilization methods include adsorption, dispersion, or covalent bonding. (i) Among these methods, in the adsorption method, the liquid crystal-forming compound is dissolved in an organic solvent that does not dissolve the supported polymer but dissolves the liquid crystal-forming compound, the supported polymer is immersed in this solution, and then This is taken out and dried to effect immobilization. (ii) In the dispersion method, the liquid crystal-forming compound is mechanically kneaded into the supported polymer, or liquid crystal formation is performed with the supported polymer using an organic solvent that can dissolve both the supported polymer and the liquid crystal-forming compound. dissolves chemical compounds,
Immobilization is performed by thoroughly stirring and then drying. (iii) In the covalent bonding method, the hydroxyl group present in the liquid crystal-forming compound and the functional group (hydroxyl group, amino group, or carboxyl group) in the supporting polymer are bonded with a difunctional reagent such as a diisocyanate, diglycidyl compound, Immobilization is performed by binding using dicarboxylic acid dichloride, epichlorohydrin, etc.

In the present invention, there is no particular limitation on the immobilization rate of the liquid crystal-forming compound to the supporting polymer, but based on the required degree of temperature sensitivity and the required strength of the polymer,
~5/95 (weight ratio), preferably 90/10 ~ 10/
90, more preferably 70/30 to 30/70.

The heating member used in the present invention may be any member as long as it can be heated by energization, for example, a known heating member using a nichrome wire or the like. Of these,
It is preferable to use a cloth coated with a carbon black-containing paint (trade name: Sunfeel (manufactured by Marubishi Electric Co., Ltd.) because it can be heated with less power consumption.

The drug control device of the present invention can be used in any form using the above members, and can be used as an external medicine. For example, an impermeable base layer for preventing evaporation of the organic solvent and water in which the physiologically active substance is dissolved is provided on top of the physiologically active substance holding layer, and a heating system is provided on top of the impermeable base material layer. Further, the drug release controlling polymer membrane of the present invention is provided below the physiologically active substance holding layer. or,
All over or around the bottom surface of the polymer membrane for controlling drug release.
A pressure-sensitive adhesive layer is applied to tightly fix the external medicine on the skin. In this way, the polymer membrane for drug release control of the present invention provided under the physiologically active substance-retaining layer responds to the heating pattern of the heating system set in advance.
Since drug release is sensitively controlled, the amount of drug permeation into the skin can be controlled.

Specifically, it is preferable to use the mode shown in FIG. 1st
The figure shows a longitudinal cross-sectional view of a device for drug control.
A drug storage tank 3 on which a heating sheet serving as a heating member 2 is placed is placed inside a backing base material 1 (backing film) made of a plastic sheet such as AL or silicone rubber. Here, the drug storage tank 3 is a bag-like substance in which a drug 6 is sealed between a film 4 made of vinyl chloride, polyethylene, polypropylene, EVA, EVAL, or silicone rubber, and a drug release control membrane 5, and the drug is released. The control membrane 5 is placed so as to face the skin of the human body.Also, the backing substrate 1 is coated with a pressure-sensitive adhesive 7 to facilitate attachment to the skin. 1 and 4
The thickness is 5 to 500 μm, preferably 20 to 200 μm.
As the drug 6, the medicinal ingredients described below are used, for example, in the form of a gel (the gel base material is 40% Equinol,
Propylene glycol 21%, Power-Bopol 9401%
, triethanolamine 0.1%, EDTAO
,0002% and water balance) or liquid (composition consisting of
For example, 40% ethanol, EDT A O,000
2% and water balance) is placed in the drug reservoir 3.

The heating member may have any thickness, but the thickness is preferably 10 to 1000 μm, preferably 20 to 50 μm.
Preferably, 0 μm is used, and as shown in FIG. 1, a connection line to an external power source is provided. Here, if a temperature control member is combined with the heating member 2, the release of the drug can be effectively controlled.

As described above, when the polymer for controlling drug release of the present invention is combined with a heating member, the liquid crystal forming molecules are The alkyl chain of the polymer fluctuates and the drug diffusivity in the polymer changes, thereby controlling drug release. That is, by controlling the heating and cooling of the heating member, the release properties of the drug can be arbitrarily controlled.

There are no particular limitations on the drug used when the present invention is applied to a drug administration system, but when the present invention is applied to a patch for angina pectoris, which is known to have side effects and decreased efficacy due to continuous transdermal administration, it is possible to control By heating, controlled release of angina drugs can be achieved. From this point of view, drugs such as nitroglycerin and isosorbide nitrate are particularly effective.

Furthermore, clonidine patches, which are antihypertensive agents,
Since it takes three days for the blood concentration to reach the effective concentration, it is desired to improve the initial transdermal absorption, and by applying the drug administration system of the present invention,
It is also possible to improve the release properties by heating at the initial stage, thereby increasing transdermal absorption.

The drug component in the drug administration system of the present invention is 0.1 to
80% by weight (hereinafter abbreviated as %), preferably 0.2~
50%, and optional components from 0 to 90%, preferably 0.1
It is used so that it becomes ~80%.

The above-mentioned optional components include polymers with various degrees of polymerization, such as polydimethylsiloxane, polyethylene glycol,
polypropylene glycol, poly(meth)acrylic acid salt), polyvinyl alcohol, polyvinylpyrrolidone,
Carboxymethyl cellulose, alginic acid (salt), carrageenan, etc., available on JR? 8 media 1. ．． Methyl alcohol alcohol, n-butyl alcohol, iSO-butyl alcohol, SeC-butyl alcohol, t-butyl alcohol, methyl ethyl ketone, acetone, ethylene glycol, propylene glycol, glycerol, ethyl acetate, 2-pyrrolidone, 1-methyl-2- pyrrolidone, 5-
Methyl-2-pyrrolidone, 1,5-dimethyl-2-pyrrolidone, 1-ethyl-2-pyrrolidone, 2-pyrrolidone-5-carboxylic acid, etc., as a transdermal absorption enhancer, to dimethyl sulfoxide, 1-dodecyl azacyclo Butane-2-
On (trade name Azone @), dimethyl laurylamide, isosorbitol, dimethylformamide, dodecylpyrrolidone, methionyl sulfoxide, methionyl sulfone, calcium thioglycolate, hydroxyoctyl sulfoxide, cyclohexylmethanol,
Lysine, arginine, ornithine, histidine, urea,
Salicylic acid and its derivatives, benzyl nicotinate, methoxypolyethylene glycol acrylate, (poly)ethylene glycol glycidyl ether, fatty acid diglyceride having 8 or more carbon atoms, adipate ester, sebacate ester, 1.3-butanediol, 1.4-butane Diol, fatty acid ethanolamide, etc., and one or two types selected from sodium lauryl sulfate, polyoxyethylene lauryl ether, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, etc. can be used as the surfactant.

The mechanism by which the polymer for controlling drug release of the present invention changes the drug release rate sensitively to temperature is considered to be as follows. In other words, when a liquid crystal-forming compound is exposed to water or a solution composition containing water, polar water molecules cannot form hydrogen bonds with hydrophobic alkyl chain moieties in the liquid crystal-forming compound, resulting in hydrophobic The water surrounding the alkyl chains strengthens hydrogen bonds with each other, forming so-called "ice-like" water clusters. And due to the formation of this cluster,
The entropy of water around the hydrophobic alkyl chain decreases,
It becomes unstable in terms of free energy.

Therefore, when such hydrophobic alkyl chains come into contact with each other, some of the structural water on the surface becomes free water and the free energy of the system is stabilized. are arranged in close contact with each other, forming a gel structure. By the way, this gel structure has a certain temperature (gel-liquid crystal transition temperature) as the temperature increases.
When this temperature is reached, a phase transition occurs, causing fluctuations in the hydrophobic alkyl chains, resulting in a transition to a so-called liquid crystal state. By the appearance and disappearance of fluctuations in the hydrophobic alkyl chains of the liquid crystal-forming compound around this gel-liquid crystal transition temperature, the polymer for controlling drug release of the present invention controls the permeation and diffusion of drug molecules. It can be controlled accordingly. At this time, if the polymer supporting the liquid crystal forming molecules is hydrophilic,
There are many ``Water'' filled with free water inside.
-Chann 1'' exists, and other drug molecules leak out while the minute aggregates of liquid crystal-forming molecules scattered inside the polymer control the diffusion. The molecule is filled with free water “-a t
er-Channel'' is almost non-existent, so of the two main diffusion mechanisms, the pore diffusion mechanism is not used, and only the other distribution diffusion mechanism is mainly used.The diffusion coefficient of this distribution diffusion mechanism is is very small and its contribution to the overall diffusion is small. Therefore, if a liquid crystal forming compound is present in this hydrophobic polymer, this liquid crystal forming compound mainly exhibits rate-determining properties, and therefore the temperature range response is Furthermore, this liquid crystal-forming compound needs to be non-dissociable in order to avoid interaction with the drug molecules whose release is to be controlled. It is necessary that the gel-liquid crystal transition temperature is higher than body temperature.

(Effects of the Invention) According to the present invention, it is possible to clearly control the release of drugs according to minute temperature changes in the system according to the initially set heating pattern, and the physiological requirements of the human body for each drug can be controlled. Enables patterned drug administration. For example, it becomes possible to improve the temporary wash-out of angina drugs and the initial absorption of antihypertensive drugs.

Furthermore, it takes three days for the blood concentration of clonidine, an antihypertensive drug, to reach its effective range.
(8merican Hart Journal +
217222, July, 1984), the initial drug absorption can be improved by applying the administration system of the present invention to a clonidine patch.

Next, the content of the present invention will be specifically explained with reference to Examples.
The present invention is not limited to these examples.

〔Example〕

Example 1 Polypropylene membrane (polyplastic, Duraguard 2
40; Pore diameter 0.02 μm, porosity 38%, critical surface tension 35 dyn/cm) Between the two sheets, melted polyoxyethylene (3 mol) trimethylolpropane tristearate (Japan Emulsion, TPS-303i)
After immobilizing the liquid crystal-forming compound by directly infiltrating the polypropylene membrane by sandwiching a gel-liquid crystal transition temperature of 39.2℃, the entire membrane was pressed (25 tons).
/cn! , for 10 minutes) to prepare a temperature-sensitive polymer membrane for controlling drug release. The immobilization rate of the liquid crystal forming compound in the obtained polymer film was 38.1% by weight.

Next, this temperature-sensitive polymer membrane for controlling drug release was attached to a glass vertical type diffusion cell 10, and 5 ml of a 2.5% isosorbide nitrate solution 13 (base solution was water/ethyl alcohol 60/ 40%w/w
), and the above base material solution 16 is placed on the lower receptor side.
I put 13ml of. Further, the upper drug solution was covered with a heat-generating sheet 12 for heating.

A schematic cross-sectional view of the device used here is shown in FIG. 2, in which a heat generating sheet 12 is installed above a cylindrical member 11, an isosorbide nitrate solution 13 is placed below it, and a polymer membrane for drug release control is placed below it. A stirrer 17 was provided on the reservoir side to stir the base solution, and the base solution was extracted from the outlet 18 at regular intervals to quantify the amount of isosorbide nitrate. In addition, in FIG. 2, another film 15 is shown.
However, in Example 1, the experiment was conducted without providing the acid film 15.

Here, the heating sheet 12 has an element size of 6 cA, an element resistance of 105 Ω, and a rated voltage of 3. Using an OV (manufactured by Marubishi Electric Co., Ltd., Sunfeel@), heating and cooling were intermittently repeated every 2 hours using two 1.5-inch dry batteries as a power source.

FIG. 3 shows the cumulative amount of drug permeation on the receptor side of the diffusion cell at that time. As you can see from Figure 3,
The drug release pattern can be freely controlled through temperature control of the heating exothermic system.

Example 2 The abdominal skin of WBN/Kob hairless rats (Saitama experimental animals) was treated under anesthesia (bentoparbital sodium 60mg).
/ kg, T, P,) was removed, the sample membrane of Example 1 was pasted on the sono-stratum corneum side, and the sample membrane of Example 1 was attached to the glass vertical type diffusion cell shown in Fig. 2 (however, the skin was
5 ml of 2.5% isosorbide nitrate solution (base solution is water/ethyl alcohol 60/40% w/w) was added to the cell above the cell, and the same exothermic temperature as used in Example-1 was added. Cover with a sheet and wash every 6 hours.
Heating to ℃ and cooling were intermittently repeated. FIG. 4 shows the cumulative amount of drug permeated through the skin on the receptor side of the diffusion cell at that time.

As can be seen from FIG. 4, the skin permeation pattern of the drug can be freely controlled in response to temperature control of the heating system.

Example 3 A bag for a drug-retaining layer was prepared by heat-sealing the same drug release control membrane as in Example 1 and a polyethylene membrane as an impermeable substrate (4CrA), in which 40% ethyl alcohol, Water 58.4%, polycarboxylic acid (Carbopol 9400, manufactured by Gutdrich Chemical Co.) 1.5
To 100 parts by weight of an ointment base containing 0.1% triethanolamine, 3 g of an ointment containing approximately 2.4% isosorbide nitrate was added to form a drug-retaining layer.

After removing the membrane part of a rabbit weighing 2.0 to 2.5 kg with an electric clipper, carefully remove the hair with an electric razor to avoid further damage to the skin, and then apply the drug-retaining layer and the drug-release controlling membrane to the skin. Applied to the side. Furthermore, it was covered with a heat-generating sheet for heating similar to that in Example 1, and fixed with adhesive tape from above as shown in FIG.

Heating was carried out from 0 hours to 10 hours, and from 20 hours to 30 hours, and the temperature was kept at 38°C or higher. Blood samples were collected from the ear veins of the rabbits at regular intervals, and blood drug concentrations were determined by liquid chromatography. I tracked it down. The results are shown in Table-1. As can be seen from Table 1, the concentration of isosorbide nitrate in the blood was high after 10 hours of heating (10th and 30th hours), and decreased after being left to cool (20th and 40th hours). This shows that the blood drug concentration can be controlled in response to the system.

Table 1

[Brief explanation of the drawing]

FIGS. 1 and 2 are schematic cross-sectional views of the device for controlling drug release of the present invention, and FIGS. 3 and 4 are views showing that the device of the present invention controls drug release. In the figure, 5.14 is a membrane for drug release control, 2.12 is a heating member, and 6 and 13 are drugs. 63.2.29 Showa year, month, day 2, title of the invention Device for drug release control 3 , Relationship to the case of the person making the amendment Name of applicant (676) Lion Co., Ltd. 4, Agent 5, Date of amendment order February 23, 1988 11i
U5hi ni-2\,ノ

Claims (1)

[Claims] A drug release control device comprising a drug release control membrane formed by fixing a nonionic liquid crystal-forming compound to a hydrophobic polymer membrane, and a heating member.