JPH0616538A - Liquid composition for drug absorption for iontophoresis - Google Patents

Abstract

PURPOSE:To obtain a liquid composition for drug absorption capable of effectively subjecting especially biologically active polypeptide based drugs to percutaneous absorption with iontophoresis. CONSTITUTION:The liquid composition for drug absorption consists of (A) 0.1-10wt.% pharmacologically permissible electrolyte enough to provide conductivity, e.g. sodium chloride, sodium carbonate, disodium hydrogenphosphate or citric acid, (B) 10-70wt.% ethanol, (C) 0.5-20wt.% monoterpenes (e.g. l-menthol, limonene or cineole) and/or a fatty acid monoglyceride, preferably a glycerin monoester of a 6-12C middle-chain fatty acid as an absorption promotor and (D) water and has pH3-7. These polypeptide based drugs include calcitonin, insulin, growth hormone, interferon and interleukin.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a liquid composition for drug absorption in iontophoresis, and in particular, it can effectively transdermally absorb a biologically active polypeptide drug. A composition is provided.

[0002]

2. Description of the Related Art Conventionally, a method of administering a biologically active polypeptide drug has been an injection method. However, injection administration is limited to specialists, and when it must be performed regularly and frequently, it is painful for the patient, and therefore development of another administration method has been desired. Conventionally, various studies have been conducted on oral administration preparations, rectal / vaginal administration preparations, nasal administration preparations and the like in order to solve such problems, but they have not always been satisfactory. In recent years, in order to solve such a problem, in order to enhance absorption by an administration method other than the above, studies have been conducted to promote percutaneous absorption of a polypeptide drug. However, since polypeptide-based drugs are macromolecules and are water-soluble, etc., like the case of low-molecular-weight drugs, they can be transdermally absorbed without any special measures. It was difficult to be absorbed by the skin and it was very difficult to absorb an effective amount. On the other hand, iontophoresis has been known for a long time as a method for effectively promoting the percutaneous absorption of ionic drugs, and it has been reported that it improves transdermal absorption of polypeptide drugs in particular (In
t. J. Pharm., Vol.44, p197-204,
1988, J. Pharm, Sci., Vol.76, N
4, p341-345, 1987, etc.), many studies have been conducted for practical use, and various reports have been made.
For example, JP-A-60-156475 and JP-A-60-1.
JP-A-88176 and JP-A-61-31169 describe an iontophoresis device having a plaster structure obtained by laminating a conductive electrode layer and a drug-containing conductive gel layer, and 63- Japanese Patent No. 102768 discloses a cup-type plaster structure including an electrode layer and a drug-containing layer. However, even if these iontophoresis techniques are applied, the amount of percutaneous absorption of a polypeptide drug is extremely low and it cannot be put to practical use.

Further, as a liquid composition for iontophoresis containing a polypeptide drug, there is known a technique of using a composition containing water and a dissociation agent having a negative Cechenov constant (Japanese Patent Laid-Open No. 2000-242242). 63-200774). However, in this case, a dissociator having a negative Cechenov constant is contained for the purpose of promoting dissociation of the polypeptide drug, and these dissociators are urea, butanol, and a water-soluble amide having 3 or more carbon atoms. Therefore, the skin may be damaged and a strong stimulus may be generated. On the other hand, research and development of transdermal absorption enhancers such as ointments and poultices have been made much, but in the case of using polypeptides as drugs, the incorporation of these absorption enhancers was not effective at all.

[0004]

DISCLOSURE OF THE INVENTION The present inventors have focused on iontophoresis as a method for promoting percutaneous absorption of a polypeptide drug, and have effective stimulation of percutaneous absorption of the drug with low irritation. As a result of earnest studies on a liquid composition for drug absorption in order to perform the above, the following findings were obtained. That is,
A pharmacologically acceptable electrolyte sufficient to impart conductivity, 10 to 70% by weight of ethanol, 0.5 to 20% by weight of an absorption enhancer composed of monoterpenes and / or fatty acid monoglyceride, and the remaining amount. It was found that the transdermal absorbability of a polypeptide drug is remarkably improved at low voltage and low current by adding a drug to the liquid composition for drug absorption for iontophoresis composed of water.

The present invention has been completed based on the above findings, and an object of the present invention is to provide an iontophoresis which can effectively percutaneously absorb a polypeptide drug by iontophoresis. To provide a liquid composition for drug absorption.

[0006]

That is, the present invention provides a sufficient amount of a pharmacologically acceptable electrolyte to impart conductivity.
To 70% by weight of ethanol, 0.5 to 20% by weight of a monoterpene and / or a fatty acid monoglyceride absorption enhancer, and a residual amount of water for a drug absorption liquid composition for iontophoresis.

The blending ratio of ethanol used in the present invention is preferably 10 to 70% by weight, and when it is less than 10% by weight, the absorbability of the polypeptide drug is lowered, and the absorption enhancer is uniformly dispersed in the composition. Can no longer be kept. On the other hand, when the content exceeds 70% by weight, the electric resistance value of the liquid composition increases and skin irritation such as burns occurs. The absorption enhancer used in the present invention comprises monoterpenes and / or fatty acid monoglycerides, and these may be used alone or in combination. As the monoterpenes, 1-menthol, limonene, and cineol are preferable, and as the fatty acid monoglyceride, caproic acid monoglyceride, caprylic acid monoglyceride, capric acid monoglyceride, lauric acid monoglyceride and the like having 6 to 10 carbon atoms.
12 medium chain fatty acid esters are preferred. In this case, if the carbon number is less than 6, the absorption promoting effect is lowered, and if the carbon number is more than 12, the composition cannot be made uniform and the absorption promoting effect is lowered. The blending ratio is 0.5
-20% by weight is preferable, and if it is less than 0.5% by weight, there is no absorption promoting effect, and if it exceeds 20% by weight, coarse separation occurs and a uniform composition cannot be obtained and the absorption promoting effect is lowered.

Examples of pharmacologically acceptable electrolytes for imparting conductivity include sodium chloride, sodium carbonate, disodium hydrogen phosphate, citric acid and the like. These electrolytes may be used alone or in combination with a (weak) base salt and an acid, depending on the physical properties of the drug. Examples of the combination include citric acid and disodium hydrogen phosphate. The amount of the electrolyte blended may be an amount sufficient to impart conductivity, and is usually 0.1 to 10
% By weight. Further, the pH of the composition is selected according to the physical properties of the drug to be blended, but preferably pH 3 to 7
If it exceeds this range, the polypeptide drug itself becomes unstable.

The thus obtained liquid composition for drug absorption for iontophoresis can be used for any known type of electrode. For example, a gel-type plaster structure formed by laminating a conductive electrode layer and a drug-containing conductive gel layer (Japanese Patent Laid-Open No. 61-31169, etc.) or a cup-type plaster structure composed of an electrode layer and a drug layer (special (Kaisho 63-102768). Moreover, since it has excellent transdermal absorbability, it can be transdermally administered at a low current and a low voltage, and a drug can be absorbed transdermally with low irritation.

The drug that can be added to the composition of the present invention is not particularly limited as long as it is a pharmaceutically effective polypeptide drug. By using the liquid composition for drug absorption of the present invention, an effective amount of a polypeptide drug can be absorbed transdermally. Specific examples of the polypeptide drug include the following drugs. That is, calcitonin, adrenocorticotropic hormone (ACTH), parathyroid hormone (PTH), insulin, secretin, oxytocin, angiotensin, β-endorphin, glucagon, vasopressin, somatostatin, gastrin, luteinizing hormone releasing hormone (LH-RH), Enkephalin, neurotensin, atrial natriuretic peptide (ANP), growth hormone, pradikinin, substance P, dynorphin, thyroid stimulating hormone (TS
H), prolactin, interferon, interleukin, G-CSF, glutathione peroxidase, superoxide dismutase (SOD), desmopressin, somatomedin, melanophore stimulating hormone (MS).
H), muramyl dipeptide, bombesin, vasoactive intestinal peptide, cholecystokinin-8, calcitonin gene-related peptide (CGRP), endothelin, thyrotropin releasing hormone (TRH) and the like. The amount of the polypeptide-based drug added to the liquid composition for drug absorption of the present invention is
It may be an amount sufficient to produce the desired drug effect, and it may vary depending on the type of drug, the weight of the patient, the symptom, etc., and may be appropriately selected according to these conditions.

[0011]

INDUSTRIAL APPLICABILITY The liquid composition for drug absorption of the present invention can effectively transdermally absorb a polypeptide drug by iontophoresis. That is, since percutaneous absorption can be performed with a low current and a low voltage, not only burns but also irritation is reduced, and absorptivity which cannot be achieved by the conventional technique using only ion photorease can be obtained. According to the present invention, a poorly absorbable polypeptide drug can be percutaneously absorbed without using conventional injections or oral administration. Therefore, pain caused by injection administration and digestive system caused by oral administration can be achieved. The polypeptide drug can be administered without causing any damage. Next, the present invention will be described in more detail with reference to Examples and Comparative Examples, but the present invention is not limited thereto.

[0012]

EXAMPLES The electrode parts used in Examples (1 to 7) and Comparative Examples (1 to 4) were as follows. The nylon porous membrane 4 illustrated in FIG. 1 (trade name Biodyne A; pore size 0.4
(5 μm, diameter 14 mmφ), an elcatonin aqueous solution was dried and then dropped to 120 IU to dry. This was attached to the side of the acrylic cup (inner diameter 12 mm, height 3 mm) opposite to the electrode side to which the carbon-coated titanium electrode 1 was attached, and used as an anode. The cup was provided with a hole 2 having a diameter of about 1 mm for the purpose of containing the liquid composition for drug absorption 3 at the time of use so that it could be plugged at the time of use. The cathode contained citric acid and disodium hydrogen phosphate and the support 6
The PVA hydrated gel 7 supported on the surface of the gel was used, and the titanium electrode 5 having a diameter of 20 mm was used on the side opposite to the skin-adhered surface of the gel. Hereinafter, unless otherwise specified, the cup-shaped electrode and the PVA hydrous gel electrode were used in Examples and Comparative Examples.

(Percutaneous absorption test by rat) The abdomen of a rat (SD 7-week-old male) anesthetized with urethane was shaved with a hair clipper and a shaver. Next, the liquid composition for drug absorption of the present invention was injected into the cup on the anode side, the porous membrane side was attached to the abdomen of the rat, and fixed with a medical adhesive tape. Similarly, a PVA hydrogel as a cathode was similarly fixed to the rat abdomen with a medical adhesive tape and then energized. The energization conditions were DC 4 mA, 40 KHz, and 30% duty. After a predetermined time, blood was collected from the jugular vein with a heparin-treated syringe and centrifuged at 3000 rpm for 10 minutes, and the supernatant was used as a sample plasma.

(Determination of Elcatonin Concentration in Plasma) A buffer solution (0.05M Tris-) was added to 100 μl of this sample plasma.
HCl buffer pH 7.4 with 0.9% NaCl, 0.01
% Triton X-100, 0.0057% thi
100 μl (including rosal), 100 μl of anti-elcatonin rabbit serum diluted 8000-fold and ¹²⁵ I-
100 μl of elcatonin solution was added, incubation was carried out at 4 ° C. for 24 hours, and then anti-rabbit IgG was added.
Donkey serum (Amersham; Amerlex-M)
donkey anti-rabbit antis
erum) (250 μl) was added, the mixture was allowed to stand at room temperature for 15 minutes, and then subjected to B / F separation with a magnet for 15 minutes. After B / F separation, the supernatant was removed and the radioactivity was measured with a γ-counter. ¹²⁵ I-for anti-elcatonin rabbit serum
The plasma elcatonin concentration was calculated from the binding ratio of elcatonin.

(Calculation of bioavailability) AUC value (6) up to 6 hours after the intramuscular injection of 40 IU of elcatonin
The bioavailability was defined as the ratio (%) of the AUC value up to 6 hours after application to the blood concentration-area under the time curve). The compositions and test results of the liquid compositions in each of the examples and comparative examples are shown in Table 1 and Table 2, respectively.

[0016]

[Table 1]

[Table 2]

(Results) As is apparent from the above test results, even if an absorption enhancer was added as in Comparative Example 3, the bioavailability was 0 and no absorption was observed unless electricity was applied. As described above, when the iontophoresis was applied using only the electrolyte, it was hardly absorbed. Even when the iontophoresis was applied using the electrolyte and ethanol as in Comparative Examples 2 and 4, the bioavailability was 8% at the most. On the other hand, when the iontophoresis was applied using the liquid composition of the present invention, the bioavailability thereof was 18 to 35%, and it was possible to realize the utility without impeding practical use.

[0018]

[Brief description of drawings]

FIG. 1 shows a cross-sectional view of plaster structures used in Examples and Comparative Examples.

[Explanation of symbols]

 1 Carbon-Coated Titanium Electrode 2 Drug Absorption Liquid Composition Injection Port 3 Drug Absorption Liquid Composition Layer 4 Nylon Porous Membrane 5 Titanium Electrode 6 Support (Mesh) 7 PVA Hydrogel Layer

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Takashi Nakagawa, 6 Umegaoka, Midori-ku, Yokohama City, Kanagawa Prefecture, Japan 2 Japan Tobacco Inc. Pharmaceutical Research Institute (72) Tomohiro Ishikawa, 1-13 Fukuura, Kanazawa-ku, Yokohama-shi, Kanagawa No. 2 Japan Tobacco Inc. Pharmaceutical Research Laboratories (72) Inventor Kenichi Sugimori 1-2-13 Fukuura, Kanazawa-ku, Yokohama, Kanagawa Japan Tobacco Industry Co., Ltd. Pharmaceutical Research Laboratories (72) Inventor Keiichiro Okabe Tokyo 8-30 Seijo, Setagaya-ku, Tokyo

Claims (3)

[Claims] 1. A pharmacologically acceptable electrolyte sufficient to impart conductivity, 10 to 70% by weight ethanol, 0.1.
A liquid composition for drug absorption for an iontophoresis, which comprises 5 to 20% by weight of a monoterpene and / or a fatty acid monoglyceride and an amount of water, and the balance of water. 2. The liquid composition for drug absorption for iontophoresis according to claim 1, which has a pH of 3 to 7. 3. The fatty acid monoglyceride has 6 to 12 carbon atoms.
A glycerin monoester of medium chain fatty acid according to claim 1.
Alternatively, a drug-absorbing liquid composition for iontophoresis according to claim 2.