JPS6258333B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to a drug administration member capable of transdermally administering a benzodiazepine drug as a central nervous system agent in a fixed amount and continuously through the outer skin. Benzodiazepines have traditionally been widely used as minor tranquilizers for purposes such as mental stabilization, hypnotic sedation, and anti-temperature seizures, but because these compounds are rapidly metabolized in the body, their pharmacological effects are limited to humans. It decreases within a short time after administration. Therefore, patients who require long-term pharmacological effects, such as depression,
For patients suffering from neurosis, etc., it must be continuously administered into the human body, resulting in an overdose (overdose) and a strong hypnotic effect that interferes with normal daily activities. Side effects include fatigue, weakness, light-headedness, dizziness, headache, nausea, vomiting, dry mouth, loss of appetite, ataxia, and difficulty speaking. In order to prevent such harm, it is necessary to maintain the blood concentration of benzodiazepine drugs at a predetermined level that allows them to exert their medicinal effects and not cause the aforementioned side effects. It is necessary to administer and absorb the drug quantitatively and continuously.
For this reason, methods have been considered in the past, such as applying multiple special coatings with different dissolution rates to oral tablets containing benzodiazepine drugs, but these methods have not been sufficiently effective. In view of the above, the present invention aims to directly apply a benzodiazepine drug having central action to the human skin surface and absorb it transdermally without using oral administration or a syringe, thereby causing side effects. The aim is to maintain pharmacological effects over a long period of time without causing any adverse effects. By the way, the above-mentioned benzodiazepine drugs have poor transdermal absorbability, and cannot be absorbed into the human body in the required amount when used alone. Therefore, an appropriate means for promoting absorption is required, but no means for promoting absorption that is necessarily effective for benzazepine drugs is known. The present inventors have continued to conduct intensive studies to explore such means for promoting absorption. As a result, the present inventors have used salicylic acid and a certain non-vaporizable substance in combination, and combined these with a benzodiazepine drug in a film with micropores (or The inventors discovered that by filling the pores of a sheet), it has an absorption promoting effect on benzodiazepine drugs and is useful as a device that exerts pharmacological effects over a long period of time, leading to the completion of the present invention. It is. That is, the present invention combines a benzodiazepine drug and salicylic acid with a solubility index value (SP value) of 10 or more in the pores of a film (or sheet) having countless micropores.
and a non-vaporizable substance having a viscosity of 700 centipoise or less at 30° C. is provided. According to repeated experiments conducted by the present inventors, the above-identified non-vaporizable substance can supply benzodiazepine drugs and salicylic acid to the human skin surface without substantially inhibiting their ability to diffuse and transfer. On the other hand, salicylic acid supplied to the skin softens (swells) the stratum corneum to a state where benzodiazepine drugs can be absorbed most transdermally, thereby allowing benzodiazepine drugs to be absorbed quantitatively and continuously through the skin. found. The film (or sheet) having micropores used in carrying out the present invention has physical or chemical through holes, and preferably has a pore diameter of 10μ or less, practically 0.01 to 5μ. If so, the material forming the film is not particularly limited, but it is more preferably a porous film with a porosity of at least 30% (volume ratio), more practically 70% or more. As the material for the film, ethylene-polyvinyl alcohol copolymer, cellulose acetate, polyamide, polyvinyl chloride, polyolefin, polyacrylonitrile, polysulfon, polyvinyl alcohol, polyimide, fluororesin, etc. are used. As a method for making the above film (or sheet) using these materials, for example, a copolymer containing polyacrylonitrile is dissolved in a solvent to make a concentrated solution, this is casted on a supporting substrate, and then a non-solvent Remove the solvent by immersing it in
It is obtained by subjecting the obtained film to heat treatment and drying it at a temperature below the heat treatment temperature. In addition, SP used in carrying out the present invention
Non-volatile substances with a value of 10 or more and a viscosity of 700 centipoise or less at 30°C include polyhydric alcohols and their derivatives such as propylene glycol, ethylene glycol, polyethylene glycol, polypropylene glycol, glycerin, etc., higher fatty acids and Derivatives thereof such as stearic acid, myristic acid, palmitic acid, oleic acid, linoleic acid, sebacic acid, etc. Substantially non-volatile solvents such as sulfoxides such as dimethyl fluoride, dimethyl formamide, or dimethyl acetanidine These liquid materials can be used in combination of two or more kinds, if necessary. If the SP value of the above substance is 10 or less, the compatibility with the benzodiazepine drug is too good and the drug is not taken in and delivered to the skin surface, which is not preferable. In addition, if the viscosity is 700 centipoise or more, benzodiazepine drugs and salicylic acid cannot be retained well in the pores, and even if they are retained, the diffusion rate of the drug is too slow and it is not possible to supply the drug well to the skin surface, which is preferable. It's something that doesn't exist. The benzodiazepine drugs of the present invention include diazepam, nitrazepam, medazepam, chlordiazepoxide, estazolam, nimetazepam,
Lorazepam, flurazepam, clotiazepam, bromazepam, oxazepam, cloxazolam, oxazolam and the like can be mentioned. The proportions of each of the three components in the compound filled into the pores are preferably in the following ranges. 1. Benzodiazepane drug: 0.1 to 20% by weight, preferably 0.5 to 10% by weight. 2 Salicylic acid: 0.05-50% by weight, preferably
It is 0.1-10% by weight. 3 Non-vaporizable substance: 30-99.85% by weight preferably
40-98% by weight. A barrier film (or sheet) that is impermeable to the drug, salicylic acid, and non-vaporizable substances is bonded to one surface of the drug administration member constructed in this manner. The film effectively prevents the drug in the pores from being rubbed off by clothing or the like from the side opposite the application side. Further, it is preferable to provide an adhesive piece larger than the administration member via this film, so that it can be easily attached to the skin surface. The drug administration member and its applied products configured in this manner can be adhered to the skin surface or fixed using other means, so that the benzodiazepine drug can be synergized with salicylic acid and a non-vaporizable substance. The action allows the drug to be administered quantitatively and continuously through the skin. Examples of the present invention will be shown below. Example: 1% by weight of salicylic acid and 5% by weight of diazepam are added to glycerin and mixed thoroughly. On the other hand, a porous film made of hydroxyethylene vinyl acetate with a thickness of 200 μm and a pore diameter of about 1 μm is prepared. The above formulation was added per cm ² into the pores of the film.
0.012 ml is adsorbed to obtain the drug administration member of the present invention. Cut this into a size of 10mm x 10mm, and 20mm x 20mm.
Paste in the center of a piece of surgical tape measuring mm. This was applied to the hair removal site on the abdomen of a ddN male mouse weighing approximately 25 g, and the pharmacological effect was assayed at predetermined intervals by the rotor rod method. The results are shown in Table 1.

[Table] The rotor rod method test method and certification evaluation are as follows. [If the mouse is placed on a rotor rod with a diameter of 30 mm and a rotation speed of 10 to 12 revolutions per minute, it will be scored 10 points if it falls within 10 seconds, and 7 points if it falls within 30 seconds.
If the animal falls within 60 seconds, it will be evaluated as 5 points, if it falls within 3 minutes, it will be evaluated as 3 points, and if it does not fall after 3 minutes, it will be evaluated as 0 points, and the average evaluation score for one group (5 animals) will be calculated. In addition, the comparative examples in Table 1 are the examples in which salicylic acid was not added, and the reference examples are the results of a similar test conducted on mice to which a predetermined amount of diazepam was orally administered.

Claims (1)

[Claims] 1. A combination of a benzodiazepine drug, salicylic acid, and a non-vaporizable substance having a solubility index value of 10 or more and a viscosity of 700 centipoise or less at 30°C in the pores of a film (or sheet) having countless micropores. A drug administration member characterized in that it is filled with.