CA2041250C - Transdermal administration method of protein or peptide drug and its administration device thereof - Google Patents

Abstract

A transdermal administration of protein or peptide drug comprises contacting and ionizing a protein or peptide drug immersed in a hydrophilic polymer with an ionizing solvent composition, forming a drug pathway on epidermis by plural skin needles or treating the skin by a razor, and transferring the ionized drug into the skin by electric force.

Description

The invention relates to the transdermal admini-stration of a protein or peptide drug and an administra-tion device therefor, and more particularly to the trans-dermal administration of the ionized drug by electric force after dissolving and ionizing a protein or peptide drug with an ionizing solvent, also to the transdermal administration device designed for applying such admini-stration efficiently and conveniently.
Generally, in delivering a protein or peptide drug, for example, insulin as physiological metabolism modulator, interferon as anticancer agent, and captopril as cardiovascular modulator, into the human body, some administration methods such as oral administration, injectables, mucosa delivery agent and pump transplant have been commonly used, but such methods cause side effects and their use is inconvenient, and may cause psychological dlscomfort to patients.
In response to this problem, some researchers have recently studied the transdermal administration method of delivering a protein or peptide drug into skin.
Among other things, a most attractive method comprises transferring a protein or peptide drug having electric charge into the epidermis by an electric current.
For instance, R.L. Stephen et al, Biomed.
Biochem. Acta 43(1984)5, 553-558, have attempted to deliver insulin into a pig's skin through the transmission of constant electric current but the result was unsuccess-ful due to the insufficient electric charge of insulin and to failure in making its monomer.
Thereafter, another method to deliver insulin into the human body by removing the stratum corneum was made, but this method has been associated with some problems including infections incurred as a result of removing epidermis and the undesirable transformation/-treatment of the skin. Also, the method of delivering - 3 ~ 2 0 4 1 2~0 insulin without any skin bruise using pulse current has been studied. However, this proved to be inefficient because of the insufficient dose of the drug delivered, and the short duration of the drug effect in the body.
In the meantime, R.R. Burnette and D. Marerro, J. Pharm. sci., 75: 738(1986), experimented to trans-dermally administer TRH (Thyrotropin Releasing Hormone), a hormone for extending by iontophoresis the pregnancy and lactation of women. Further, J.E. Marchand and N. Hagino, J. Urol., 97:874(1982) have exemplified in animal experi-ments the possibility of administering vasopressins into the skin.
B. Robert Meyer et al, Clin. Pharm & Therape, 44, 6, 607 (1988) describe attempts to deliver LH (Lutein-izing Hormone) across the skin by a direct current.
The aforementioned methods have recognized several disadvantages as follows: when a protein or peptide drug is delivered transdermally, its molecular chains are susceptible to being destroyed by electric current and depression of biological activities occur.
Moreover, since the delivery of a required drug amount is not available at one time, because of the high permeation resistance in skin, only a small percentage of the drugs could be transdermally delivered in several divided times.
Besides, the transdermal delivery might raise other specific problems such as skin irritation or impairment, and more potent use of enhancers might also induce the deformation of the human skin system.
Therefore, the present invention seeks to provide an efficient method, wherein by means of a skin stimulate needle (hereinafter "skin needle"), a sufficient amount of protein or peptide drug can be transdermally delivered into the skin on a continual basis with reduced side effects.

~ 4 ~ 2041250 The present invention also seeks to provide a transdermal administration device comprising a storage reservoir of ionizing solvent, a drug reservoir and a skin needle through which the sustained administration of a protein or peptide drug may be available for three to four days by a simple one-time treatment.
The present invention further seeks to provide a -composition of ionizing solvent which functions to dis-solve a protein or peptide drug having more than three peptide units of amino acid into the monomer, increase the ionizing degree, and enable the drug to efficiently pass through the epidermis layer.
The detailed description of this invention is as set forth hereunder.
The invention relates to the transdermal admini-stration of a protein or peptide drug being characterized by the following procedure: contacting and ionizing a protein or peptide drug immersed in polyelectrolyte with a composition of ionizing solvent comprising solvent, polyelectrolyte and enhancer, forming a drug delivery pathway into the skin, and penetrating the above ionized drug into the skin by electric force.
The formation of the drug delivery pathway may be achieved, for example, by an electric razor.
The invention is illustrated by reference to the accompanying drawings in which:
FIG. 1 is a vertical section of an integration-type transdermal administration device as one embodiment of this invention;
FIG. 2 is a vertical section of a separation-type transdermal administration device as another embodiment of this invention, and FIG. 3 is a graph showing the change of blood glucose level with the lapse of time when insulin is administered transdermally in accordance with Example 4 of this inven-tion.
With further reference to Fig. 1, there is shown a transdermal administration device according to this invention in the form of an integration-type transdermal administration device of patch-type used by attaching to the skin, in which an upper side of the device has a reservoir 2 for ionizing solvent and an electrode 1 open to the outside, a lower part is formed by a drug-immersed hydrophilic polymer drug reservoir 3.
A water swelling polymer skin needle supporter 5 is disposed below reservoir 3 and a pluralit.y of skin needles 4 is vertically disyosed in a fixed state. A
stacking structure adhesive layer 6 is formed around the skin needle supporter 5.
A solvent inlet 7 communicates centrally with storage reservoir 2.
A release paper 9 engages adhesive 6 and skin needles 4.
With further reference to Fig. 2, another embodiment of the transdermal administration device of this invention is a separation-type transdermal admini-stration device of patch-type used by attaching to the skin, in which the device has a reservoir 12 for ionizing solvent and an electrode 11 open to the outside on an upper side. A semi-permeable membrane 18 having a mole-cular cut-off ranging from 200 to 20,000 forms a lower side of reservoir 12. A drug-immersed hydrophilic polymer drug reservoir 13, is disposed adjacent membrane 18. A
patch body 30 composed of an adhesive layer is formed around reservoir 13. The device includes a skin needle plate 15 comprising skin needles 14 on a water-swelling polymer sheet, the needles 14 being vertically disposed in a fixed state.

The device further includes a release paper 19 and adhesive 16.
Also, this invention relates to the composition of ionizing solvent for the solvent dissolving and ioniz-ing protein or peptide drugs, which comprises in propor-tion to water 100%, by volume, 1 to 50%, by volume, of a solvent, for example any one or more solutions selected from sodium acetate, sodium-EDTA, sodium salicylate, salt buffer solution of phenol derivatives, acetic acid, hydrochloric acid, ammonia water, and caustic soda; 1 to 30%, by volume, of polyelectrolyte; 1 to 30%, by volume, of enhancer.
This invention can be described in more detail as set forth hereunder.
In general, a protein or peptide drug being used in the treatment of various human diseases has an innate isoelectric point wherein its dissolution is made avail-able only in the case of exceeding the isoelectric-point or as a result of a lower pH. Since such drug has a constant dipole polarity, the ionization of monomeric drug having a positive or negative electric charge depends on the pH of the solvent.
Therefore, in the case of a target drug having a cation (less than the isoelectric point of the drug) an anode is used and a cathode is used in an anionic drug (more than the isoelectric point). Thus, a drug may be transferrable by an electric repulsion force.
By applying such a principle, this invention relates to the method of administering a protein or peptide drug across human skin; in this invention, the ionizing solvent used in dissolving a protein or peptide drug into monomer having either cation or anion, uses a composition of ionizing solvent comprising the following:
in proportion to water 100%, by volume, 1 to 50%, by volume, of solvent, 1 to 30%, by volume, of polyelectro-lyte, and 1 to 30%, by volume of enhancer.
The solvent may be selected from organic and inorganic acids and organic and inorganic bases, for example sodium acetate, sodium-EDTA, sodium salicylate, and salt buffer solutions of phenol derivatives, acetic acid, hydrochloric acid, ammonia water, and caustic soda.
However, in the case of using a cathode. a solvent such as inorganic or organic base or salt buffer solution is appropriate, and in the case of using an anode, a solvent such as inorganic or organic acid is appropriate.
If the electrode of polyelectrolyte which plays a role in preventing the pH change of solvent by elec-trolysis is an anode, any one or more soluble or insoluble polymers may be used, polyacrylamide (more than M.W.
10,000), polyvinylamine (more than M.W. 10,000), polymers comprising quadrivalent ammonium, or pyridinium. If the electrode is a cathode, any one or more solvents may be used as the pH-controlling polyelectrolyte including polyacrylic acid, carboxymethylcellulose (C.M.C.), and alginic acid.
When the above polyelectrolyte is added, the pH
change of electrodes is described in Table 1.

Table 1 - pH Resistance of 1% polyelectrolyte solution after applying lmA current for 2 hrs.
Polyelectrolyte pH Change of Cathode pH Change of Anode Polyacrylamide - 7.5 -~ 9.1 Polyvinylamine - 7 5 -, 7 9 Polyacrylic acid7.0 - 6.6 C.M.C. 7.0 -~ 4.3 Alginic acid 7.0 -~ 4.4 D.I. Water 7.0 -~ 1.8 7.5 -~ 12.5 In order to facilitate the drug delivery, any one or more enhancers may be used, and may be selected from the following:
(a) EDTA as chelating agent, citric acid, N-alkyl derivative, (b) bile salts (sodium dioxychelate, sodium tarocholate), (c) fatty acids (oleic acid mono-olein, saponin).
The electric current may suitably have a density ranging from 0.01 to 1 mA/cm. A pulsating current is more preferable than a direct current because the occurrence of impedance by the current leads to a great increase of resistance and voltage, thus providing vulnerability to skin burn, while the pulsating current source eliminates the impedance wherein high currents may be available under the low voltage.
By way of example to make the operation of the invention more clear, reference is again made to the accompanying drawings with reference to a specific embodi-ment.
Fig. 1 is an integration-type transdermal administration device embodying the concept of the present invention comprising a solvent reservoir 2 made of plastic film, for example polyethylene or polyethylene terephtha-late, supporting the frame of the device and having no solvent permeability and on the upper side, electrode 1 and solvent inlet 7 are open to the outside. The elec-trode 1 consists of metal sheet comprising silver, lead or tin and the solvent inlet is made of "V" type rubber, so that under an air-tight condition from the outside, the composition of ionizing solvent may be injected into the solvent storage reservoir 2 by a syringe.
In the lower part of the solvent reservoir 2, drug reservoir 3 comprising a drug-immersed (in powder) hydrophilic polymer layer is formed. The soluble polymers 20412~0 g usable as the drug reservoir 3 include polyacrylamide, carboxymethylcellulose, polyvinylimine, polyacrylate, alginate, karaya gum, and gelatin. The major functions of the water soluble polymer are to support the drug, and heighten the drug permeability by hydrating the human skin.
In the skin needle supporter 5 stacked at the lower part of the drug supporter 3, 1 to 15 pieces of skin needle 4 per unit area (cm) are disposed in a fixed state, of which the length protruding to the outside of the drug supporter should be 0.2 to 2mm.
The skin needles 4 suitably have a diameter ranging from 50 to 400 ~m and may be of sterilized stain-less steel.
If the diameter of the skin needles 4 exceeds 400 ,um, it is very difficult to permeate the skin and if smaller, the manufacture of the skin needles is not easy.
However, it appears that the thickness of the skin needles does not greatly affect the permeable amount of drug.
Also, a protrusion of skin needle 4 of more than 2mm leads to bruising of the capillary vessel in the corium layer, thus causing coagulation. If the length of skin needle is less than 0.2mm, the needle cannot permeate the skin adequately, thus resulting in a drastic decrease in delivery of the drug.
Should the distribution of skin needles 4 per unit area of skin needle supporter 5 be overly high, an excess of drug might be delivered and the skin's infection might not be neglected after treatment. However, if small, a drug delivery effect of substantial amount cannot be expected. The skin needle supporter 5 is made of water-swelling polymers and can be of a polymer of the same class as indicated for the drug reservoir 3.
The skin needle supporter 5 is surrounded by the adhesive layer 6 which allows the attachment of the - 10 - 20~12~0 administration device to skin, and the skin needle supporter 5 and adhesive layer 6 are covered with a release paper 9.
The use of an integration-type transdermal administration device is as follows: injecting the ioniz-ing solvent into solvent reservoir 2 through solvent inlet 7 by a syringe, removing the release paper 9 from the device, and compressing the device on the skin and obtain-ing adhesion to the skin by adhesive layer 6.
Then, connecting an anode or cathode to the electrode 1 protruding on the upper side, according to the kind of drug or solvent, and having the opposite electrode connected to a conductive pad, e.g. karaya gum, etc. (not illustrated), attached to the side of the device, or connected to another device, then, using two devices simultaneously.
In this way, the composition of ionizing solvent stored in solvent reservoir 2 dissolves the drug contained in drug reservoir 3 and ionizes the drug into cations or anions; the ionized drug moves to the skin under the electric force generated with the electrode 1.
In the meantime, the skin needle 4 attached to skin needle supporter 5 may penetrate the epidermis layer by compression power, when the administration device is attached to the skin, thus forming the pathway for the drug delivery. With the lapse of time, when solvent permeates -from solvent reservoir 2, the skin needle supporter 5 becomes swelled by a water swelling effect and the skin needle comes out from the skin.
If no electric current is applied to the pathway formed by skin needle 4, the drug cannot penetrate across the skin mainly because the hydrophobic epidermic layer does not allow the permeation of hydrophilic drug and the pathway formed by skin needle 4 is temporarily closed by the swelling of the skin.

- ll- 20412S0 Therefore, the electric current applied in the device makes the ionized drug and solvent move towards the opposite electrode and then the hydrophilic protein and polypeptide of the skin become arranged in equilibrium towards the cathode, which causes a "contraction" of the skin. By the above phenomenon, the pathway of epidermis layer becomes open and the drug in the pathway may pene-trate into the corium layer.
Fig. 2, as described above, shows a separation-type transdermal administration device embodying another concept of the present invention in which a patch body and skin needle plate 15 are separated.
The patch body is made of the solvent reservoir 12, where ionization solvent is stored, semipermeable membrane 18, drug reservoir 13, where the drug is dis-persed, adhesive layer 16, and release paper 19. In addition, several skin needles 14 are fixed vertically in the skin needle plate 15 separated from the body frame.
The characteristics of a separation-type device are that since the ionizing solvent is already contained in the device, the administration of another ionizing solvent is unnecessaryi there is a semipermeable membrane 18 between ionization solvent reservoir 12 and drug reservoir 13; there is a skin needle plate separated from the patch body.
A semipermeable membrane 18 whose molecular cut-off is in the range from 200 to 20,000 is preferred because the selection of a semipermeable membrane 18, having a molecular cut-off lower than that of the delivery drug, prevents the reduction of drug activity as the drug is not mixed-in solvent reservoir 12.
The semipermeable membrane to be used in this invention is suitably selected from the following: poly-propylene, cellulose, and ethylene vinylacetate. By making the molecular cut-off of the semipermeable membrane smaller than that of the drug and polyelectrolyte con-tained in the ionizing solvent, the latter cannot permeate the membrane. Then, the pH of the ionizing solvent remains unchanged and skin irritation can be eliminated by preventing contact between polyelectrolyte and skin.
Thus, the solvent molecule and enhancer only can pass through the semipermeable membrane 18.
The formation of skin needle plate 15 should be the same as that of a skin needle placed in an integra-tion-type administration device and the common type of textile fiber is suitable.
The method of using a separation-type admini-stration device is as follows: Lightly compressing the skin needle plate 15 on the skin, and forming the drug delivery pathway on the skin, removing the skin needle plate 15, and, on that skin, compressing the patch body 30 after removing release paper 19. The operation and principle of other parts are the same as those of the integration-type device.
The method of using the separation-type admini-stration device may suitably include lightly shaving the skin by a common type of razor without using the skin needle plate 15, and alleviating the permeation resistance of epidermis layer, and on that skin, compressing the patch body 30 after removing release paper 19.
Protein or peptide drugs applicable to this invention including the following: as the drugs having more than three peptide bond units in amino acid, for example, cardiovascular modulator (captopril, bradykinin, atriopeptin, calcitonin gene factor, C.N.S. chole-cystokinin (CCK-8, 32) as C.N.S. active peptide, ~-endor-phin, nerve growth factor, melanocyte inhibitor-I, gastric modulator (gastrin antagonist, neuro-tension, somato-statin), antibiotics and anticancer drugs (interferon, cyclosporin, encephalins), and biological metabolism - 13 - 20412~o modulators (albumin, insulin, vasopressins, oxytocin, growth hormone, LH (Leutinizing Hormone) and TRH (Thyro-tropin Releasing Hormone).
Referring to the influx mass of a protein or peptide drug in this invention, the ionophoresis of the ionized drug can be described as follows:

dc D2. Z. e. E. C
J = -D -- + --------______ dx KT

Where J is the mass of the drug delivered, D is the diffusion coefficient of nonionized class, D2 is the diffusion coefficient of ionized class, Z is the number of electric charges in the molecule, e is the ionized degree, E is the potential difference, C is the concentration of ionized class, K is Planck's constant, and T is the absolute temperature.
As shown in the above formula, a higher electric conductivity of solution makes the ionized classes dominate the diffusion in a more competitive manner. As a result, the diffusion of nonionized class can be neglected because of "dc/dx = O".
Thus, the above formula is expressed as follows:

D2. Z e. E. C
J _______ KT

In general, there is a method of increasing the number of electric charge (Z) to heighten the electric current of ionized drug: in case the drug having a limited number of electric charges is bound with a functional group such as sulfate base having plentiful numbers of electric charge, the drug derivatives of increased numbers -of electric charge may be obtained. Such drug derivatives may be more ionized than the general drugs which have a relatively lower number of electric charges among solvents, and further, their competitive movement by being highly sensitive to the electric current results in increasing the mass of the drug delivered.
With reference to the ionized degree "e" as described in the foregoing, the ionization rate will increase in accordance with the selection of ionizing solvent. Therefore, as the ionization solvent, organic and inorganic acids and organic and inorganic salt bases may be used; as the case may be, it may be used as the type of salt such as sodium chloride, phosphate or organic acid salts.
The invention will now be illustrated by the following examples.

MANUFACTURE OF INTEGRATION-TYPE ADMINISTRATION DEVICE
An aqueous solution of 0.5M sodium salicylate containing 1% polyacrylic acid salts (trade-mark Carbopol) is added to 100 IU/ml insulin and the mixture is dispersed evenly. 3mg/ml Phenol and 16mg/ml glycerin are added into this mixture and mixed sufficiently at less than 10C to manufacture a gel mixture for the drug supporter.
On a woven sheet of polypropylene fibre, 100 ~m diameter T-type skin needle is fixed in a range of 10 pieces/cm toward the bottom from the upside, evenly coating the opposite sheet face of protruding skin needle with the gel mixture of the drug reservoir, and drying it by a freezing dryer, thus manufacturing a drug reservoir and skin needle supporter.
The drug supporter and skin needle supporter may be heat-sealed to the lower side of an already manu-factured solvent storage reservoir with polyethylene terephthalate, and applying an adhesive layer and release paper to the fringe and thus, manufacturing an integra-tion-type administration device.
The composition of ionizing solvent usable in the integration-type administration device suitably contains 0.5M sodium salicylate salt buffer solution containing 3% polyacrylamide, 3mg/ml phenol, 16mg/ml glycerin, and 1% saponin. Such ionizing solvent is added into the solvent storage tank prior to using the integra-tion-type device.

MANUFACTURE OF SEPARATION-TYPE ADMINISTRATION DEVICE (1) The composition of ionizing solvent is added into a polyethylene solvent reservoir having a silver electrode attached, and heat-sealing in a row a cellulose membrane having a molecular cut-off of 3500; an already manufactured drug reservoir is placed in the lower side.
The ionizing composition contains citric acid at pH 3, 0.2% polyacryl acid (M.W. 150,000), 3.5mg/ml phenol, 16mg/ml glycerin, and a small amount of polyoxyethylene ether.
The manufacture of drug supporter is as follows:
completely dissolving 100 IU/ml insulin and citric acid at pH 3 to porous polyurethane foam and mixing it with 10%
polyacrylate salts (trade-mark Carbopol), and drying in a vacuum.
On a flexible aluminium foil, T-shape skin needles are vertically fixed in a range of 10 pieces/cm and a woven polyester sheet is formed on top. By com-pletely fixing the needle with adhesives, a skin needle plate is manufactured. The manufacture of other parts is the same as that of Example 1.

MANUFACTURE OF SEPARATION-TYPE ADMINISTRATION DEVICE
A composition of ionizing solvent contains lM
sodium acetate, 0.1% polyethyleneimine (M.W. 200,000), - 16 - 2~ 41250 3mg/ml phenol, 16 mg/ml glycerin, and a small amount of mono-olein.
The ~emipermeable membrane is a cellulose membrane having a molecular cut-off of 1,000. The manu-facture of the drug supporter is as follows: 35% alginate gel containing lM sodium acetate is added to 100 IU/ml drug and a small amount of phenol and glycerin, this mixture is mixed and dryed by freezing.

USE OF INTEGRATION-TYPE ADMINISTRATION DEVICE
The back hair of a white New Zealand-origin rabbit is removed by shaving and its blood glucose is measured, an integration-type administration device, as manufactured in accordance with Example 1, is attached to the shaved area. A cathode is attached to the electrode, and an anode is connected to an E.C.G. electrode (trade-mark Biolect) made from karaya gum, a current of electri-city of 0.5 mA, 2 KHz is transmitted for 20 mins.
As a result of conducting the said procedure on 20 experimental animals, it was noted that the average blood glucose level was decreased from 100 mg/dl to 60 mg/dl within 6 hours, and such effect was maintained for 12 hours. Fig. 3 herein illustrates the result of this example.

USE OF SEPARATION-TYPE ADMINISTRATION DEVICE
The back hair of a white New Zealand-origin rabbit was shaved and a skin needle plate of a separa-tion-type administration device, as manufactured in accordance with Example 2, was lightly compressed on the shaved area, the plate was removed and a patch body was attached.
A cathode was attached to the electrode, and an anode was connected to an E.C.G. electrode, and a current ~ - 17 ~ 2 0 41250 of electricity of 0.5 mA, 2 KHz was transmitted for 20 mins.
The average blood glucose level of 20 experi-mental animals was measured and was found to decrease from 100 mg/dl to 50 mg/dl within 4 hours, and such effect was maintained for 12 hours.

SIMULTANEOUS USE OF BOTH INTEGRATION- AND SEPARATION-TYPE
ADMINISTRATION DEVICES
By attaching a cathode to an integration-type administration device of Example 1 and having an anode connected to a separation-type administration device, an experiment was conducted in the same way as in Examples 4 and 5.
The average blood glucose level of 20 experi-mental animals was measured and was found to decrease from 100 mg/dl to 30 mg/dl within 4 hours, 17 animals among them were dead due to hypoglycemia within 8 hours.

USE OF ELECTRIC RAZOR
This Example was conducted in the same way as Example 5 using a separation-type administration device of Example 2. Shaving the back hair of a rabbit by an electric razor instead of the skin needle plate, and attaching to it a patch body of a separation-type admini-stration device.
The average blood glucose level of 20 experi-mental animals was measured and was found to decrease from 100 mg/dl to 50 mg/dl within 4 hours, 15 animals among them showed less than 20 mg/dl hypoglycemia within 12 hours.

This Example was conducted in vitro with a separation-type administration device of Example 2 by changing the administered drug to insulin (Example 8), T.R.H. (Example 9), L.H. (Example 10), and cacitonin (Example 11), respectively.
The outer surface of mouse skin was adhesively fixed to the adhesive part of the administration device, a diffusion cell adding saline solution was fixed in the inside, and treated with an electric current of 0.1 mA for 20 mins. while connecting an administration device and diffusion gel to the electrode.
The drug in the diffusion cell delivered through the mouse skin was separated and assayed by HPLC and the result was described in Table 2.
Table 2. Drug delivery in diffusion cell through the mouse skin Hour Example 8 Example 9 Example 10 Example 11 (Insulin/IU) (TRH/mM) (LH/mM) (Calcitonin/IU) 2 3.0 22 8 4 4 4.4 31 12 10.5 8 9.8 45 15 15.1 12 12.4 70 16 26.7 18 14.7 83 21 32.1 A transdermal administration method for protein or peptide drug according to this invention has the following merits: a) may prevent the transformation of drug, by separating the ionizlng solvent from the drug and avoiding contact between the drug and electrode, b) may prevent the reduction of drug activity owing to the pH
change of solvent by using a pH-controlling poly-electrolyte.
Further, since the drug is immersed in a water-soluble polymer, the skin-administration effect of the drug can be enhanced by contacting a highly concentrated drug with the skin and hydrophilizing the skin. Further-more, the use of a skin needle and/or razor makes it possible to form a drug delivery pathway on epidermis, thereby solving the following specific problems as shown in the transdermal administration of protein or peptide r 2 0 4 1 2 5 0 drug, i.e. insufficiency of drug delivered, the trans-formation of skin owing to chemical enhancer or electric irritation, and the reduction of drug activity in the skin. Along these lines, the sustained transdermal administration of the said drug may be available for three to four days by one-time use.
The comparison between the skin treatment by razor and drug administration by skin needle according to this invention is shown below.
Data on the delivery effect of insulin based upon the skin treatment by using a skin needle and razor, respectively:
Blood Glucose Level of Rabbit(mg/dl) HourControl Skin Needle Razor (No insulin) Remarks:
a) Condition of electric current: 0.5 mA. on/off =l b) Treatment time: 20 mins.
c) Skin needle: 3 pieces/cm d) Razor: Treated by an electric razor for 20 secs.
The change of blood glucose in rabbit by the treatment of electric razor:
Blood Glucose Level of Rabbit (mg/dl) Hour2 secs. 10 secs.20 secs. 40 secs. 60 secs.

8 87 88 40 low 24 113 72 11 dead dead The delivery effect by the razor has not been fully established in its mechanism. It would seem that like that of the skin needle, the mechanism by the razor ~ - 20 - 2041250 might be as follows: reducing the resistance to drug permeability into the skin, facilitating the electric current and thus, easily permeating the drug into the skin.
The thickness of epidermis is, even if variable, said to be in the range of 0.2 to 0.01 mm. By treating the epidermis by a razor, the upper part is partially removed and results in increasing the permeability of drug and electric conductance. In other words, similar case can be seen that an alcoholic lotion treatment after shaving gives a feeble irritation.
In case of a skin needle, although there is little skin resistance in the permeation pathway across the skin, the whole delivery effect is negligibly small because of a limitation of usable skin needles. The blood glucose level of rabbit treated by an electric razor is lower than that of skin needle, which may be due to the fact that an electric razor gives a large surface area of treated skin compared to that of skin needles.

Claims (25)

1. An integration-type transdermal admini-stration device of a patch-type which may be attached to the skin comprising the following:
A) a solvent reservoir for ionizing solvent and polyelectrolyte, said solvent reservoir having a solvent inlet, B) a drug reservoir comprising a drug immersed water-swellable polymer located opposite the solvent inlet such that the solvent reservoir is interposed between the drug reservoir and the inlet, a lower support, a plurality of skin needles vertically dispersed in a fixed state on said support, said support being interposed between the drug reservoir and the skin needles, C) a stacking-structural adhesive layer formed around the lower support.

2. The integration-type transdermal admini-stration device according to claim 1, wherein the solvent reservoir and the drug reservoir are, con-structed from one or more polymers from the group con-sisting of polyacrylamide, carboxymethylcellulose, polyvinylimine, polyacrylate, alginate, karaya gum and gelatin.

3. The device according to claim 1 or 2, wherein the drug reservoir contains a drug selected from the group consisting of captopril, bradykinin, atriopeptin, calcitonin gene factor, cholecystokinin (CCK-8, 32), .beta.-endorphin, nerve growth factor, melano-cyte inhibitor -I, gastrin antagonist, neuro-tension, somatotatin, interferon, cyclosporin, encephalins, albumin, insulin, vasopressins, oxytocin, growth hor-mone, LH (Leutinizing Hormone) and TRH (Thyrotropin Releasing Hormone).

4. The device of claim 1 or 2, wherein the ionizing solvent in the solvent reservoir contains 1 to 50% by volume of a solvent selected from the group consisting of salt buffer solutions of phenol derivatives, acetic acid, hydrochloric acid, ammonia water and caustic soda.

5. The device according to claim 1 or 2, wherein the polyelectrolyte contained in the solvent reservoir contains 1 to 30% by volume of one or more polyelectrolytes selected from the group consisting of soluble or insoluble polyacrylamide, polyvinylimine, quadravalent ammonium, polyacrylate, carboxymethyl cellulose and alginate, based on 100% by volume of water.

6. The device according to claim 1 or 2, wherein said lower support is mechanically attached or thermally bonded to the reservoir and the needles are thermally bonded to the lower support.

7. A device according to claim 1 or 2, wherein said lower support is a water-swelling polymer skin.

8. A device according to claim 6, wherein said lower support is a water-swelling polymer skin.

9. A separation-type transdermal administration kit of the patch-type which may be attached to the skin comprising the following:
a) an electrode located uppermost and furthest from a place of skin attachment;

b) a solvent reservoir for ionizing solvent and polyelectrolyte located below the electrode;
c) a semi-permeable membrane which forma a lower portion of the solvent reservoir;
d) a drug reservoir comprising a drug-immersed water-swellable polymer located below the semi-perme-able membrane;
e) a patch body comprising an adhesive layer formed around the drug reservoir; and f) a plurality of skin needles fixed vertically in a skin needle plate separated from the patch body.

10. A kit according to claim 9, wherein said semi-permeable membrane has a molecular weight cut off range in the range of from 200 to 20,000.

11. A kit as claimed in claim 9 or 10, in which the semi-permeable membrane is selected from the group consisting of polypropylene, cellulose and ethylene vinylacetate.

12. A kit according to claim 9 or 10, wherein the drug reservoir contains a drug selected from the group consisting of captopril, bradykinin, atrio-peptin, calcitonin gene factor, cholecystokinin (CCK-8, 32), .beta.-endorphin, nerve growth factor, melanocyte inhibitor -I, gastrin antagonist, neuro-tension, soma-totatin, interferon, cyclosporin, encephalins, albumin, insulin, vasopressins, oxytocin, growth hor-mone, LH (Leutinizing Hormone) TRH (Thyrotropin Releasing Hormone).

13. A kit according to claim 9 or 10, wherein the ionizing solvent in the solvent reservoir contains 1 to 50% by volume of solvents selected from the group consisting of salt buffer solutions of phenol derivatives, acetic acid, hydrochloric acid, ammonia water and caustic soda.

14. A kit according to claim 9 or 10, wherein the polyelectrolyte contained in the solvent reservoir contains 1 to 30% by volume of one or more polyelectrolytes selected from the group consisting of soluble or insoluble polyacrylamide, polyvinylimine, quadravalent ammonium, polyacrylate, carboxymethyl cellulose and alginate, based on 100% by volume of water.

15. A kit according to claim 9 or 10, wherein said needle plate and skin needles are attached to the drug reservoir and positioned opposite the electrode.

16. A kit according to claim 9 or 10, wherein said needles are thermally bonded to the support.

17. A kit according to claim 9 or 10, wherein said skin needle plate is a water-swelling polymer sheet.

18. A kit according to claim 15, wherein said skin needle plate is a water-swelling polymer sheet.

19. A kit according to claim 15, wherein said skin needle plate is a water-swelling polymer sheet.

20. A transdermal administration method for a peptide drug comprising the steps of:
i) contacting the drug immersed in polyelectro-lyte with ionizing solvent composition wherein the drug is ionized, ii) forming a drug pathway on the skin epidermis by penetrating a plurality of skin needles into the skin epidermis at a treatment site, iii) transferring the ionized drug into the skin at the treatment site by iontophoretic force.

21. The transdermal administration method according to claim 20, wherein the drug is selected from the group consisting of captopril, bradykinin, atriopeptin, calcitonin gene factor, cholecystokinin (CCK-8, 32), .beta.-endorphin, nerve growth factor, melano-cyte inhibitor-I, gastrin antagonist, neuro-tension, somatotatin, interferon, cyclosporin, encephalins, albumin, insulin, vasopressins, oxytocin, growth hor-mone, LH (Leutinizing Hormone), TRH (Thyrotropin Releasing Hormone).

22. The transdermal administration method according to claim 20, wherein the ionizing solvent contains 1 to 50% by volume of solvents selected from the group consisting of salt buffer solutions of phenol derivatives, acetic acid, hydrochloric acid, ammonia water and caustic soda; based on 100% by volume of water.

23. The transdermal administration method according to claim 20, wherein the polyelectrolyte is used for adjusting pH in drug solution and electro-lytic medium and contains 1 to 30% by volume of one or more polyelectrolytes selected from the group consist-ing of soluble or insoluble polyacrylamide, poly-vinylimine, quadravalent ammonium, polyacrylate, car-boxymethyl cellulose and alginate, based on 100% by volume of water.

24. A transdermal administration method for a drug selected from the group consisting of captopril, bradykinin, atriopeptin, calcitonin gene factor, cholecystokinin (CCK-8, 32), .beta.-endorphin, nerve growth factor, melanocyte inhibitor -I, gastrin antagonist, neuro-tension, somatotatin, interferon, cyclosporin, encephalins, albumin, insulin, vasopressins, oxytocin, growth hormone, LH (Leutinizing Hormone) and TRH
(Thyrotropin Releasing Hormone), comprising the steps of:
i) contacting the drug immersed in a polyelectrolyte with an ionizing solvent composition wherein the ionizing solvent contains 1 to 50% by volume of solvents selected from the group consisting of salt buffer solutions of phenol derivatives, acetic acid, hydrochloric acid, ammonia water and caustic soda; and the polyelectrolyte contains 1 to 30% by volume of one or more polyelectrolytes selected from the group consisting of soluble or insoluble poly-acrylamide, polyvinylimine, quadravalent ammonium, polyacrylate, carboxymethyl cellulose and alginate, based on 100% by volume of water;
ii) forming the drug pathway on the skin by micropiercing by penetrating a plurality of skin needles into the skin epidermis at a treatment site;
and iii) transferring the ionized drug into the skin at the treatment site by iontophoretic force.

25. The method according to claim 24, further comprising: abrading the skin in the area of admini-stration prior to forming the drug pathway of step (ii).