JP2818771B2 - Interface for iontophoresis - Google Patents

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a method for surface treatment of an interface for iontophoresis for allowing a drug to electrically penetrate the skin. In particular, it is expected to be used in the medical field where it is required to effectively absorb a small amount of an ionic bioactive peptide drug having high activity into the skin.

[0002]

2. Description of the Related Art Conventionally, as a method of administering a physiologically active peptide or a physiologically active protein, a method of orally dissolving a drug, which is caused by digestion by digestive enzymes in the gastrointestinal tract, digestive enzymes by the intestinal wall, degradation by intestinal bacteria, adsorption by meals, and the like. Due to poor absorption efficiency, injection methods are generally used. Injection administration is painful for patients, and self-administration cannot be excluded except in some cases. Therefore, it is necessary to rely on specialists, and it has been desired to develop a medication instead of injection. Research on a new DDS (drug delivery system) is currently being actively pursued, and studies on oral, rectal, nasal, and transdermal formulations in combination with absorption enhancers are being made vigorously. Although there are still things that are satisfactory. In particular, for the administration of hormone-like peptides that require time-controlled or intermittent administration, new technologies are being developed. These bioactive peptides are poorly absorbable, difficult to absorb an effective drug amount, and are amphipathic molecules, so when present in an aqueous solution, they are adsorbed to various storage containers and consequently from equipment. Recovery was poor, and there was a great inconvenience over the trace amount formulation. For this reason, the container has been conventionally treated with silicon, or a protein having a relatively low adsorptive activity coexists with these physiologically active peptides, or the adsorption to the storage container has been achieved by mixing a surfactant, a carbohydrate, an amino acid, or the like. Has been prevented. (JP-A-61-221125, JP-A-63-57527) Iontophoresis, which can control the permeation of a drug, is a percutaneous absorption promotion system using electric force. A technique known from the early 1900, in which a positively charged molecule penetrates into the skin layer from the anode side and a negatively charged molecule penetrates into the skin layer from the cathode side (J. Controlled). Release 18,213-220, 1992), the era of these bioactive peptide administration systems has been re-evaluated. It has been reported that iontophoresis improves the transdermal absorbability of polypeptide-based drugs, and many studies have been made for practical use. In iontophoresis, it is known that a peptide having a smaller molecular size permeates the skin more easily, and that a formulation devised to suppress the association of molecules increases the skin permeation efficiency. In the interface for iontophoresis as a drug carrier, an aqueous member layer for holding an ionic chemical liquid impregnation made of a sponge or a porous material such as a paper material, a cloth material, a fibrous synthetic resin continuous foam or a water-absorbing resin is used. And an interface made of a ceramic or other non-conductive material having a porous body or a porous or capillary structure. However, in these iontophoresis interfaces, bioactive peptides are applied, adhered, coated or impregnated, or dried to form a solid or sub-dry state. As for the absorbed amount, sufficient drug use efficiency has not been obtained. The main cause is apparent from the fact that these bioactive peptides are not available because they are adsorbed on drug carriers. As a method to solve this problem, we have already coated a non-conductive material with a porous or capillary structure with a high molecular weight protein to prevent adsorption of the drug to the porous material, and a small amount of highly effective A method has been reported in which transdermal absorbability can be ensured and safety is excellent (JP-A-6-16535). This method is very effective, but if the coating agent used is an expensive protein, for example, BSA (bovine serum albumin), there is a problem in stability, and long-term storage is complicated. The development of an excellent method was required. As described above, a method for coexisting, for example, benzalkonium chloride or benzethonium chloride with a concentration of 0.1-2.0% in a solution containing a drug as described above in order to prevent adsorption of a physiologically active peptide to a device is reported. However, in transdermal drug delivery systems using iontophoresis, the target drug ions and coexisting ions compete electrically, resulting in a decrease in the transport number in drug permeation, and from the viewpoint of improving utilization efficiency. There's a problem.

[0003]

The conventional iontophoresis technique has disadvantages such as inaccurate dosage due to adsorption of a physiologically active peptide-based drug to the skin or a porous device, which is problematic in practical use. was there. In view of this situation, an object of the present invention is to provide an inexpensive, stable, and practical interface coating technology for iontophoresis that enhances the use efficiency of a physiologically active peptide-based drug with good reproducibility.

[0004]

Means for Solving the Problems The inventors of the present invention have made intensive efforts to solve the above-mentioned problems, and have made the surface of an interface device for iontophoresis comprising a porous or capillary structure of a non-conductive material an ion disinfecting material. It was found that transdermal absorption of a drug with a surfactant coating significantly increased the transdermal absorbability of the drug without irritation to the skin and increased the drug use efficiency. The invention has been completed. That is, the present invention provides (1) an interface for iontophoresis in which a coating layer of an ionic surfactant is formed on a drug holding member, and (2) the drug holding member according to the above (1) is in contact with a drug or a drug solution. (3) The drug holding member according to the above (1) has a porous or capillary structure of a non-conductive material, and (4) the ionic surfactant according to the above (1) is: (5) The ionic surfactant described in (1) above is a pharmaceutical additive such as benzalkonium chloride and benzethonium chloride, and (6) the ionic surfactant described in (1) above. The ionic surfactant described in (1) is a pharmaceutical additive such as benzalkonium chloride and benzethonium chloride. In practical use, the ionic surfactant does not elute in the drug solution or is zero even if it is eluted. . Ranges at a concentration of 1% or less, to a (7) above (1) bioactive peptides drug is increased drug utilization according.

[0005] The drug used in the present invention is not particularly limited as long as it is a pharmaceutically effective bioactive peptide.
The following drugs are exemplified. That is, calcitonin,
Adrenocorticotropic hormone, parathyroid hormone, insulin, secretin, oxytocin, angiotensin, β
-Endorphin, glucagon, vasopressin, somatostatin, gastrin, luteinizing hormone-releasing hormone, enkephalin, neurotensin, atrial natriuretic peptide, growth hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone, prolactin, interferon, interleukin, G
-CSF, glutathione peroxidase, superocoside dismutase, desmopressin, somatomedin, melanophore-stimulating hormone, muramyl dipeptide, bombesin, vasoactive intestinal peptide, cholecystokinin-
8. calcitonin gene-related peptide, endothelin,
Thyrotropin-releasing hormone, and derivatives of these bioactive peptides. The amount of the physiologically active peptide to be added to the liquid composition of the present invention may be an amount sufficient to exhibit a desired medicinal effect, which varies depending on the type of the drug, the weight of the patient, and the symptoms. May be selected as appropriate according to the conditions.

[0006]

According to the present invention, effectiveness and safety can be ensured in transdermal absorption of physiologically active peptides by iontophoresis, and high absorption which cannot be achieved by conventional iontophoresis can be obtained. be able to. Next, the present invention will be described more specifically with reference to examples, but the present invention is not limited thereto.

Next, the specification of the interface for iontophoresis of the present invention will be described. The present invention is not particularly limited by this. In FIG. 1, two polyethylene cups (9) and (9 ') are arranged on a flexible and rigid support (10), and distilled water for injection (Fuso) is provided in the cup (9'). A drug solution (7) made of Yakuhin Kogyo Co., Ltd.) is stored to form a reservoir (12). In (9), a conductive gel (3) made of, for example, a PVA hydrogel containing NaCl is incorporated. ing. Cup (9) at the lower part of the support (10)
A hole (14) is formed in the lower part of the support (10) so as to penetrate the front and back sides when used with the support (10). Further, the ion exchange membrane (4) (for example, an AS membrane (Asahi Kasei Corporation) )), A nonwoven fabric (5) (for example, Bemberg (manufactured by Nippon Vilene)), and a porous nylon body (6) (for example, Biodyne Plus (manufactured by Nippon Pall)) are arranged in a laminated manner, and an applicator (13) is formed. Non-woven fabric (5)
Extends further to the lower part of the support (10) and below the cup (9 '),
In the lower part of the cup (9 ') of (0), where the non-woven fabric (5) is located, a hole (15) is formed so as to penetrate the front and back when used. Ion exchange membrane (4),
These non-woven fabric (5) and the porous nylon body (6) have these drug holding members (holding in this case includes at least contact, and may be a drug contact member).
Is uniformly coated or impregnated in a 0.01% aqueous solution of benzalkonium chloride, or treated by immersing them in the same aqueous solution, drained, and dried. Of the AS membrane, nonwoven fabric and nylon porous material thus obtained, a physiologically active peptide is further attached to the skin contact surface side of the nylon porous material by means of spray coating, impregnation, etc., and kept dry. Have been. The drug (11) is fixed to a portion of the porous nylon body (6) that comes into contact with the living skin. On the periphery of the nylon porous body (6) and the lower part of the support (10), for example, blender (3M)
An adhesive tape (8) made of, for example, the same is disposed.

[0008]

[Example] (Percutaneous absorption test using rats) Method: Under anesthesia with pentobarbital, a male 7-week-old abdominal skin of an SD rat was shaved with a hair clipper, treated with a shaver, and gently rubbed with absorbent cotton containing a 70% ethanol aqueous solution. Degreasing and disinfection. The interface or device shown in FIG. 1 was replaced with calcitonin (synthetic salmon calcitonin, SIGM).
(Company A) is fixed so that the skin contact surface where 2 IU of each drug film is dry-held is adhered to the rat abdominal skin. The applicator (13) supplies water from the reservoir (12) immediately before use to redissolve the dry drug (11). Specifically, the supply of water from the reservoir (12) passes through the nonwoven fabric (5) having a capillary structure through the opening (15) shown in FIG. 1 and reaches the nylon porous body (6). Energization was performed at DC6V, 30 kHz, 30% duty for 45 minutes. After a predetermined time, blood is collected from the jugular vein.
2000r. p. m. After centrifugation for 5 minutes, the supernatant was used as a sample serum. The serum calcium was determined by the ortho-cresol phthalein complexone method (Calcium C-Test Wako, manufactured by Wako Pure Chemical Industries, Ltd.).

(Results) As is evident from the test results in FIG. 2, when a nylon porous membrane not subjected to a surfactant coating treatment was used (untreated group), the decrease in calcium in rat serum due to calcitonin was not observed. In contrast, when the benzalkonium chloride-treated nylon porous membrane was used (treatment group), the reduction of calcium in rat serum by calcitonin was up to about 2%, whereas the maximum was about 17%.
The efficacy of the drug calcitonin was as high as 8%, indicating an increase in drug use efficiency.

[Brief description of the drawings]

FIG. 1 shows a top view and a cross-sectional view of a structure of an applicator device including an interface used in an example.

FIG. 2 is a view showing test results of an example.

[Explanation of symbols]

1. 1. Anode-side electrode (for example, printed Ag (manufactured by Advance Corporation)) 2. Anode side electrode terminal 3. Conductive gel (eg, PVA hydrogel containing NaCl) 4. Ion exchange membrane (for example, AS membrane (made by Asahi Kasei Corporation)) 5. Non-woven fabric (for example, Bemberg (manufactured by Japan Vilene)) 6. Nylon porous material (for example, Biodyne Plus (manufactured by Pall Corporation)) 7. Drug solution (for example, distilled water for injection (manufactured by Fuso Pharmaceutical Co., Ltd.)) Adhesive tape (for example, Blendham (manufactured by 3M)) 9.9 ′. Polyethylene cup 10. Support 11. 11. Dry drug (for example, synthetic salmon kaushitonin (manufactured by Sigma)) Reservoir 13. Applicator 14. 14. Opening (drill holes so that front and back sides pass when used) Open hole (Drill holes so that the front and back sides pass through when used)

Continuation of front page (56) References JP-A-5-97662 (JP, A) JP-A-61-149168 (JP, A) JP-A-61-159937 (JP, A) JP-A-6-16535 (JP, A) , A) JP-A-61-221125 (JP, A) (58) Fields investigated (Int. Cl. ⁶ , DB name) A61N 1/30

Claims (7)

(57) [Claims] 1. An interface for iontophoresis wherein a surface coating layer of an ionic surfactant is formed on a drug holding member. 2. The iontophoresis interface according to claim 1, wherein the drug holding member includes at least a member that comes into contact with a drug or a drug solution. 3. The medicine holding member according to claim 1, wherein the medicine holding member has a porous or capillary structure made of a non-conductive material.
2. The interface for iontophoresis and the method for treating the same according to 1. 4. The interface for iontophoresis according to claim 1, wherein the ionic surfactant is used for preservation and disinfection. 5. The interface according to claim 1, wherein the ionic surfactant is a pharmaceutical additive such as benzalkonium chloride and benzethonium chloride. 6. The ionic surfactant is a pharmaceutical additive such as benzalkonium chloride or benzethonium chloride. Even if the ionic surfactant does not elute or elutes in a drug solution in practical use. The interface for iontophoresis according to claim 1, wherein the concentration is in a range of 0.01% or less. 7. A bioactive peptide characterized in that drug use efficiency is increased by using the interface for iontophoresis according to claim 1 for a drug.