AU2003271179A1 - Portable ion introduction unit and method for dosing medicine - Google Patents

Description

Commonwealth of Australia Patents, Trade Marks and Designs Acts VERIFICATION OF TRANSLATION I TAKAKUWA, Akiko of 3-16-17. Minami-Yukigaya, Ota-ku, Tokyo 145-0066, JAPAN am the translator of the English language document attached and I state that the attached document is a true translation of Portable Ion Introduction Unit and Method for Dosing Medicine a) *PCT International Application No. PCT/JP2003/013079 as filed on 10 October 2003 (with amendments) A; A, -ertfl4 cop of the spoeification accompmnyiag Patent (Utility Medel) Applicationl No. d in on-i filed in 4) *- dsg aAppletiea-Ne filed in on ~~abaeleeuses Datedthis. ... ............ dayof.... . --------.----- 20 Ab Signature of Translator . ........ F.B. RICE & CO PATENT ATTORNEYS DESCRIPTION PORTABLE ION INTRODUCTION UNIT AND METHOD FOR DOSING MEDICINE Technical Field The present invention relates to a portable ion introduction unit for transdermally or intravascularly ion-introducing a medicine, particularly to a portable ion introduction unit for carrying out iontophoretic delivery of a medicinal or skin beautifying component as a medical or cosmetic method including the prevention, treatment or diagnosis provided for subjects and a method of dosing a medicine by utilizing the portable ion introduction unit. Background Art In a broad sense, the present invention relates to a portable ion introduction unit for carrying out, as a medical or cosmetic method including prevention, treatment or diagnosis provided for subjects, iontophoretic delivery of a medicinal or skin beautifying component and a method for dosing a medicine utilizing the unit. The present invention relates to a new improved system for topically and continuously applying an ion introduction method to a specific site of a human body, thereby causing a medicament to penetrate into the skin and moreover into the deep portion of the body. The ion introduction method is a method of applying -2 a feeble current to the skin to cause an ionized substance to penetrate into the deep portion of the skin. Instead of subcutaneous injection, a variety of methods have so far been designed as an effective method which is free from the pain due to injection or free from the risk of infectious diseases. A number of electrode methods have been disclosed to adapt the ion introduction method to human bodies. Galvanic current (direct current) therapy has a polarity effect for ionized molecules. In this method, ionized molecules are usually activated on the skin surface via the horny layer of the skin. As an ion introduction example of an element itself, some ions such as zinc and copper can be used for the treatment of various infectious diseases of the skin or chlorine ions have been used for the amelioration of scars on the skin surface. Examples of ion introduction of a medicament include vasodilators usable for rheumatism and peripheral vascular diseases and local anesthetics for anesthetizing affected areas or treated areas. Gastrointestinal side effects caused by oral administration of a medicament, or side effects or toxicity caused by a medicine distributed across the entire body except the affected area can be avoided by the administration of the medicament through ion introduction. Although many effective examples of the ion introduction method have been found, it is sometimes accompanied by undesirable side effects, for example, skin - 3 damage caused by burn or stimulation or formation of skin follicles or vesicles at the ion-introduced body portion. In order to overcome these problems, an iontophoretic treatment system enabling long-term administration of single or plural medicaments of any polarity at a higher concentration has been developed by periodically reversing the electric current at ultralow frequencies to mitigate tissue damage (Patent Document 1). Similarly, in order to overcome the above-described problems, a safe skin beautifying apparatus capable of bringing about sufficient ion introduction effects even in a short application time and not causing any skin troubles to, not to speak of, those who have tough skin but also to those who have delicate skin even after long-term continuous use has been developed by simultaneously actuating an ion introduction electrode and an ultrasonic vibrator (Patent Document 2). Patent Document 1: Japanese Patent Laid-Open No. Hei 6 178815 Patent Document 2: Japanese Patent Laid-Open No. 2001 259045 Disclosure of the Invention Problems to be Solved by the Invention In the ion introduction according to conventional technology, however, the delivery is almost limited to that of a medicament having a single electric-charge - 4 polarity to a specific skin site at a relatively low concentration. In addition, satisfactory ion introduction units of which design is relatively simple and which is economical and also which is capable of safely and continuously delivery a medicament for a long period of time when they are once placed under the operation conditions suited for patients have not yet been developed. Thus, the conventional attempts to meet these demands of consumers have not yet been proved to be practically usable and satisfactory. Moreover, the conventional technology has not been proved to be effective when a medicament of a relatively large molecular size is introduced at a high concentration. A pH regulating buffer is sometimes necessary as a solvent for dissolving a medicament therein, but it is difficult to control the pH at the skin site to which the medicament is applied. Sometimes, a sufficiently high penetration rate of a medicament cannot be obtained owing to a relatively high electric resistance or poor penetration at the introduction site. Owing to the various harms or problems as described above, the conventional ion introduction units have not yet succeeded in the smooth systemic circulation of a medicament or smooth delivery of it to a specific organ or tissue. Any of the ion introduction units according to the above-described conventional technology has an improved -5 electrode portion and cannot be taken along all the time. It is not suited for medicines requiring urgency or to be applied upon use such as contraceptives, dental anesthetics or analgesics, hemorrhoidal drugs, first-aid wound healing drugs, anti-inflammatory analgesics, suppressants for heart attack and suppressants for asthma attack. In order to overcome the above-described problems, the present invention provides an ion introduction unit which is made potable by limiting the waveform and frequency to a specific mode and adopting an impulse flat current as essential requirements; minimizing the number of parts and functions necessary for the unit; and downsizing the power supply and operation portion of the ion introduction unit, thereby reducing the weight and size of the ion introduction unit. The specific mode of the unit enables most efficient subcutaneous or intravascular penetration of a medicine and at the same time, does not cause discomfort or side effects to patients. In addition, the ion production unit provided by the present invention can be operated in a simplified manner because it has a relatively simple design, and can be used easily by anyone under any using condition. Means for Solving the Problems In view of the foregoing problems, the present invention has bee made. An object of the present - 6 invention is to provide a portable ion introduction unit comprising the pocket-type main portion of the portable ion introduction unit made portable by an attaching means such as a belt through which the main portion is suspended from one or more body portions selected from the group consisting of shoulder, hip, back and thigh, characterized in that the main portion of the portable ion introduction unit comprises a unit of charging in a mode of an Elliptic R waveform, a frequency of from 1500 to 1530 Hz and an impulse flat current, an introduction side electrode terminal and an opposite side terminal, said two electrode terminals being formed so that they can be attached to a target body portion and an opposite side body portion, respectively. Another object of the present invention is to provide the above-described portable ion introduction unit characterized in that the surface of the electrode of the pocket type main portion of the portable ion introduction unit is made of one or more materials selected from the group consisting of metal materials, nonwoven fabrics and plastic electroconductive materials. A further object of the present invention is to provide a method for dosing a medicine, which comprises injecting, by a pocket type main portion of an ion introduction unit equipped with a medicament-impregnated pad which is a pad impregnated with a medicine whose clinical pharmacological effects are developed and -7 enhanced by causing it to penetrate into a blood vessel in small portions continuously for long hours from the skin and/or the surface of the mucous membrane by the ion introduction unit to distribute it to all over the body and an introduction side electrode terminal of ions to be applied to the skin and/or mucous membrane of a body portion at which the blood vessel exists while interposing the medicament-impregnated pad between the terminal and the skin or mucous membrane, the medicine into the blood vessel continuously. A still further object of the present invention is to provide a method for dosing a medicine according to Claim 3, wherein the medicine is caused to penetrate, by the pocket type main portion of the portable ion introduction unit, into one or more blood vessels selected from the group consisting of cubital fossa, anterior carpal region, carotid artery, neck region and anterior region of the neck, axilla, heart, navel, anus, groin, inner aspect of the thigh, popliteal fossa, tarsal, medial retromalleolar region and lateral retromalleolar region. A still further object of the present invention is to provide a method for dosing a medicine according to Claim 3 or 4, wherein the medicine to be ion-introduced using the pocket type main portion of the portable ion introduction unit is a medicine whose clinical and pharmacological effects are developed and enhanced more preferably by intravascular injection in small portions - 8 for long hours continuously than by a medicine dosing method depending on single injection. A still further object of the present invention is to provide a method for dosing a medicine, which comprises injecting, by a portable ion introduction unit which is equipped with an introduction side electrode terminal of the pocket type main portion of the portable ion introduction unit to be applied to the thin skin or mucosa membrane via a medicine-impregnated pad which is a pad impregnated with a medicine whose clinical pharmacological effects are developed and enhanced by being caused to penetrate inside of an organ or tissue and an opposite side electrode terminal to be applied to the opposite side of the introduction side electrode terminal with the organ or tissue therebetween, the medicine to the organ or tissue only for a necessary and desired time from the surface of the skin and/or mucous membrane. A still further object of the present invention is to provide a method for dosing a medicine according to Claim 6, characterized in that the organ or tissue to be ion-introduced by the pocket type main portion of the portable ion-introduction unit is any one of external ear, gingival, oral cavity, heart, lung, trachea, nasal cavity, vagina, uterus, testicle, anus, wound, and inflamed or affected site. A still further object of the present invention is to provide a method for dosing a medicine according to - 9 Claim 6 or 7, characterized in that the medicine to be ion-introduced by the pocket type main portion of the portable ion introduction unit is a medicine requiring urgency or application upon use such as contraceptives, dental anesthetics or analgesics, hemorrhoidal drugs, first-aid wound healing drugs, anti-inflammatory analgesics, suppressants for heart attack and suppressants for asthma attack. Brief Description of the Drawings FIG. 1 is a perspective view illustrating one example of the present invention; FIG. 2 is a perspective view illustrating the rear side of the one example of the present invention; FIG. 3 is a perspective view illustrating the one example of the present invention equipped with a suspender; FIG. 4 is a graph of the test results of effective resistance value in the one example of the present invention when a constant current circuit is employed; FIG. 5 shows conditions used in the test of effective resistance value in the one example of the present invention when a constant current circuit is employed; FIG. 6 shows the specification of the one example of the present invention; and FIG. 7 is a waveform adopted for ion introduction - 10 in Example in the one example of the present invention. Indicated at numeral 1 is a power source and operation portion, 2 is a switch, 3 is a polarity adjusting button, 4 is an output adjusting button, 5 is an output adjusting dial, 6 is a polarity adjusting dial and 7 is a suspender. Advantage of the Invention In the present invention, an impulse flat current is adopted while limiting the waveform and frequency to specific modes so that subjects can avoid pain caused by injection, limitation of behaviors and risk of infected diseases and a medicine can be delivered while limiting the distributed areas of the medicine to blood and a specific organ or tissue. By integrating a power supply portion with an operation portion and adopting a specific mode, more specifically, a frequency range of from 1500 to 1550 Hz, more preferably 1530 Hz, a waveform of an Elliptic R wave, and an impulse flat current as an electric current; a medicine can be delivered efficiently to an affected area; the introduction unit can be taken along at any time owing to reduction in weight and size; even when a medicine develops and enhances clinical pharmacological effects more preferably by long-term continuous injection in small portions into a blood vessel than single injection or a medicine requires urgency or application upon use, ion - 11 introduction of it can be carried out readily irrespective of time or place; frequent hospital visit is not necessary and pain or troubles of subcutaneous injection, and risk of infected diseases can be avoided. By the ion introduction under the mode permitting most efficient ion introduction, more specifically, under the conditions of a frequency within a range of from 1500 to 1550 Hz, more preferably 1530 Hz, waveform of Elliptic R wave, and impulse flat current as an electric current, a medicament can be delivered to a specific skin site at a higher concentration compared with the conventional technology so that even in the case where effective ion introduction therapy is disturbed by the limitation of the concentration, effective treatment can be carried out by the ion introduction in the above-described mode. Examples of the drug efficacy caused by the administration of provitamin C include inhibition of melanin production by the administration of provitamin C to melanocytes; promotion of collagen rigidity in dermal fibroblast cells and inhibition of collagenolytic enzyme MMP-2&-9 production, protective effects against double strand break of each DNA, 8-OHdG base lesion or apoptosis caused by ultraviolet rays; slowdown effect of provitamin CAsc2P against DNA telomere shortening due to cell division and its prolongation effect of cell lifetime; protection against cell breakdown or cell death caused by lipid peroxide which has appeared as a result of quality - 12 change of squalene or ceramide in the sebum; and inhibitory effects against production increase of active oxygen which can be observed from the skin having inflammation or tumor, transfer of transcriptase NF-KB to nucleic acid, activation of collagenolytic enzyme MMP-2,9 or deterioration of metastatic suppressor gene nm23. Such efficacies of provitamin C can be enhanced by the high rate ion introduction of it through the portable ion introduction unit of the present invention. By adopting a constant current circuit which is effective up to 10 kQ, ion introduction can be carried out safely at a fixed current irrespective of the constitution of a patient. In addition, the ion introduction unit has a built-in timer so that side effects such as burn which will otherwise occur by using the unit for a time exceeding the prescribed time can be prevented. Moreover, by ion introduction using an impulse flat current as an electric current while making the value of electric- current variable, it becomes possible to carry out therapy without causing undesirable side effects such as skin damage due to burn or stimulation, and formation of skin follicles or vesicles or without causing discomfort which appears when current is applied upon ion introduction. This leads to a reduction in the burden of patients. Best Mode for Carrying out the Invention - 13 Examples of the present invention will hereinafter be described based on accompanying drawings. FIG. 1 is a perspective view illustrating one example of the present invention, while FIG. 2 is a perspective view illustrating the rear side of the one example of the present invention. In FIG. 1, indicated at numeral 1 is a pocket-size main portion of a portable ion introduction unit, 2 is a switch, 3 is an output adjusting button. The output is adjusted in four stages. The electric current is variable and 3.0 mA at the maximum. The output adjustment of the frequency and waveform is conducted by a dial indicated at numeral 7 in FIG. 2. The frequency, waveform and electric current are adjusted to 1530 Hz, Elliptic R wave and impulse flat current, respectively. The polarity is switched between + to - by a button indicated at numeral 4. The ion introduction unit has, built therein, a timer by which the set time can be confirmed. The power source is a charging type power source usable in any country. Indicated at numeral 5 is a pad to be applied to each site or tissue of the body. A code is a hook type which facilitates attachment. The portable ion introduction unit adopts a constant current circuit in order to provide a predetermined impulse flat current regardless of a resistance value. The resistance value varies depending on the conditions, but that up to 10 kQ is effective. The unit of the present invention has a size of, for example, 19 mm long, 33 mm wide and 145 mm high. The unit is not - 14 limited to this size and shape and can be downsized or be made portable. FIGS. 4 and 5 are a graph of the test results of the effective resistance value of the ion introduction unit adopting a constant current circuit and conditions when the test of the effective resistance value is carried out, respectively. The term "impulse flat current" used in the present invention means repetition of seven waveforms having a minus polarity, followed by one waveform having a plus polarity, for example, as illustrated in FIG. 7. The impulse flat current is employed in order to prevent the skin from being charged and to deliver a medicine efficiently to an affected area (refer to FIG. 7). The portable ion introduction unit of the present invention is used, for example, in the following manner. First, a medicine-impregnated pad for causing a medicine to penetrate into an organ or tissue, thereby developing and enhancing its clinical pharmacological effects therein is applied to a thin skin at a wound, inflamed or affected site or mucous membrane, for example, external ear, gingival, oral cavity, heart, lung, trachea, nasal cavity, vagina, uterus, testicle, or anus. One of electrode terminals of the ion introduction unit is then placed onto the pad as an introduction side electrode terminal. As an opposite-side electrode terminal, the other electrode terminal of the ion introduction unit is then placed on the opposite side of the introduction side electrode - 15 terminal while sandwiching said organ or tissue between them. These two terminals are then fixed with an adhesive tape or the like. The portable ion introduction unit can also be used in the following manner. One or more blood vessels selected from a group consisting of cubital fossa, anterior carpal region, carotid artery, neck region and anterior region of the neck, armpit, heart, navel, anus, groin, inner aspect of the thigh, popliteal fossa, tarsal, medial retromalleolar region and lateral retromalleolar region are used as a blood vessel to be ion introduced by the portable ion introduction unit. A medicine impregnated pad and electrode terminals are applied to a thin skin in the vicinity of the above-described one or more blood vessels in a similar manner to that described above. The ion introduction unit is equipped with a holder 7 as illustrated in FIG. 3 in order to carry it easily. The introduction unit is portable by hanging this suspender 7 on a body portion such as a shoulder and attaching it by another attaching means. The shape of the holder, the attached position of the ion introduction unit and material of it are not limited to those as illustrated in this drawing and those having a function of hanging the main portion of the ion introduction unit on a body portion and an attaching function are all embraced in the present invention.

- 16 Examples of the medicine to be ion introduced by the portable ion introduction unit include medicaments capable of developing and enhancing more preferred clinical pharmacological effects by continuous intravenous injection in small portions for long hours than by the administration of a medicine by single injection such as vitamin C, provitamin C, vitamin E, provitamin E, anticancer drugs, metastasis suppressing drugs, cancer inhibitors, immunoenhancing drugs, insulin-hydrocortisone, progesterone, estradiol and testosterone. Further examples of the medicine to be ion introduced by the portable ion introduction unit include medicines requiring urgency or application upon use such as contraceptives, dental anesthetics or analgesics, hemorrhoidal drugs, first-aid wound healing drugs, anti inflammatory analgesics, suppressants for heart attack and suppressants for asthma attack. In the development of the ion introduction unit of the preset invention, Elliptic R wave of a direct current and Elliptic R wave of an impulse flat current which are popularly used in the conventional technology, and in addition, squarish R wave and Rectangular wave were compared as a preset mode of the ion introduction unit in order to determine the best mode among them. In each waveform, appropriate frequency was found from conventionally popular frequencies, that is, from 500 Hz to 1550 Hz. As a drug to be ion introduced, Asc2P'Na, - 17 which is a provitamin C, was used and test was carried out using a cultured product of a small skin section excised from human being. As an ion introduction unit, "High Vitaliot" (product of Indiba Japan) was employed. This apparatus can be operated at three frequencies (Mode 1, Mode 2 and Mode 3) within a range of from 500 Hz to 1530 Hz and also can be operated in three waveforms (Mode 1, Mode 2 and Mode 3), that is, squarish-R wave, rectangular R wave, and Elliptic R wave, with "rectangular wave'integrating wave" of an impulse flat current as a main waveform. An actual current value was measured by a multimeter by applying a minus electrode terminal of the ion introduction unit to the horny layer of the small skin section while inserting therebetween a double layered gauze impregnated with a solution of Asc2P-Na and applying a plus electrode terminal to the subcutaneous portion of the section. Four hours after ion-introduction of a 4% aqueous solution of Asc2P'Na, the small skin section was separated into epidermis and dermis and the amounts of provitamin C, total vitamin C (sum of reduced type vitamin C and oxidized type vitamin C), and oxidized type vitamin C (dehydroascorbic acid) were determined, respectively. Determination was also performed under similar conditions except that the epidermis to which the above-described drug had been externally applied without ion introduction was used as a reference. As a result, no vitamin C was detected from the dermis to which the drug was - 18 administered only by the external application. Even from the epidermis, the detected amount of the vitamin C was 1.4 nmol/g tissue, meaning almost 1.2 VM. The amount of vitamin C was less than 3% of the blood level (VC-blood) of vitamin C of the healthy human being. As a result, among the various modes, the vitamin C introduction effect is considerably good under the conditions of an Elliptic R wave and 1530 Hz (Mode 3-3). The amount of vitamin C at epidermis is 19.7 times as much as that attained by external application. Even at dermis, the vitamin C concentration is as high as 2.2 nmol/g tissue, meaning 1.9 KM. The electrical characteristics of Mode 3-3 in "High Vitaliont" (product of Indiba Japan, Co., Ltd.) in Mode 3 3 are shown in FIG. 6 and the wave form is illustrated in FIG. 4. According to the conventional technology employed for ion introduction units, it was impossible to carry out ion introduction of a solution of Asc2P'Na, that is, a provitamin C while bringing its concentration close to the saturated concentration. When the test was made using the above-described "High Vitaliont" (product of Indiba Japan Co., Ltd.), however, the total amount of vitamin C introduced into the dermis showed a drastic increase under the conditions of frequency of 1530 Hz and Elliptic wave form (Mode 3-3). The optimum concentration of Asc2P*Na is 30% and even at the dermis into which vitamin C was not introduced easily, the concentration of total vitamin C - 19 was as high as 27 nmol/g tissue, meaning a concentration of 27 VM. As a result of the test, provitamin C is most preferably introduced in the mode having a frequency of 1530 Hz and Elliptic waveform (Mode 3-3) judging from the introduction amounts at varied current values in a comprehensive manner. The ion introduction effect was preferred both at epidermis and dermis in the mode (Mode 3-3) of a frequency of 1530 Hz and Elliptic R waveform, while setting the electric current at 1.0 mA and the actual current measurement value at 0.99 mA. This value was the maximum electric current value which did not cause discomfort of subjects. The vitamin C concentration in the epidermis was as high as from 2240 to 3890 VM, which was from 56 to 97 times as much as that of the blood vitamin C level. The concentration in the dermis was also as high as from 127 to 281 pM. Almost no vitamin C was detected from the dermis when the drug was externally applied so that the above results have revealed that the penetration of provitamin C was enhanced greatly by ion introduction. A reduction ratio of vitamin C attained by the conventional ion introduction unit is poor and stays from 30 to 60%, while that attained by "High Vitaliont" (product of Indiba Japan Co., Ltd.) is from 97 to 100% when the frequency of 1530 Hz and Elliptic R waveform (Mode 3-3) are employed. The reduction rate of vitamin C - 20 is an index that indicates how much vitamin C converted from provitamin C is maintained in the form of reductive vitamin C having a safe pharmacological effect. The durability of vitamin C was studied four hours and six hours after the introduction, that is, time when the vitamin C is presumed to reach the highest level. As a result, the durability for 6 hours was recognized and it was longer than that of attained by the conventional ion introduction unit. Based on the above-described test results, the portable ion introduction unit of the present invention is designed so that the frequency and waveform are limited to a specific mode enabling most efficient ion introduction, an impulse flat current is employed and its design is simplified and reduced in size and weight. The specification of the portable ion introduction unit according to one example of the present invention is as illustrated in Table 3. The followings are examples using the portable ion introduction unit according to the one example of the present invention. Example 1 After Asc2P'Na (sodium salt of ascorbyl-2-0 phosphate, product of Showa Denko K.K.), provitamin C, was dissolved in 1 mL of pure water (distilled water or MilliQ ultrapure water) to give a concentration of 20%, a water absorbing pad of 30 x 30 x 5 mm was impregnated with the - 21 resulting solution. The pad thus obtained was applied to the vein inside of the right elbow of a 21-year-old male. The minus electrode terminal of the portable ion introduction unit of the present invention as illustrated in FIG. 1 was placed on the pad, while the plus electrode terminal was placed at a position 10 cm toward the shoulder from the right arm. These two terminals were fixed with an adhesive tape. The main portion of the ion introduction unit was hung from his shoulder while using a string so that it came on the body side. The ion introduction was carried out in a mode of Elliptic R waveform and frequency of 1530 Hz while setting a current value at 0.3 mA, a duty ratio of 50% and 1:8 reversal in electrical polarity resetting (Table 3). As a result, the level of vitamin C in blood before the introduction was 13.4 ± 0.2 umol/L, which increased to 18.5 ± 0.3 umol/L one hour after introduction and to 30.1 ± 1.9 umol/L two hours after the introduction. It increased to 34.2 3.8, 57.0 ± 4.9, 83.3 ± 7.6, 68.9 ± 4.1, 88.9 ± 6.5, 71.0 6.4 and 73.1 ± 4.7 umol/L, respectively, 3, 4, 5, 6, 8, 10 and 24 hours after the introduction. Thus, the level of vitamin C in blood was maintained ideally. Such a high vitamin C blood level is attributable to a stable vitamin C maintaining effect which is not available by the single administration of vitamin C. At the same time, the above described results suggest that the vitamin C introduction effect is kept even if ion introduction is performed for - 22 as long as 24 hours. The vitamin C in blood was separated and detected by HPLC (high performance liquid chromatography) on an ODS column and graphite coulometric EDC (electrochemical detector). On the second day, the test was performed in a similar manner to that employed above by applying the water absorbing pad to the same vein but inside the left elbow. For the test, a new provitamin C solution was prepared. The level of vitamin C in blood one hour after the ion introduction was 65.2 t 3.6 umol/L and 70.3 ± 4.8 umol/L two hours after the introduction. It increased to 74.6 ± 2.0 umol/L, 73.3 5.9 umol/L, 68.6 ± 1.7 umol/L, 87.1 ± 4.5 umol/L and 71.5 3.8 umol/L, respectively, 4, 6, 8, 10 and 24 hours after the introduction. It has been revealed that the level of vitamin C in blood can be maintained stably by the ion introduction on consecutive days. Example 2 After aTocP (a-tocopherol phosphoric acid, product of Sigma Aldrich), provitamin E, was dissolved in 1 mL of pure water (distilled water or MilliQ ultrapure water) to give a concentration of 8%, a water absorbing pad of 30 x 30 x 5 mm was impregnated with the resulting solution. The pad thus obtained was applied to the vein on the flexor aspect of the right knee of a 31-year-old female. The minus electrode terminal of the portable ion introduction unit of the present invention as illustrated in FIG. 1 was placed on the pad, while the plus electrode - 23 terminal was placed at a position 10 cm toward the toe from the right knee. These two terminals were fixed with an adhesive tape. The main portion of the ion introduction unit was hung from the hip while using a string. The ion introduction was carried out in a mode of Elliptic R waveform and frequency of 1530 Hz while setting a current value at 0.5 mA, a duty ratio of 50% and a 1:8 reversal in electrical polarity resetting (Table 3). As a result, the level of vitamin E in blood before the introduction was 17.5 ± 0.6 umol/L, which increased to 19.5 ± 0.4 umol/L one hour after the introduction and to 20.4 ± 3.0 umol/L two hours after the introduction. It increased to 23.0 ± 7.1, 26.1 ± 1.4, 24.2 ± 5.8, 26.9 5.0, 29.1 ± 4.3, 24.8 ± 5.5 and 23.0 ± 5.5 umol/L, respectively, 3, 4, 5, 6, 8, 10 and 24 hours after the introduction. The level of vitamin E in blood was maintained ideally. The vitamin E in blood was separated and detected by HPLC (high performance liquid chromatography) on an ODS column and a fluorescence flow detector. Example 3 After human insulin (having a molecular weight of 5807; product of Novo) was suspended in 1 mL of pure water (distilled water or MilliQ ultrapure water) to give a concentration of 100 U/mL which was thicker than that of an ordinary injection solution, the resulting suspension was impregnated in a water absorbing pad of 30 x 30 x 0.5 - 24 mm inside of a gel-coated nonwoven cloth of 50 x 50 x 1 mm. The pad thus obtained was applied to the vein on the back of the shaved right armpit of a 39-year-old female who fasted for 6 hours. The minus electrode terminal of the portable ion introduction unit of the present invention as illustrated in FIG. 1 was placed on the pad, while the plus electrode terminal was placed at a position 5 cm outside toward the elbow from the right shoulder. These two terminals were fixed with an adhesive tape. The main portion of the ion introduction unit was hung from her shoulder with a string to locate it on the right body side. The ion introduction was carried out in a mode of Elliptic R waveform and frequency of 1530 Hz while setting a current value at 0.7 mA, a duty ratio of 50% and a 1:7 reversal in electrical polarity resetting (Table 3). As a result, the level of insulin in blood before the introduction was 11.5 t 0.6 RU/mL, which increased to 13.5 t 0.4 umol/L one hour after the introduction and to 20.4 3.0 umol/L two hours after the introduction. It increased to 23.0 ± 7.1, 36.1 ± 1.0, 27.2 ± 4.6, 32.9 ± 5.9, 30.8 ± 5.4, 33.7 ± 6.4 and 28.0 ± 3.4 umol/L, respectively, 3, 4, 5, 6, 8, 10 and 24 hours after the introduction. The level of insulin in blood was maintained ideally. The insulin in blood was measured by radioimmunoassay. The measured value corresponded to the result obtained by HPLC (high performance liquid chromatography) on an ODS column and UV flow detector.

- 25 Example 4 After Lidocaine Hydrochloride, a local anesthetic, was dissolved in 1 mL of pure water (distilled water or MilliQ ultrapure water) to give a concentration of 50 mg/mL which was thicker than a Xylocaine intravenous injection solution (100 mg Lidocaine/5 mL) produced by Fujisawa Pharmaceutical Co., Ltd., a water absorbing pad of 10 x 10 x 2 mm was impregnated with 0.4 mL of the resulting solution. The lower teeth and gingival excised from a 8-week-old Wister rat was dipped at the root portion thereof in a DMEM buffer and organ culture was performed. Then, the pad obtained above was applied to the buccal gingiva of the anterior teeth. The plus electrode terminal of the portable ion introduction unit of the present invention as illustrated in FIG. 1 was placed on the pad, while the minus electrode terminal was placed at the pharyngeal gingiva of the anterior teeth and these two terminals were temporarily fixed together with the teeth via a connecting clip. Although the main portion of the ion introduction unit was located outside the organ culture, it can be hung from the shoulder or neck of a patient via a belt in actual medical sites. The ion introduction was carried out in a mode of Elliptic R waveform and frequency of 1530 Hz while setting a current value at 0.5 mA, a duty ratio of 50% and a 1:7 reversal in electrical polarity resetting (Table 3). Thirty minutes after the ion introduction, the buccal portion of the - 26 gingival was excised into a 5 x 5 mm piece, followed by slicing into sections of 4 pm thick by a cryostat. About 100 sections were collected from the gingival surface in repetition and five fractions each having a depth of about 400 pm was weighed. The gingival tissue was homogenized by freezing and thawing with liquid nitrogen and a vortex mixer. From the cell homogenate of each fraction, lidocaine was collected by ethanol extraction, followed by separation by HPLC on an ODS column and measurement of the lidocaine concentration by UV flow detector. As a result, the level of lidocaine in the gingiva exhibited the following depth distribution: the concentration of the fraction from the surface to 400 n in depth was 76.2 8.2 nmol/g tissue, that of the fraction from 400 to 800 pm in depth was 43.0 ± 11.2 nmol/g tissue, that of the fraction from 800 to 1200 pn in depth was 39.4 ± 7.0 nmol/g tissue, that of the fraction from 1200 to 1600 pm in depth was 24.5 ± 8.9 nmol/g tissue, and that of the fraction from 1600 to 12000 Mm in depth was 11.3 ± 0.8 nmol/g tissue. The above-described results suggest that an adequate amount of a local anesthetic spreads over the tissue regions in which nerves are distributed in a short time without causing pain or bleeding.

Claims (8)

1. A portable ion introduction unit comprising the pocket-type main portion of the portable ion introduction unit made portable by an attaching means such as a belt through which the main portion is suspended from one or more body portions selected from the group consisting of shoulder, hip, back and thigh, characterized in that said main portion of the portable ion introduction unit comprises a unit of charging in a mode of an Elliptic R waveform, a frequency of from 1500 to 1530 Hz and an impulse flat current, an introduction side electrode terminal and an opposite side terminal, said two electrode terminals being formed so that they can be attached to a target body portion and an opposite side body portion, respectively.

2. A portable ion introduction unit according to Claim 1, characterized in that the surface of the electrode is made of one or more materials selected from the group consisting of metal materials, nonwoven fabrics and plastic electroconductive materials.

3. A method for dosing a medicine, which comprises injecting, by a pocket type main portion of an ion introduction unit equipped with a medicament-impregnated pad which is a pad impregnated with a medicine whose clinical pharmacological effects are developed and enhanced by causing it to penetrate into a blood vessel in - 28 small portions continuously for long hours from the skin and/or the surface of the mucous membrane to distribute it to all over the body and an introduction side electrode terminal of ions to be applied to the skin and/or mucous membrane of a body portion at which the blood vessel exists while interposing the medicament-impregnated pad between the terminal and the skin or mucous membrane, the medicine into the blood vessel continuously.

4. A method for dosing a medicine according to Claim 3, wherein the medicine is caused to penetrate into one or more blood vessels selected from the group consisting of cubital fossa, anterior carpal region, carotid artery, neck region and anterior region of the neck, armpit, heart, navel, anus, groin, inner aspect of the thigh, popliteal fossa, tarsal, medial retromalleolar region and lateral retromalleolar region.

5. A method for dosing a medicine according to Claim 3 or 4, wherein the medicine to be ion-introduced is a medicine whose clinical and pharmacological effects are developed and enhanced more preferably by intravascular injection in small portions for long hours continuously than by a medicine dosing method depending on single injection.

6. A method for dosing a medicine, which comprises injecting, by a pocked-type portable ion introduction unit which is equipped with an introduction side electrode terminal of the pocket type main portion of the portable - 29 ion introduction unit to be applied to the thin skin and mucosa membrane via a medicine-impregnated pad which is a pad impregnated with a medicine whose clinical pharmacological effects are developed and enhanced by being caused to penetrate inside of an organ or tissue and an opposite side electrode terminal to be applied to the opposite side of the introduction side electrode terminal with the organ or tissue therebetween, the medicine to the organ or tissue only for a necessary and desired time from the surface of the skin and/or mucous membrane.

7. A method for dosing a medicine according to Claim 6, characterized in that the organ or tissue to be ion-introduced is any one of external ear, gingival, oral cavity, heart, lung, trachea, nasal cavity, vagina, uterus, testicle, anus, wound, and inflamed or affected site.

8. A method for dosing a medicine according to Claim 6 or 7, characterized in that the medicine to be ion-introduced is a medicine requiring urgency or application upon use such as contraceptives, dental anesthetics or analgesics, hemorrhoidal drugs, first-aid wound healing drugs, anti-inflammatory analgesics, suppressants for heart attack and suppressants for asthma attack.