JPH09235230A - Iontophoresis preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To administer prostaglandin E1 (PGE1 ) to skin or mucous membrane by means of iontophoresis to remarkably increase the cutaneous absorption rate of medicines to attain sufficient medicinal concentration and effectively improve the stability of PGE1 which is unstable by itself with the passage of time. SOLUTION: Iontophoresis is applied to PGE1 to produce a cutaneous or mucocutaneous preparation of PGE1 where the PGE1 is clathrated in cyclodextrin and the objective iontophoresis preparation contains the clathrated PGE1 .

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a preparation for iontophoresis containing prostaglandin E ₁ which is administered transdermally or transmucosally, and more specifically, in the medical field, it contains bioactive substances and drugs in vivo. A prostaglandin E ₁ containing formulation used for transdermal or transmucosal administration of prostaglandin E ₁ using the principle of iontophoresis used for delivery to
Chronic arterial occlusion (Buerger's disease, arteriosclerosis obliterans),
The present invention relates to a prostaglandin E ₁ -containing iontophoretic preparation for application to patients with oscillatory disease, progressive systemic sclerosis, systemic lupus erythematosus and the like.

[0002]

2. Description of the Related Art Prostaglandin E ₁ (hereinafter, abbreviated as "PGE ₁ ") is known to have various effective specific pharmacological activities such as platelet aggregation inhibitory activity and peripheral vasodilatory activity in a trace amount. Has been. Among them, it shows a remarkable pharmacological effect particularly in peripheral vasodilatory action. Therefore, it is associated with limb ulcers in chronic arterial occlusion such as Buerger's disease and arteriosclerosis obliterans, improvement of resting pain, and peripheral blood circulation disorder in oscillatory diseases It is used for the purpose of improving subjective symptoms, recovering various disorders such as peripheral circulation function, nerve function, and motor function, and treating skin ulcer in progressive systemic sclerosis and systemic lupus erythematosus.

The above PGE1 Injectables, suppositories, oral agents as well as ointments for transdermal administration and transmucosal administration have been studied and studied as the dosage forms for the affected area. Among them, transdermal or transmucosal administration has various advantages over other administration methods such as easy administration, maintenance of blood concentration, and avoidance of side effects of the drug on the digestive tract. However, PGE ₁ has poor absorbability by the conventional transdermal administration method and transmucosal administration method, and therefore, it takes a long time to be absorbed, and the drug concentration at the affected area does not increase, so that the expected effect is not always obtained.

Regarding various absorption promoting methods for absorbing more physiologically active substances and drugs from the skin and mucous membranes,
Although various researches and developments have been made so far, these methods include a chemical promotion method using an absorption enhancer and a physical promotion method using iontophoresis or phonophoresis. . Among these, iontophoresis is to administer a drug into the body through the skin or mucous membrane by applying a voltage to the skin or mucous membrane and electrically migrating the ionic drug.

On the other hand, PGE ₁ is an excellent drug having various pharmacological properties as described above, but is a generally unstable compound itself, and is easily decomposed by acid, alkali, heat, light or the like. It is known that a dehydration reaction occurs particularly under acidic conditions or under heating to be converted into prostaglandin A ₁ , while under alkaline conditions isomerization occurs and converted to prostaglandin B ₁ . Therefore, in the case of formulating such PGE ₁ as a pharmaceutical, it is strongly desired to improve the stability particularly with time.

[0006] The present applicant has the ointment composition containing PGE _1, the PGE ₁ in particular clathrate by etherification cyclodextrins, to the inclusion compound, saturated fatty alcohols, glycols and / or absorption enhancers An ointment composition having excellent stability, percutaneous absorbability and medicinal effect by containing the above was previously developed and filed (Japanese Patent Application Laid-Open No. 3-8
3926). However, the present inventor has conducted a number of further experiments on a formulation which works effectively and has excellent stability when PGE ₁ is applied by iontophoresis rather than as an ointment composition as such, While continuing research, by using PGE ₁ as an inclusion compound that is clathrated with cyclodextrins, the percutaneous absorption rate of the drug is applied as an ointment composition as in the invention according to the above development. The present inventors have reached the present invention by discovering that a high concentration of a drug can be locally administered in a short time, much faster than expected from the case.

[0007]

That is, the present invention solves the above-mentioned drawbacks of the conventional PGE ₁ preparation,
The absorption rate of the drug is extremely fast during drug administration by iontophoresis, sufficient drug concentration can be obtained in a short time, excellent drug effect is exhibited, and PG itself is unstable.
It is an object of the present invention to provide a PGE ₁ -containing iontophoresis preparation having excellent stability over time when E _{1 is} used as a preparation.

[0008]

The present invention relates to a prostaglandin E ₁ -containing preparation for iontophoresis, which is applied transdermally or transmucosally by applying iontophoresis, said prostaglandin E ₁ The present invention provides a prostaglandin E ₁ -containing iontophoresis preparation characterized in that it is included in cyclodextrins.

[0009]

BEST MODE FOR CARRYING OUT THE INVENTION In the present invention, the above-mentioned PGE ₁ is used as an active ingredient, cyclodextrin is mixed and contained therein, and the preparation in which PGE ₁ is included is particularly useful for treating Buerger's disease and arteriosclerosis obliterans. It can be effectively applied to patients with chronic arterial occlusion, vibration disease, progressive systemic sclerosis, systemic lupus erythematosus and the like. According to the present invention,
During drug administration by iontophoresis, a sufficient drug concentration is maintained in the affected area of the patient, unstable PGE ₁ is stabilized, and its temporal stability is extremely effectively improved.

The cyclodextrins are not particularly limited as long as they are cyclodextrins, but α, β, γ-cyclodextrins and their derivatives are preferable. Examples of this derivative include dimethyl-cyclodextrin, hydroxypropyl-cyclodextrin, diethyl-cyclodextrin, triether-cyclodextrin, carboxymethylethyl-cyclodextrin, cyclodextrin sulfate, and cyclodextrin alkylsulfate.

The formulation for iontophoresis of the present invention comprises
It is prepared by adding and mixing those cyclodextrins to PGE ₁ which is an active ingredient. As a result, PGE ₁ is included in the cyclodextrin to form an inclusion compound. In this case, the amount of cyclodextrin to PGE ₁ used is 1: 0.1 to 1:10 in molar ratio.
It is in the range of 0, preferably in the range of 1: 0.5 to 1:10. As a method for preparing this inclusion compound, for example, PGE ₁
And cyclodextrin are dissolved in an organic solvent such as ethanol, methylene chloride or ethyl acetate, and then the organic solvent is distilled off.

In the preparation for iontophoresis containing PGE _{1 of the} present invention, P is added together with the cyclodextrin clathrate.
As the stabilizer for GE ₁ , one kind or two or more kinds of organic acids can be added. This organic acid has a function of making the pH value of the preparation acidic and stabilizing PGE ₁ . The type of organic acid is not particularly limited, but preferably citric acid, succinic acid, tartaric acid, lactic acid and the like, and is added in a proportion of 1 to 1000% by weight with respect to the cyclodextrin clathrate compound. The PGE ₁ -containing iontophoresis preparation of the present invention may further contain a surfactant and a plasticizer, if necessary. The surfactant is not particularly limited as long as it is harmless to the skin and mucous membranes, preferably polyoxyethylene octyl phenyl ether, polyoxyethylene stearyl ether, polyoxyethylene cetyl ether, polyoxyethylene polyoxypropylene glycol. , Sorbitan monooleate, polyoxyethylene sorbitan monolaurate and the like are used.

The plasticizer may be glycerin,
Sorbitol, polyethylene glycol and the like,
Other than these, diethylene glycol monoethyl ether, propylene glycol, propylene glycol monomethyl ether, dipropylene glycol monoethyl ether and the like may be appropriately added. Further, if necessary, an antioxidant (for example, ethylenediaminetetraacetic acid, ether chelating agent, propyl gallate, butylated oxyanisole, etc.) and other components usually used in this type of preparation can be added.

As described above, the PGE ₁ -containing iontophoresis preparation of the present invention comprises chronic arterial occlusion such as Buerger's disease and arteriosclerosis obliterans, oscillatory disease, progressive systemic sclerosis, systemic lupus erythematosus, etc. Can be effectively applied to the patient of, but in the mode of application of this preparation for iontophoresis, that is, when this preparation is applied to the skin or mucous membrane of the affected area by iontophoresis,
For example, by applying an electrode E (guide gate) containing and holding the preparation of the present invention to an affected area of a patient's extremity together with an electrode that is a pair with it, that is, a non-guide conductor, and applying a voltage through both electrodes. It can be carried out.

The electrode E containing and holding the present preparation can be basically constituted by a support, an electrode and a drug holding layer as one mode thereof. Of these, the support is made of a material that is non-reactive and impermeable to drug components, and examples of the material include polyethylene, polypropylene, polyethylene terephthalate, and polyvinyl chloride.
Polyvinylidene chloride, plasticized vinyl acetate copolymer, plasticized vinyl acetate-vinyl chloride copolymer, polyamide, cellophane, cellulose acetate, ethyl cellulose and other plastic films or sheets are used. These plastic films or sheets may be appropriately laminated with aluminum foil, aluminum vapor-deposited, ceramic-coated, or the like.

Next, the electrode is laminated on the support as described above, and a drug-retaining layer (PGE ₁ and a drug-retaining layer containing cyclodextrins, that is, PGE ₁ clathrated by cyclodextrins) is provided. (Including the drug layer). In this case, as a method for laminating the electrode on the support surface, a coating method or any other suitable method can be used, but preferably, the layers are laminated by print printing. Further, as the material constituting the electrode itself, preferably silver, silver chloride, platinum, platinum black, aluminum, iron, carbon, conductive rubber, conductive resin and the like can be used.

The drug-retaining layer is formed on the electrode surface, and this layer is preferably formed by impregnating and supporting the drug on the substrate. That is, a base material is laminated on an electrode, and a drug is impregnated and supported on the base material. Examples of the base material include non-woven fabric, paper, gauze, absorbent cotton, or polyethylene, polypropylene, vinyl acetate, nylon 66, polyolefin, polyamide. A porous film or foam made of a material such as polyurethane can be used.

The conductor E is arranged with respect to the electrode to form the electrode E having the drug holding layer. In general, as a method of applying a voltage in the iontophoresis device configured as described above, there are a direct current type, a pulse type, a pulse depolarization type, and the like, and the electrode E in which the drug holding layer holds the formulation of the present invention is Although any of these methods can be applied, the pulse depolarization type is preferable from the viewpoint of skin irritation.

[0019]

EXAMPLES Examples of the present invention will be described below, but it goes without saying that the present invention is not limited to these examples.

Example 1 Diameter 5 cm, thickness 0.1 mm
With the polyethylene terephthalate film of
An 0.01 mm-thick silver chloride was print-printed thereon as an electrode, and a 0.5 mm-thick non-woven fabric was laminated as a drug holding film to prepare an applicator. On the other hand, 1m
g of PGE ₁ and 25 mg of β-cyclodextrin were dissolved in ethanol, and then ethanol was distilled off to remove PGE.
Inclusion compound consisting of ₁ and β-cyclodextrin (P
GE ₁ -β-cyclodextrin inclusion compound) was obtained.
20 mg of the PGE ₁ -β-cyclodextrin inclusion compound thus obtained was dissolved in 1 ml of distilled water for injection, and the resulting solution was added dropwise to the above nonwoven fabric to obtain the preparation of Example 1 according to the present invention.

Example 2 An applicator was produced in the same manner as in Example 1. While 1 mg PGE ₁ and 25 mg
Of carboxyethylmethyl-β-cyclodextrin was dissolved in ethanol, and then ethanol was distilled off to produce PG.
An E ₁ -carboxyethylmethyl-β-cyclodextrin inclusion compound was obtained. 20 mg of this PGE ₁ -carboxyethylmethyl-β-cyclodextrin inclusion compound was dissolved in 1 ml of distilled water for injection, and the resulting solution was added dropwise to the nonwoven fabric of the applicator described in Example 2 of the present invention.
A formulation was obtained.

Example 3 An applicator was produced in the same manner as in Example 1. Meanwhile, 1 mg of PGE ₁ and 25 m
After dissolving g of dimethyl-β-cyclodextrin in ethanol, ethanol was distilled off to obtain a PGE ₁ -dimethyl-β-cyclodextrin inclusion compound. 20 mg of this PGE ₁ -dimethyl-β-cyclodextrin inclusion compound was dissolved in 1 ml of distilled water for injection, and the resulting solution was dropped on the nonwoven fabric of the above applicator to obtain the preparation of Example 3 of the present invention.

Comparative Example 1 As a formulation example for iontophoresis containing no cyclodextrin, PGE ₁ -β-cyclodextrin inclusion compound 2 in Example 1
A preparation was obtained in the same manner as in Example 1 except that 0 mg was replaced with 20 mg of PGE ₁ , and this was used as the preparation of Comparative Example 1.

Example 4 An applicator was produced in the same manner as in Example 1. Meanwhile, 1 mg of PGE ₁ and 25 m
After the α over cyclodextrin g was dissolved in ethanol and the ethanol was distilled off to give PGE ₁ over α over cyclodextrin inclusion compound consisting of a PGE ₁ and α over cyclodextrin. 20 mg of this PGE ₁ -α-cyclodextrin inclusion compound was dissolved in 1 ml of distilled water for injection, and the resulting solution was added dropwise to the above nonwoven fabric to obtain the preparation of Example 4 according to the present invention.

Example 5 An applicator was produced in the same manner as in Example 1. Meanwhile, 1 mg of PGE ₁ and 25 m
After the β over cyclodextrin g was dissolved in ethanol and the ethanol was distilled off to give PGE ₁ over β over cyclodextrin inclusion compound consisting of a PGE ₁ and β over cyclodextrin. 20 mg of this PGE ₁ -β-cyclodextrin inclusion compound and 10 mg of lactic acid were dissolved in 1 ml of distilled water for injection, and the resulting solution was added dropwise to the above non-woven fabric to obtain the preparation of Example 5 according to the present invention.

Experimental Example 1 Stability Test P in the PGE ₁ -containing iontophoresis preparation of the present invention
In order to examine the stability of GE ₁ , each formulation obtained in Examples 1 to 5 and Comparative Example 1 was filled in an aluminum tube and stored in a thermostatic chamber at a temperature of 40 ° C. for 40 days, and then 3
-Bromomethyl-6,7-dimethoxy-1-methyl-1,2-dihydroquinoxalin-2-one (Br-DM
EQ) was reacted to cause fluorescence, and the residual amount of PGE ₁ was quantified using liquid chromatography. An octadecylsilanized silica gel column was used as the liquid chromatography, and a mixed solution of acetonitrile / methanol / water (35/30/35: volume ratio) was used as the mobile phase. The excitation wavelength was 370 nm and the fluorescence wavelength was 455 nm.
Was detected. Table 1 shows the results. As is clear from Table 1, the formulations of Examples 1 to 5 according to the present invention show that the degradation of PGE ₁ is extremely effectively suppressed by the inclusion effect of cyclodextrin, as compared with the formulation of Comparative Example 1. .

[0027]

[Table 1]

Experimental Example 2 Skin Blood Flow Test A polyethylene terephthalate film having a diameter of 5 cm and a thickness of 0.1 mm was used as a support, and silver having a thickness of 0.05 mm was printed as an electrode on the surface of the support, and the thickness was further increased. 0.5
mm non-woven fabric was laminated. 1 ml of physiological saline was dropped on the non-woven fabric to serve as a control electrode. The iontophoresis preparation of the present invention and a control electrode were attached to the back of the foot of a patient with chronic arterial occlusion and energized at a voltage of 10 V for 1 hour. that time,
With the probe fixedly attached to the back of the foot on the first metatarsal,
Laser Doppler blood flow meter (ALF2100 Adva
nc) was used to continuously measure the skin blood flow in the foot, which is an index showing the amount of drug absorbed.

As a control (preparation containing no drug), 1 m of distilled water was used instead of the PGE ₁ -β-cyclodextrin inclusion compound solution in Example 1.
1 was added dropwise, electricity was applied for 1 hour, and skin blood flow was continuously measured in the same manner as above. 5 minutes before administration and 1 hour after administration 5
The average value of skin blood flow for each minute was calculated and compared. Table 2 shows the results. As is clear from Table 2, in the PGE ₁ iontophoresis preparation according to Example 1 of the present invention, a significant increase in the skin blood flow rate (an index of drug absorption) was obtained as compared with Comparative Example 1 and the control. Is recognized.

[0030]

[Table 2]

[0031] "Experimental Example 3" To study the PGE ₁ in the skin permeability of the application of the PGE ₁ containing iontophoresis formulation of percutaneous absorption test present invention, by using the abdominal skin of hairless mice, Example 1 and Comparative Example 1
An in vitro percutaneous absorption test was conducted on each of the preparations obtained in 1. After applying each preparation adjusted to a circle with a diameter of 3 cm to a hairless mouse, the skin was set on a flow cell connected to a fraction connector, and electricity was applied at a voltage of 10 V for 3 hours. PGE ₁ in the sample collected in the fraction connector was quantified by high performance liquid chromatography to determine the amount of drug permeation over time. Further, as a control, the formulation of Example 1 was applied for 3 hours without applying current. Table 3 shows the total amount of permeation from the start of energization to 3 hours later. From the results shown in Table 2, it is clear that the preparation of the present invention of Example 1 has superior transdermal absorbability as compared with the preparation of Comparative Example 1 and the control.

[0032]

[Table 3]

[0033]

As described above, the PGE ₁ -containing preparation for iontophoresis of the present invention has a markedly fast drug absorption rate during administration of PGE ₁ to the skin and mucous membranes by iontophoresis, for a short time. In addition to obtaining a sufficient drug concentration and achieving excellent drug efficacy, the stability of PGE ₁ which is unstable by itself can be improved very effectively. Further, since this preparation is extremely stabilized as a preparation, it can be stored for a long period of time, can be easily commercialized, and is excellent in quality control, and various effective effects can be obtained.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI technical display location // A61N 1/30 A61N 1/30 (72) Inventor Tsunehisa Sakurai Nekoto-dori, Chikusa-ku, Aichi 1-43 Lyons Mansion Neko-dong 414 (72) Inventor Keiko Yamamura 3-30-1 Maeda-cho, Mizuho-ku, Aichi Prefecture Nagoya (72) Inventor Gozo Saeki, Tenpaku-cho, Tenaku-ku, Nagoya City Aichi Ueda Tower Nomae 124 Sounds Hill No. 105

Claims (4)

[Claims] 1. A prostaglandin E ₁ -containing iontophoresis preparation which is transdermally or transmucosally administered by applying iontophoresis, wherein the prostaglandin E ₁
A prostaglandin E ₁ -containing iontophoresis preparation characterized in that it is included in cyclodextrins. 2. The prostaglandin E ₁ -containing iontophoresis preparation according to claim 1, wherein the ratio of cyclodextrins to prostaglandin E ₁ is adjusted to a molar ratio in the range of 0.1 to 100. To 3. A formulation, as a stabilizer for prostaglandin E _1, a prostaglandin E ₁ containing iontophoresis according to claim 1 or 2, wherein the blending at least one kind of organic acid Formulation. 4. The preparation according to any one of claims 1 to 3, wherein the preparation is for application to patients with chronic arterial occlusion, oscillatory disease, progressive systemic sclerosis, systemic lupus erythematosus and the like. Preparation for iontophoresis containing prostaglandin E ₁ .