KR920002264B1 - Method of patching - Google Patents

Abstract

Two translucent patch-type administration devices (TAD) used by attachment to the skin, are new. Integration type TAD, comprises; (a) a solvent reservoir (2) of ionising solvent, the upper side forming an electrode (1) open to the outside; (b) a hydrophilic polymer drug reservoir (3) contg. the drug, forming the lower part; (c) a water-swellable polymer skin needle supporter (5) in which a number of skin stimulating needles (4) (skin needles) are vertically fixed; (d) a stacking-structural adhesive layer (6) around the supporter (5); and (e) a solvent inlet (7) in the upper central part. The TADs are for electrical admin. of insulin in an ionising solvent. The TAD avoids inconvenient other methods of admin. such as injection, and avoids disadvantages of prior art TADS which may degrade the protein or cause irritation.

Description

Percutaneous administration method of insulin and administration device used therein

1 is a longitudinal sectional view of a patch type administration device showing one embodiment as an insulin transdermal administration device used in the method according to the present invention,

2 is a longitudinal cross-sectional view of another embodiment of an insulin transdermal device for use in the method according to the present invention.

Figure 3 shows the change in blood glucose with time when the patch-type administration device is attached to the skin in the case of transdermal administration of insulin by the method according to the present invention.

* Explanation of symbols for main parts of the drawings

1, 11: insulin solvent storage 2: polymer support

3, 13: skin needle support member 4, 14: skin needle

5, 15 electrode 12 solvent supply membrane

18: void 20: body

21: Matrix

The present invention relates to a transdermal administration method of insulin for administering insulin through the skin and to an administration device used at that time, and more particularly, to an administration device through a dermal needle attached to the administration device by attaching the administration device to the skin. It relates to a method for transdermal administration of insulin contained therein.

Methods for delivering drugs into the blood through the skin have been widely studied and used for decades. As the body types of drugs for drug delivery through the skin, ointment, patch type, and spray type are used. (Spray Type) is used.

However, the use of this type of method is a waste of the drug, was not able to maintain the proper effective blood concentration of the drug at the time of administration, and various methods of administration continue because of the extremely limited drug available in this form Research and development.

In particular, the skin delivery patch system was developed to improve the problem in the conventional method as above. Such a patch system has been able to continuously administer the drug effect for 3-7 days with only one administration, and has made a lot of advances in that there is little toxicity or side effects by controlling the effective blood concentration of the drug in the system.

In addition, the development of an accelerator to increase the skin permeability of the drug using such a system has been developed a method that can easily deliver drugs such as nitroglycerin, scopolamine, estradiol, which was difficult to transfer the skin to the skin.

However, the skin delivery patch, which can be said to be advanced in this way, has the following problems.

First, even if an accelerator that modifies or expands the skin epidermal layer is used, the molecular weight of the drug should be less than 500 because molecules having a molecular weight of 500 or more cannot penetrate the epidermal layer of the skin.

Second, since the structure of the skin is a hydrophilic protein, mainly keratin, is surrounded by hydrophobic fat, strong hydrophobic drugs are easily dissolved in the fat, so the stronger the hydrophobic nature of the drug, the easier the delivery is. .

Third, since it is difficult to maintain high plasma concentrations through the skin, it is difficult to use drugs that require high plasma concentrations.

Nevertheless, in recent years, skin-delivery patches have been continuously developed. Examples of systems for delivering a low molecular weight and hydrophobic drug close to the above-mentioned problem solving conditions are as follows.

In other words, US Patent No. 4, 041, 894 mixed scoflavin with a mixed solvent of mineral oil (10 to 100 CP) and polyisobutylene in a reservoir consisting of a packaging film made of PVC, PET or PE. For control, a film made of polypropylene, cellulose or polyacrylonitrile (porosity 0.1 to 0.85, thickness 0.01 to 0.001 Cm) was used, and a technique using polyisobutylene and mineral oil as an adhesive is disclosed.

In U.S. Patent No. 4, 201, 211 (1980.5.6), colloidal SiO ₂ , mineral oil, polyisobutylene and clonidine were mixed in a reservoir of a polyester film to control the release with a polypropylene membrane. A technique is disclosed which contains components such as the contents of a reservoir.

However, until now it is known that it is impossible to deliver insulin into the skin by the above method, because insulin does not have the conditions necessary for skin delivery. In other words, since insulin has a molecular weight of 6,000 or more and is composed of macromolecules, even though chemical properties are used to modify skin properties, it is impossible to penetrate the epidermal layer.Insulin is a hydrophilic drug that is a peptide conjugate of amino acids. Therefore, the affinity with the hydrophobic epidermal layer is bad, there is a problem that can not penetrate the epidermal layer. Due to these difficulties, there are no commercialized cases of skin-delivered insulin patches.

In general, the human carrier type and administration method of insulin include injection, oral administration, mucosal delivery agent and pancreas transplantation, and insulin pump transplantation.

However, these methods are all wasteful of insulin, low dosing efficiency and inconvenient to use. In some cases, there is a risk of damage to the site of administration or infection of germs, resulting in many problems in use.

Therefore, in recent years, a method of delivering insulin to the epidermis has been continuously studied. Among them, particularly related to the present invention, a method of transferring electric charges to the epidermis is provided by using electric flow.

As a method of delivering insulin using this electrical flow, R.L. Stephev et al. Biomed. Biochim. In Acta 43 (1984) 5, 553-558, a method of permeating insulin through a constant current to pig skin was attempted. However, this method failed to deliver the human body because of insufficient charge amount of insulin and failure to make insulin into a monomer.

Subsequently, Bruce Kari attempted to deliver insulin through Diabets, 35 (1986) 217, for 2 hours, in a rabbit whose epidermal layer had been completely removed. In this method, the epidermal layer, which was the biggest impediment of drug delivery, was removed, resulting in insufficient insulin charges, and increased insulin delivery even when polymerized insulin was used.

However, because this method has serious problems with infection or skin deformation and treatment caused by the removal of the epidermis, this method has made it possible to deliver insulin to the skin, but the problem is that the removed skin has to be treated again. It became serious.

Meanwhile, Yie. W. Chiem Int. J. Pharm. At 44 (1988) 197-204, pulse current was used to deliver insulin without injuring the skin. As a result, it was shown that the permeation amount of insulin was increased, but the delivery amount was not enough and the biological duration time of the delivery amount was short within 60 minutes. In addition, as a result of using a DC power source, the biological duration increased, but the current was too strong, causing burns on the skin and risk of electric shock.

As discussed above, patches that increase drug delivery by using chemical accelerators and modifying the skin are limited in their application to macromolecules such as insulin. In addition, the method of delivering insulin to the skin by using electric flow has made considerable progress, but there is a problem that it is not possible to deliver the required amount of insulin to the human body. There is no way to solve another problem.

Therefore, the present inventors use a patch-type administration device as the conventional method of administering insulin through the skin, but find a solvent composition that can make insulin into a monomer, and the insulin solution can be easily moved during the electric conduction. In order to increase the amount of charge and supply sufficient amount of insulin in the blood while minimizing the wound on the epidermal layer, a skin needle is used in the administration device to create a passage through which the insulin can pass through the epidermis. It was found that the solution to the present invention was completed.

Accordingly, the present invention, in the transdermal administration of insulin using a patch-type administration device, unlike the prior art, by monomerizing insulin and using the needle to allow insulin to pass through the epidermal layer, a satisfactory amount of insulin through the skin It is an object of the present invention to provide a method of transdermal administration of insulin and an administration device used therein for delivering the same into a blood vessel.

Hereinafter, the present invention will be described in detail.

In the present invention, the insulin is transdermally administered using a patch-type administration device, and the insulin is mixed with an insulin solvent and an insulin stabilizer mixed with one or two or more components selected from a reactive magnetic solvent, a salt buffer solution and an aqueous solution of an acid or a base. And the ionization degree at the same time to increase the degree of ionization, and by using a current to control the amount of skin delivery of insulin, while administering the transdermal administration of the insulin mixture solution through a plurality of dermal needles formed in the administration device will be.

As such, the administration device according to the present invention is newly developed in the present invention as illustrated in FIGS. 1 to 2, and one embodiment thereof is generally applied to the skin as shown in FIG. 1. In a conventional patch-type administration device used by bonding, an insulin solvent reservoir (1) constituting the main portion of the patch body, a polymer support (2) having water swellability while insulin is dispersed in powder form, and releasing solvent after skin adhesion According to the skin immersion support (3), the skin immersion support (3) perpendicularly distributed in a vertical distribution, the plurality of skin needles (4) to come into contact with the skin, and the reservoir (1) and the skin It is characterized by a patch-type dispensing mechanism consisting of an electrode (5) provided inside the upper end of the reservoir (1) to enable the electricity to flow.

Here, reference numeral 6 denotes a backing film constituting the insulin solvent storage tank 1, 7 an adhesive layer adhered to the skin, 8 a solvent inlet in which a V-shaped flaw is formed, and 9 an adhesive layer 7. It is a release paper attached to.

In another embodiment of the administration device according to the present invention, as shown in FIG. 2, the solvent supply membrane 12 having the pores 18 so as to permeate the solvent from the insulin solvent reservoir 11 and the reservoir 11 thereof. And a body portion 20 consisting of an electrode 15 installed inside the upper end of the reservoir 11 and the reservoir 20 so as to make electricity into the skin, and separated from the body portion 20. It is characterized in that it is composed of a matrix 21 consisting of a plurality of skin needles 14 and the skin needle support 13 to vertically support the skin needles (14).

Here, reference numeral 16 is a support film forming the insulin solvent storage tank 11, 17 is an adhesive layer to be bonded to the skin, 19 is a release paper attached to the adhesive layer 17.

The present invention will be described in more detail with reference to the accompanying drawings as follows.

In order to administer transdermal insulin using the patch-type administration device illustrated in FIG. 1, the present invention is administered by the following method. In other words, the patient can remove the release paper 9 of the patch and adhere it to the skin, and then, for example, may be made of rubber while administering the insulin solvent therein in an airtight state at the top of the reservoir 1 of the patch. Inject the insulin solvent into the insulin solvent reservoir 1 through the solvent inlet 8 in which the male flaw is formed, connect the power to the electrode 5 protruding from the top, and the opposite power supply to the electrode next to the patch (not shown). Do not do so).

Then, the insulin is monomerized and ionized by the insulin solvent stored in the insulin solvent storage tank 1, so that the insulin easily penetrates the skin through the dermal needle 4 to deliver the insulin to the blood. At this time, the current flowing through the power supply is used in a direct current or pulse flow of 10 ~ 500 ㎂ / ㎠ to control the amount of insulin released.

In Figure 1 showing an embodiment of such an administration mechanism, the insulin solution reservoir (1) is composed of a support film (6) for supporting the entire administration mechanism while preventing the drug containing the insulin permeable, The inside contains a solvent of an acetic acid solution containing an insulin solvent according to the present invention, such as medacresol, phenol and polyethylene glycol, as an insulin solvent. In the lower part of the reservoir 1, the skin supporter 3 composed of a polymer support 3 having water swellability while insulin is dispersed in powder form and a polymer gel exhibiting swelling behavior as the solvent is released is formed. A plurality of skin needles 4 are vertically fixed to the support 3.

The upper end of the reservoir 1 has an electrode 5 made of a thin plate of silver or silver alloy, and has an adhesive layer 7 at the bottom thereof so that it can be adhered well to the skin and does not give skin irritation. . At this time, the adhesive layer 7 is attached to the release paper 9 that can be easily removed when used, which serves to prevent the leakage of the drug and to protect the adhesive.

On the other hand, according to another embodiment of the present invention, a separate dosing device as shown in Figure 2 can be used in oral administration of insulin, in this method the drug-swelled water swellable matrix 21 to the skin After being in close contact with each other, the release paper 19 of the insulin solvent storage tank 11 constituting the body 20 is removed, and the body 20 is placed on the matrix 21 and the skin using the adhesive layer 17. Just press lightly to glue it.

According to another embodiment as illustrated in FIG. 2, the insulin solution storage tank 11 stores a buffer containing, for example, phenol, glycerin, polyethylene glycol, salicylate, and the like. It dissolves and plays a role in facilitating electrical flow.

In addition, the support film 16 forming the reservoir 11 is as described above, the electrode 15 is the center thereof is exposed to the outside to receive the current supplied from the outside. The solvent filled in the reservoir 11 passes through the solvent supply membrane 12 when discharged to the outside of the reservoir 11, and the membrane 12 is a membrane having a plurality of pores 18 of about 0.1 μm. It is configured, so that a constant concentration of insulin is dissolved in the matrix 21 to be in close contact with the supply of the solvent, the material is acid, such as cellulose, polypropylene, fluorocarbon, polycarbonate or nylon, Insoluble in base and insoluble in organic solvents.

In addition, the adhesive layer 17 for adhering the body portion 20 having the reservoir 11 to the skin is made of, for example, a material such as polyacrylate or polybutene, and should be free of skin irritation and by the solvent. The adhesion should not be degraded or dissolved.

Meanwhile, the matrix 21 separated from the body portion 20 is a water-soluble polymer gel, which is fixed vertically to the skin impregnation support 13 containing insulin and is a skin needle which injures the epidermal layer during skin adhesion. It is composed of (14), the water-soluble polymer gel constituting the support 13 is a material showing a swelling behavior of more than 10% by the above-described insulin solvent, for example, conductive such as gelatin, gum arabic, xanthan gum, alginate This is good.

Such a separate dispensing device firstly attaches the matrix 21 to the skin by directly contacting the skin needle 14 with the skin, removing the release paper 19 of the body portion 20, and removing the matrix 21. While pressing lightly on top of the body portion 20 to adhere and fix the skin. Then, when the power supply is connected to the electrode 15 exposed to the outside from the top of the administration device, the insulin is monomerized and ionized by the insulin solvent to easily deliver the insulin to the blood through the skin needle 14. Will be.

Dermal needles (4,14) used in the patch-type or detachable administration device according to the present invention as described above is a simple rod form to serve as a guide for delivery of insulin to the skin, the diameter of which is 50 ~ 400㎛ It is configured to have a length of 1 to 5 mm and an external length of 0.2 to 2 mm, and is attached to the administration device. Such skin needles 4 and 14 are, for example, wire mesh, fiber mesh or other skin needle supporting members 3 and 13. Although it is fixedly attached perpendicularly to 1, it is preferable that 1-15 pieces per unit area (cm <2>) are attached, and the material is most preferably sterilized stainless steel.

If the diameter of the skin needles 4 and 14 is larger than 400 μm, it is difficult to penetrate the skin due to the pressure due to the adhesive force in use, and if the skin needles are too small, the skin needle preparation is difficult. However, it is thought that the thickness does not significantly affect the permeation amount. In addition, when the external length of the needles 4 and 14 is longer than 2 mm, the capillaries of the dermal layer are wound and cause blood clots. If the length is shorter than 0.2 mm, the skin needles 4 and 14 cannot penetrate the skin, and thus insulin The amount of delivery is drastically reduced.

In addition, if a large amount of needles 4 and 14 are fixedly attached per unit area of the skin needle supporting members 3 and 13, an excessive amount of drug is delivered or a risk of skin infection after treatment increases. Do not expect a large amount of insulin delivery effect.

Thus, in the oral administration of insulin using the administration method and the administration device according to the present invention, the selection of the solvent is a very important factor in order to facilitate the skin delivery of insulin.

In general, proteins have their own isoelectric point, especially for insulin, about 5.3. Therefore, when the isoelectric point of insulin in the water-soluble solvent is 5.3 to precipitate the insulin present in the form of a polymer, there is a problem that the insulin molecules can not be delivered to the skin in this state.

Therefore, it is important to make insulin monomeric. Insulin generally becomes soluble only when the pH in the aqueous solution is below 5.3 or above. In other words, the insulin molecules in the solution above and below the equipotential point are present in the state of the monomer in the polymer state.

However, so far it has not been possible to make insulin molecules completely monomeric as the solution changes pH, which is why insulin molecules induce protein-specific molecules in the acid or alkaline solution and cause dipole moments. This is because some degree of intermolecular balance is maintained by hydrogen ions, hydroxy ions or other ions liberated in the inside, and hexamers, tetramers, and dimers are formed depending on the composition and concentration of the solvent.

Thus, in this state, the molecular weight of insulin is so large that it cannot pass through the epidermal layer, the largest barrier of the skin.

In order to solve this problem, according to the present invention, as a method of making insulin into a monomer, a method of dissolving insulin in a semiprotic solvent or dissolving in a salt buffer solution is employed.

Examples of the semiprotic solvent used in the present invention include dimethyl sulfoxide, dimethyl sulfolane, 5,5-dimethyl-1,3-cyclohexanedione, and the like. The antiprotic solvent is 15,000 IU / ml of insulin. As a very excellent solvent that can be dissolved until, the semi-protic solvent is surrounded in the polar region of the insulin molecule to remove the polarity, the insulin is present as a monomer, it is stable in any chemical and physical conditions.

In addition, as the salt buffer used in the present invention, sodium acetate, sodium salicylate, sodium glycocholate, sodium citrate, citrate, sodium chloride, phosphate, and the like may be used. It relaxes the polarity and loosens or dissociates the hydrogen bonds present between the molecules, thereby contributing to making the insulin a monomer.

Here, sodium acetate buffer solution is used from 1 to 50 mg / ㎖, the appropriate amount is 15 to 30 mg / ㎖, sodium salicylate buffer solution is used from 50 to 300 mg / ㎖, the appropriate amount is 60 to 160 mg / Ml, sodium glycochorate is used in the 1 ~ 10mg / ㎖, the appropriate amount is preferably used as insulin buffer 2 ~ 4mg / ㎖. In addition, sodium chloride, phosphate, and citrate may be used in a solution of 0.5 to 2 moles, and each buffer may be used separately or two or more may be used for 50 to 300 IU / ml of insulin.

Furthermore, in the solvent, in addition to the insulin stabilizer, phenol, glycerin or m-cresol may be used as an accelerator. At this time, the addition amount of phenol may be used from 1 to 10mg / ㎖, the appropriate amount is 2 ~ 4mg / ㎖ is the best. Glycerin may be used in an amount of 1 to 100 mg / ml, but an appropriate amount is preferably 10 to 25 mg / ml, and m-cresol is used in the same amount as the phenol addition amount.

At this time, glycerin is commonly used in the salt buffer solution composition, and phenol or m-cresol may be added and used. In addition, in the case of using general organic or inorganic salts in addition to the above as the salt buffer solution solubility is increased.

In addition, according to the present invention, the insulin has an isoelectric point changed in an aqueous solution of acid or base, and thus the conductivity is also increased as will be described in more detail above. Therefore, in the present invention, an acid or base aqueous solution may be used in addition to the above-mentioned aprotic solvent or salt buffer solution as the insulin solvent, and as the acid aqueous solution, for example, organic and inorganic acids, such as acetic acid, hydrochloric acid, salicylic acid, phosphoric acid, citric acid and oxalic acid, may be used. An aqueous solution can be used, and aqueous solution of caustic sodium, potassium hydroxide or ammonia can be used as the base aqueous solution.

At this time, the pH of the acid aqueous solution is a solution of pH 2.5 ~ 3.5 that is the concentration that can be charged by the insulin molecule, and preferably a solution of pH 3.2 ~ 3.0 is the best. In addition, as a base aqueous solution, pH 7 to 8, in which the insulin molecule may have a negative charge, are suitable. At pH 8 and above, there is a risk of decomposing insulin by hydroxyl group (OH). That is, in the present invention, in addition to insulin, acid and base solutions are used, wherein glycerin is mixed and phenol or m-cresol may be mixed.

As a result, when one or more of the above-mentioned antiprotic solvent, salt buffer, acid or base aqueous solution is used as the insulin solvent in the present invention, insulin is monomerized and ionized due to the use of the solvent to prevent penetration of the skin. It can be seen that it can be facilitated.

On the other hand, according to the administration method of the present invention, the electrical conductivity of the insulin in addition to the selection of the solvent also plays an important role in the control of the delivery flow of insulin by the current.

The conductivity of insulin in the solution mixed in the above solvent was measured by MHO-meta, and it was found that the solution had little conductivity as 2 μmho at a concentration of 100 IU / ml of insulin in a semiprotic solvent such as dimethyl sulfoxide. . It is determined that the polarity present in the insulin molecule is surrounded by the aprotic solvent and thus the polarity is removed. In addition, insulin dispersed in distilled water has a very low conductivity of 13 μmho.

Therefore, in the method of the present invention, since the flow of insulin must be controlled by using electricity, it is advantageous for skin administration that the insulin is charged a lot. In order for the insulin to be charged a lot, the insulin molecules have an isoelectric point above or Since it becomes charged insulin when it exists below, it is preferable to use the above-mentioned aqueous solution of an acid or a base as mentioned above. That is, the equipotential point of insulin in the aqueous solution of acid or base is changed, and thus the conductivity is also increased.

To help understand this fact, changes in the conductivity of insulin in aqueous solvents of acids or bases are shown in the following table.

* The concentration of hydrochloric acid is 6M

On the other hand, the insulin with increased conductivity is ionized by the flow of current, in order to determine the flow rate of insulin ion ionization of the ionized insulin is expressed as a value calculated by the following formula.

Where J is the transfer amount, D ₁ is the diffusion coefficient of the non-ionized species, D ₂ is the diffusion coefficient of the ionized species, Z is the number of charges of the molecule, e is the ionization degree, E is the potential difference, and C is the concentration of the ionized species. Where K is Planck's constant and T is the absolute temperature.

In other words, the transfer amount J in the electrolyte is expressed as the sum of diffusion of non-ionized species and diffusion of ionized species.

In this equation, the diffusion of non-ionized species can be neglected because the higher the conductivity of the solution, the more dominated the diffusion of the ionized species, the dc / dx = 0. Therefore, the above formula

Becomes

According to the present invention, a method of increasing the number of charges (Z) of a molecule to increase the electrical movement of ionized insulin to combine a functional group containing a large number of charges, such as sulphate with a limited number of insulin In this case, an insulin derivative having an increased number of charges can be obtained.

Insulin derivatives with increased number of charges can be ionized more than ordinary insulin with relatively low number of charges in solvents, and are more sensitive to electrical movement, thus increasing the amount of transfer because they move competitively. As mentioned above, since the ionization rate increases according to the selection of the solvent, in the present invention, an organic or inorganic acid and an organic or inorganic base may be used in the insulin solvent, and in some cases, may be used in the form of a salt. As the salt, sodium chloride, phosphate or organic acid salt can be used. However, the insulin dissolved in the saline solution moves competitively with the free salt ions in the electric field, and the small size and strong ionization ions are transmitted first during skin delivery, which may impede the penetration of insulin into the skin. do.

On the other hand, transdermal administration of insulin goes through several barriers until insulin monomer is supplied to the blood through the skin. Among them, the largest barrier is the epidermal layer, which is composed of about 20% lipid and 40% protein and has a thickness of 0.1 mm or more, and has a structure in which lipids surround each segment of the protein. It is hydrophobic. In addition, since the moisture content of the epidermal layer is smaller than 40% in the dermis or transdermal layer, the electrical resistance is large, and it acts to protect the dermal layer from thermal stimulation or external stimulation.

Insulin is transported into capillaries via the epidermis and dermis, which are the obstacles following this epidermal layer. Some of the insulin administered by secreting many enzymes in the dermal cells for foreign substances or irritation is metabolized. Some are deposited intracellularly, and the remaining amount enters the blood.

In order to allow the insulin to penetrate the skin layer in the delivery route of insulin, as described in detail above, the insulin is monomerized, the ionization strength is increased, and the mobility of the insulin molecules is increased by iontophoresis. By using dermal needles on the epidermal layer in the administration device, insulin delivery can be increased by increasing insulin delivery.

According to the present invention, the path through which the insulin passes through the skin to the blood is maximized by using a dermal needle. The passage formed by the dermal needle can hardly penetrate the insulin molecules when there is no electric flow. The reason is that the nature of the epidermal layer is hydrophobic so that it does not accept hydrophilic insulin and the passage formed by the dermal needle is temporarily closed by the swelling of the skin. Therefore, when electrical flow is applied, ionized insulin and solvents move toward the opposite electrode, and the hydrophilic proteins and polypeptides of the skin are contracted by equilibrating toward the anode, which causes passage of the epidermal layer. It opens up and insulin in the passage passes through the dermis.

At this time, looking at the path through which the insulin penetrates into the skin by the dermal needle, the protein of the epidermal passage formed by the dermal needle is oriented equilibrium toward the anode by the dipole under the current condition and the protein causes contraction and the size of the passage Increases. In addition, the lipid layer, which is one of the epidermal layer constructs, increases the miscibility between the hydrophobic region of the lipid and the hydrophilic region of insulin by additives such as glycerin and polyethylene glycol (PEG) added to the insulin solvent, and also phenol, m-cresol, The addition of lipolytic substances, such as salicylic acid, increases the fluidity of the lipids, thereby allowing the passage of hydrophilic insulin easily through the passage.

The role of such acupuncture on the skin is to reduce the resistance by focusing the drug in the large passage of the skin so that it does not receive the resistance that is received when the drug is administered to the general skin, that is, the passage of the epidermis or the diffusion. It solves the hydrophobic condition by limiting many hydrophobic conditions in the passages of the skin needles, thereby minimizing the amount of additives to enable the delivery of a large amount of insulin.

Here, in the electric field, the helix structure of the polypeptide, which is the protein construct of the skin, is arranged in an equilibrium by electrical vibration. When the normal helix structure is equilibrated, the hydrogen bonds of the peptides in the neighbor are temporarily destroyed, thereby dipoles. Repulsion of the liver increases the size of the voids. Thus, in this state, the ionic insulin molecules and water move to the pores to neutralize the repulsion between the dipoles, and eventually the ionic insulin is delivered.

As described above, in the case of the method of permeating insulin through the skin, until now it was not possible to deliver a sufficient amount of insulin to treat diabetes, but in the method of the present invention, the monomer is ionized and ionized by using an appropriate solvent. Skin permeation is facilitated and the amount of ionized insulin permeation can be controlled by electrical flow. In addition, by making a passage through the skin needle to penetrate the epidermal layer, which is the biggest barrier to skin penetration, it is possible to deliver a sufficient amount of insulin to maintain an effective blood glucose level.

Therefore, the method of the present invention currently overcomes the problems of insulin administration by injection, oral, transplantation, etc., and furthermore, many applications are expected for skin administration of insulin-like peptide / proteinaceous drugs.

In addition, by using the administration method or administration device according to the present invention, like the general method of transdermal administration of the drug, it is possible to prevent the insulin, which is a prophylactic drug, from being metabolized in the liver or destroyed by gastrointestinal conditions, and to adjust the dosage by electric flow In addition, it is possible to reduce other side effects due to hypoglycemia or hyperglycemia, and even if diarrhea side effects occur, the patient can quickly remove the administration device.

In addition, it is possible to continue to supply the drug for more than three days without side effects by a single dose of administration, which is convenient for the patient, and also has the advantage of relieving the psychological burden of the patient, such as injection or transplant surgery.

Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited by Examples.

Example 1

Insulin-dispersed matrix is uniformly dispersed by adding 300 units of insulin powder to 1 g of 3% gelatin solution, and then mixed with 7 mg of phenol at a temperature of less than 10 ° C.

The mixed solution is gently poured onto the skin needle where the skin needles (10/10/10 cm2) are fixed vertically and vacuum-dried in a lyophilizer to obtain an insulin matrix.

On the other hand, the insulin solvent is prepared by mixing 2 ml of acetic acid solution at pH 3.2, 0.4 ml of P.E.G having a molecular weight of 4,000 and 32 mg of glycerin.

Example 2

Insulin-dispersed water-soluble polymer support is dispersed evenly by putting 300 units of insulin powder in 1 g of 3% alginate solution, and 50 mg of glycerin and 6 mg of meta-cresol are mixed well at a temperature below 10 ° C.

The mixed solution is poured evenly over the skin needles (10 pieces / cm 2) where the skin needles are fixed vertically, dried for 12 hours in a vacuum dryer, and cut into a circular shape such that the total area becomes 6 cm 2.

Insulin-dispersed skin infiltrates are mounted in a patch-type administration device as illustrated in FIG. Insulin solvent is dissolved by saline buffer solution 200mg sodium salicylate and 2ml of acetic acid solution of pH 3.0 and then dissolved enough, put the glycerin 32mg into the insulin solvent storage tank.

Example 3

The insulin matrix was prepared in the same manner as in Example 1, and the insulin solvent was evenly mixed with 2 ml of aqueous hydrochloric acid solution at pH 3.2, 32 mg of glycerin and 6 mg of phenol.

Example 4

The insulin matrix is prepared in the same manner as in Example 1, and the insulin solvent is evenly mixed with 20 ml of 1 molar aqueous solution of sodium salicylate, 32 mg of glycerine and 6 mg of phenol, and used as a solvent.

Example 5

A water-soluble support in which insulin is dispersed is prepared in the same manner as in Example 2, and 6 mg of phenol is added to the support instead of meta-cresol. As an insulin solvent, 2 mg of dimethyl sulfoxide, 80 mg of sodium glycochorate and 32 mg of glycerin were mixed with a salt buffer, followed by addition of 2 ml of an aqueous solution of pH 3.2.

Insulin transdermal administration device made through Examples 1 to 5 as described above was attached to rabbit skin and subjected to electrotreatment, and the resultant blood glucose reduction is shown in Table 1.

TABLE 1

* Value measured 1 hour after treatment

[Test Example]

Insulin skin permeation experiments were performed in vitro and in vivo, respectively. Electrical conditions required for skin penetration were used as a direct current or a pulse current of 0.1 to 1.5 mA. In the case of pulse flow, a square wave having an interruption ratio of 1 to 2 and a frequency of 1 to 3 KHz was used. In addition, the skin was electrically energized at 60 minutes.

In vitro, the rats' hairs are removed with a razor and placed in water at 60 ° C for 30 seconds. After several hours, the transdermal and epidermal layers are separated using a sharp knife. The skin is then spread evenly on a glass plate, and the epidermal layer is lightly pressed with a 0.2 mm long needle.

Then, cut to a certain size, placed in a diffusion cell for drug delivery, put insulin solution on one side, and filled with physiological saline on the other side, and then passed a current through the electrode connected to the diffusion cell for a predetermined time. Samples are taken from cells that do not exist and the amount of insulin permeated is determined by HPLC.

HPLC conditions for quantifying insulin were as follows.

The instrument uses Waters, the pressure of the pump is 8.5 atm, the flow rate is 0.5ml / min, the wavelength of the detector is 214m, the separation column is NOVA-PAK C ₁₈ , the sensitivity is 0.1AUFS, The composition A was prepared by mixing 650 ml of water containing 1 ml of CF ₃ COOH and 350 ml of acetonitrile. A solution B was prepared by mixing 750 ml of water containing 1 ml of CF ₃ COOH and 250 ml of acetonitrile. The ratio of solution A and solution B was mixed again at 60/40.

In vitro experiments are performed after intravenous injection of Alloxan into New Zealand laboratory rabbits to cause diabetes.

Injectable solution is injected with a oxalic acid (125mg / kg) in a 10% solution of saline solution every 2 to 3 days once a day. When the blood sugar is 200mg / dl or more, water and food are freely supplied, and the hair is removed on both sides of the back and experimented after 24 hours.

The patch described above is attached to the dorsal area, a current is passed for a certain time, and blood is collected from the animal's ear vein, and the blood glucose is measured using a glucometer.

The results of in vitro experiments show that the results of the comparison between the treatment with and without the electrocution and those with and without the skin needle are shown in Table 2.

TABLE 2

* Experimented in vitro with rat skin and analyzed by HPLC

When the current did not pass, the amount of insulin delivered through the skin could not be confirmed, and the skin treated with acupuncture needles had a 10-fold increase in permeation rate compared to normal skin.

In addition, when the current was in the form of a pulse, the insulin delivery amount was 1.5 times or more even though the current was about 3 times lower than the DC power.

This fact indicates that normal iontophoresis cannot be used to supply insulin for the human body without using acupuncture needles. However, the use of acupuncture needles can provide sufficient insulin (10 to 80 IV / 1 day) for diabetics. will be.

Next, the amount of insulin penetrating the skin with time after energizing the electric flow for 60 minutes is shown in Table 3 below.

The current type used pulse current and the electrical and analysis conditions are the same as in Table 2 above.

TABLE 3

* Value analyzed by HPLC after experiment in vitro with rat skin

The permeation amount of insulin increased rapidly during the 6 hours after the electrotreatment, and then the release amount gradually decreased.

It is assumed that the skin tissue is in a relaxed state as mentioned above, as the passage generated by the dermis passes through a continuous current and a solvent containing insulin.

In addition, the decrease in the amount of permeation after 6 hours is considered to be due to the obstruction of the permeation of insulin as the relaxed tissue gradually recovers.

On the other hand, in vitro experiments, the amount of insulin delivered through the abdominal skin of rats is as shown in Table 4 below.

TABLE 4

* For each case of skin needle, it is based on 1mm in length, 10 in number and 0.1mm in thickness.

In addition, the results of comparing the blood glucose reduction of insulin through rabbit skin with normal skin and acupuncture skin in the in vivo experiment are shown in Table 5 below.

TABLE 5

* Value measured 1 hour after treatment

In addition, the blood glucose decrease with time after treatment was applied to rabbits weighing 3 kg by applying a solvent containing 3.5 mg / ml of phenol and 80 mg / ml of sodium salicylate to skin blisters containing 150 units of insulin. The ratio (%) is shown in Table 6 below.

TABLE 6

In other words, rabbit skin was treated with acupuncture needles and the blood glucose reduction ratio caused by the delivery of insulin through the current was measured over time. As a result, it showed a rapid decrease in blood glucose after 2 hours and gradually increased over time. .

The above results show a similar tendency to the diffusion cell test results in vitro shown in Table 3. This is considered to have overcome the problems caused by the literature published so far, that is, the effective blood glucose concentration duration of insulin is 2-3 hours, and the problems caused by skin wounds.

On the other hand, the change in blood glucose with respect to the adhesion time shown through FIG. 3 shows that the blood glucose can be reduced by passing a current every predetermined time after the insulin is administered in a patch form. As a result, the permeation resistance of the epidermal layer decreases by forming the insulin permeation pathway in the epidermal layer, so that the permeation pathway is kept open due to the orientation of the skin tissue protein from which the current is removed. .

In addition, after about 20 hours, the oriented protein in the permeate passage is restored to its original form, and when the amount of permeation decreases, if the current is repeatedly passed, the original restored protein is oriented again and the delivery of insulin is rapidly increased, so that the same form Will be displayed.

The blood glucose reduction in rabbits showed a similar trend as the results obtained in the diffusion cell experiment (Table 2). Glucose decrease was less than 15% in rabbits of normal skin, but up to 61% was reduced in case of using acupuncture needle and current flow.

Claims (7)

In the transdermal administration of insulin using a patch type administration device, the insulin is contacted with one or more insulin solvents selected from a protic solvent, a salt buffer solution, and an aqueous solution of an acid or a base and the insulin stabilizer. While increasing the degree of ionization at the same time as the monomerization, and using a plurality of dermal needles to form an insulin delivery path in the epidermal layer, through which the ionized insulin is delivered into the skin by electrical force, characterized in that Transdermal administration of insulin. The method of transdermal administration of insulin according to claim 1, wherein at least one selected from dimethyl sulfoxide, dimethyl sulfolane, and 5,5-dimethyl-1,3-cyclohexanedione is used as the semiprotic solvent. The method for transdermal administration of insulin according to claim 1, wherein the salt buffer solution is selected from one or more of sodium acetate, sodium salicylate, sodium glycocholate, sodium chloride and phosphate. The method of transdermal administration of insulin according to claim 1, wherein at least one selected from acetic acid, hydrochloric acid, salicylic acid, phosphoric acid, citric acid and oxalic acid is used as the acid. The method of transdermal administration of insulin according to claim 1, wherein the base is selected from caustic sodium, potassium hydroxide or ammonia. The method of transdermal administration of insulin according to claim 1, wherein phenol, glycerin or m-cresol is used as the insulin stabilizer. The method of transdermal administration of insulin according to claim 1, wherein the current used is 10 to 500 mA / cm 2 or in direct current or pulse flow.

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