Title:  Percutaneous absorption promoters for electroporation

United States Patent: 6,721,595

Issued:  April 13, 2004

Inventors:  Tokudome; Yoshihiro (Yokohama, JP); Owaku; Koji (Yokohama, JP); Goto; Kenichi (Yokohama, JP); Sugibayashi; Kenji (Kawagoe, JP)

Assignee:  Pola Chemical Industries Inc. (Shizuoka, JP)

Appl. No.:  110589

Filed: April 11, 2002

PCT Filed: April 6, 2000

PCT NO: PCT/JP00/02244

PCT PUB.NO.: WO01/26688

PCT PUB. Date:   April 19, 2001

Abstract

The present invention relates to percutaneous sorbefacients for electroporation consisting of monoterpene and being useful in elevating percutaneous absorbability of drugs, etc. By adding these percutaneous sorbefacients to compositions for electroporation, the percutaneous absorbability of drugs can be elevated.

SUMMARY OF THE INVENTION

Under the aforementioned circumstances, the present invention has been made and is aimed at providing a percutaneous sorbefacients in electroporation and a composition for percutaneous administration which is suitable for electroporation comprising the same.

In consideration of such circumstances, the present inventors have made extensive studies with efforts in pursuit of a composition for electroporation having excellent percutaneous absorption effects. As a result, the inventors have found that monoterpenes such as menthol exhibit excellent percutaneous sorbefacient effects under electroporation and that incorporation of monoterpenes in compositions for electroporation can give rise to compositions for electroporation having excellent percutaneous sorbefacient effects, thereby achieving the present invention. That is, the present invention provides a percutaneous sorbefacient for electroporation consisting of monoterpene and compositions for electroporation comprising the same.

(1) Percutaneous sorbefacient for electroporation of the present invention

The percutaneous sorbefacient for electroporation of the present invention consisits of monoterpene. Preferred examples of the monoterpene include menthol and optical isomers thereof, menthone, thymol, geraniol, pinene, citral, citronellal, etc. Of those, menthol is preferred and 1-menthol is more preferred. This is because menthols in particular 1-menthol have excellent percutaneous sorbefacient effects in electroporation. There are some monoterpenes that exhibit percutaneous sorbefacient effects in ordinary percutaneous administration where no electric field is applied. In such a case, the percutaneous sorbefacient effect is only a few times larger than that of a case where no monoterpene exists. In contrast, the percutaneous sorbefacient effect of the monoterpenes under electroporation according to the present invention is from several tens to several hundreds of times larger than that of a case where neither electric field is applied to nor monoterpene is added. Thus, there is exhibited a percutaneous sorbefacient effect enhanced to such an extent as is by no means expectable from the conventionally known percutaneous sorbefacient effect. In the compositions for electroporation of the present invention, a preferred content of the monoterpenes, which are percutaneous sorbefacients of the present invention is 0.1 to 10% by weight, more preferably 0.5 to 5% by weight. This is because if the monoterpenes are too much, they cause irritation in some cases and if they are too little, no percutaneous sorbefacient effect can be obtained in some cases.

(2) Compositions for electroporation of the present invention

The composition for electroporation of the present invention comprises the aforementioned percutaneous sorbefacient for electroporation. The compositions for electroporation of the present invention may comprise besides the monoterpenes (the percutaneous sorbefacients of the present invention), which are essential components, optional components for manufacturing pharmaceutical preparations used in ordinary composition for electroporation. Preferred examples of such optional components include hydrocarbons such as squalene, vaseline, microcrystalline wax, esters such as jojoba oil, carnauba wax, and octyldodecyl oleic acid, triglycerides such as olive oil, beef tallow, and coconut oil, fatty acids such as stearic acid, oleic acid and ricinoleic acid, higher alcohols such as oleyl alcohol, stearyl alcohol, and octyldodecanol, anionic surfactants such as sulfosuccinic acid esters and sodium polyoxyethylenealkylsulfates, amphoteric surfactants such as alkylbetaine salts, cationic surfactants such as dialkylammonium salts, nonionic surfactants such as sorbitan fatty acid esters, fatty acid monoglycerides, polyoxyethylene adducts of these, polyoxyethylene alkyl ethers and polyoxyethylene fatty acid esters, viscosity bodying and gelling agents, antioxidants, ultraviolet absorbents, coloring agents, preservatives, powders and the like. Further, as drugs that are percutaneously administered by such an electroporation, those usually used as medical preparations can be applied without any particular limitation. Preferred examples of such drags include analgesic antipyretic anti-inflammatory agents such as codeine, morphine, hydromorphone, oxycodone, pethidine, buprenorphin hydrochloride, pentazocine, and tramadol hydrochloride, protein-based drugs such as insulin, carcitonine, elcatonin, adrenocorticotrophic hormone (ACTH), parathyroid hormone (PTH), selectin, oxytocin, angiotensin, .beta.-endorphin, vasopressin, glucagon, somatostatin, luteinizing hormone-releasing hormone (LH-RH), enkephalin, neurotensin, atrial sodium diuretic peptide (ANP), growth hormone, bradykinin, substance P, dynorphin, thyroid stimulating hormone (TSH), prolactin, G-CSF, glutathione peroxidase, super-oxide dismutase (SOD), desmopressin, somatomedin, melanocyte stimulating hormone (MSH), calcitonin gene related peptide (CGRP), endothelin, and thyrotropin releasing hormone (TRH), interleukins, interferons, anti-platelet drugs, vasodilaters, argatroban as anti-arteriosclerotic drug, salpogrelate hydrochloride, sodium beraprost, limaprost alfadex, and cilostazol and the like. These drugs should be administered with passage of time by necessary amounts so that they are agreeable to the properties of percutaneous administration. The compositions for electroporation of the present invention are processed into preparations forms in conformity with the physical properties of the active ingredients, such as solutions, emulsions, semi-solids, and solids, by treating the aforementioned essential components, preferred components, optional components and active ingredients, and are used in electroporation. That is, by using the compositions of the present invention, drugs as active ingredients can be percutaneously administered by electroporation. Upon electroporation, they are used together with a device for electroporation. Among the aforementioned preparation forms, preferred one includes aqueous preparation forms and particularly preferred are an aqueous solution preparation form, aqueous gel preparation form and emulsion preparation form.

(3) Unit for administrating a drug for external application to the skin

The unit for administrating drugs for external application to the skin of the present invention includes the composition for electroporation and a device for electroporation of the present invention in combination. The device for electroporation is not particularly limited as far as it is used usually in such a use, and for example, those devices described in Japanese Domestic Patent Laid Open Publication No. Hei 11-507341(laying open of a Japanese translation), Japanese Domestic Patent Laid open Publication No. Hei 11-505445(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 10-502827(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 11-503349(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 08-511680(laying open of a Japanese translation), Japanese Domestic Patent Laid Open Publication No. Hei 03-502416(laying open of a Japanese translation), etc. may be used. Further, those commercially available devices for such an electroporation include ECM-600 produced by BTX Co., GENE PULSER produced by BIO-RAD Co., etc. Also, these may be used. As for the conditions of electroporation, it is preferred to impress electric current for about 30 seconds with the voltage set to about 300 V and the capacitance of capacitor set to about 25 RF.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail by way of providing examples. Of course, the present invention is not limited to the examples.

EXAMPLE 1

According to the recipe shown in Table 1, compositions for electroporation of the present invention were prepared. As a model labeled drug, 1 mM sodium calcein was used. These were stirred and solubilized to prepare a composition (liquid agent) for electroporation of the present invention. This was measured for its percutaneous sorbefacient effect by a percutaneous permeability test by using a Franz cell. More particularly, to a Franz cell 1, a skin sample 2 which had been obtained from the abdominal part of a hairless rat and from which subcutaneous fat had been removed was attached as a separator with the keratin layer directed toward the donor side. The receiver side was filled with physiological saline 3 while the donor side was filled with 3 ml of the composition 4 for electroporation of the present invention. The receiver side was stirred at 1,200 rpm by a stirrer 6 by use of a star-head type stirrer 5. Each 0.3 ml aliquot was collected with passage of time and the same amount of physiological saline was added and percutaneous permeability was examined. The amount of sodium calcein was measured by using a fluorometer. As the control, 1 mM sodium calcein physiological saline solution was used. The electroporation was conducted under the conditions of using GENE PULSER produced by BIO-RAD Co. as a pulse voltage generator 7 at 300 V with a capacitance of a capacitor of 25 .mu.F with applying 1 pulse (0.5 minute intervals) in first 5 minutes out of 60 minutes and turning off the voltage for the remaining 55 minutes. The results are shown in Table 1 in terms of cumulative permeation amount for 6 hours (nmol/cm²). From this, it is evident that the composition for electroporation of the present invention has excellent percutaneous sorbefacient effect. Comparing this with a case without any electroporation, such an effect is a synergistic effect due to combined use with electroporation (EP) Further, it can be seen that the effect obtained by addition of monoterpene is superior to any of the percutaneous sorbefacient effects of various percutaneous sorbefacients in ordinary cases where no electric field is applied.

EXAMPLE 2

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 3

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 4

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 5

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 6

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 7

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the components in the recipe were stirred and solubilized to prepare a composition for electroporation.

EXAMPLE 8

According to the recipe shown below, a composition for electroporation of the present invention was prepared. That is, the recipe component A was stirred, dispersed and solubilized and the recipe component B was added thereto to neutralize the mixture and obtain a composition (gel) for electroporation.

INDUSTRIAL APPLICABILITY

According to the present invention, a percutaneous sorbefacient in electroporation and a composition for percutaneous administration which is suitable for electroporation can be provided and the present invention is useful in the field of drugs.

Claim 1 of 6 Claims

What is claimed is:

1. A unit for administrating a drug for external application to skin, comprising a composition for administrating the drug by electroporation, which consists essentially of the drug and a percutaneous sorbefacient consisting of one or more monoterpenes and a device for electroporation in combination, wherein a content of the percutaneous sorbefacient is 0.1 to 5% by weight and wherein the absorption of the drug is from several tens to several hundreds of times larger than absorption of the drug in the absence of the one or more monoterpenes and electroporation.

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