KR100403051B1 - Composition of matrix type patch for transdermal testosterone delivery and process for preparing the same - Google Patents

Abstract

The present invention is impermeable to a drug adhesive layer and testosterone comprising 2 to 8% by weight of testosterone or a salt thereof, 25 to 80% by weight of a tacky polymer material, 2 to 5% by weight of a dissolving aid, and 1 to 5% by weight of an absorption accelerator. The present invention relates to a simple substrate-type transdermal absorption patch containing a support, which significantly increases the rate of skin penetration of testosterone, and thus, adheres to general skin such as belly, back, and abdomen as well as skin under the scrotum, unlike the conventional simple matrix-type transdermal absorption formulation. Even if it can exhibit sufficient efficacy.

Description

Composition of matrix type patch for transdermal testosterone delivery and process for preparing the same}

The present invention relates to a transdermal absorbent formulation containing testosterone or a salt thereof as an active ingredient, and a method for preparing the same. More specifically, the testosterone crystal is not formed even after prolonged periods of time, and thus it is convenient to use by increasing the transdermal absorption amount. The present invention relates to a simple substrate-type transdermal absorption patch having low skin irritation and a method of manufacturing the same.

To date, various transdermal formulations have been proposed, which fall into three broad categories.

That is, i) a reservoir type in which a drug is encapsulated in a polymer membrane, ii) a monolithic type in which a drug is mixed and dispersed in a polymer matrix, and iii) a drug storage layer containing a drug. ), A laminated type composed of a multilayer structure such as an adhesive layer attached to the skin, a backing layer, and a release control membrane (membrane) that controls the release rate of the drug while being positioned between the skin and the drug storage layer ( laminated type).

In recent years, however, simple substrate types have been developed that require less skin irritation due to low amount of solvent use and simple manufacturing process and manufacturing process, which takes up most of the commercially available products.However, testosterone has a very poor percutaneous absorption. As a type, only products with limited application areas to the scrotum have been developed.

Percutaneous administration of the drug is better than other methods of administration to avoid the first-pass effect of drug degradation or metabolism in the liver and gastrointestinal tract to inactivate the drug. As a result, the bioavailability of the drug is increased to avoid side effects caused by unwanted metabolites, and the desired drug concentration can be obtained with low dosage and low frequency. In addition, it is possible to minimize the deviation in the patient and the deviation between patients with respect to the gastrointestinal tract or metabolism, and there is an advantage that the effect of the drug can be enhanced by maintaining a constant drug concentration in the body.

On the other hand, testosterone deficiency symptoms, or sexual dysfunction, which occurs in about 1% of men aged 20 to 50 years, are the main cause of aging and are associated with diseases such as diabetes, cancer, kidney failure, and AIDS. Testosterone preparations used to treat such testosterone deficiency symptoms are commercially available in tablets, injections, pellets, and the like, and US Patent No. 5,116,606 discloses a topical solution preparation of testosterone. In addition, in the case of oral administration of testosterone, the absorbed testosterone is widely metabolized in the gastrointestinal tract and liver, and has a short half-life, so it is troublesome to take it 2-3 times a day, and intramuscular injections or pellets are accompanied by pain. Inconvenience is required for improvement. In order to solve these problems, administration of testosterone via transdermal absorption has been studied.

Representative examples of transdermal absorption agents of testosterone are disclosed in US Pat. Nos. 4,704,282 and 5,152,997 and the like. US Pat. No. 4,704,282 discloses a patch consisting of a reinforcing means serving as a support, a polymer matrix layer containing testosterone at a subsaturated concentration, and a desorption layer that is removed during use while protecting the formulation from the external environment. It is starting. The reinforcing layer acts as a secondary reservoir of testosterone and has an effect of constantly controlling the release rate. However, this patch is inconvenient to be applied to male scrotum, and there is a side effect of generating a lot of dehydrotestosterone (DHT), a metabolite of 5α-reductase which is ubiquitous in scrotum. In addition, while the normal effective amount of testosterone is about 5 to 10 mg per day, there is a problem that only about 3.7 mg per day is absorbed from the patch. U. S. Patent No. 5,152, 997 discloses a reservoir patch consisting of a drug, an absorption accelerator and a gelling agent and a means for retaining the reservoir layer. Glycerol monooleate and methyl laurate were used as absorption accelerators. This patch is designed to adhere to the skin of the whole body except the scrotum and has a very high skin absorption rate. However, the patch is manufactured as a storage type, which makes the manufacturing process more cumbersome compared to the simple substrate type, and increases the manufacturing cost. There is this.

Typically, absorption enhancers are used to enhance the skin penetration of drugs. For example, US Pat. No. 4,906,463 uses fatty acid esters of C ₂ -C ₄ alkanediols and fatty alcohol alcohols, and European Patent Application No. 430,491. Oleic acid and propylene glycol were used in combination with ethylene glycol or polysorbate 80 in European Patent Application No. 328,806, and in combination with propylene glycol monolaurate and diethylene glycol monoethyl ether in US Pat. No. 4,973,468, US Pat. No. 4,942,158 Isopropyl and isobutyl alcohol are used in the arc, and US Pat. No. 4,438,139 uses polyvinylpyrrolidone, polyvinyl alcohol and glycerol in combination. In addition, US Pat. No. 5,122,383 used sorbitan esters as absorption accelerators.

However, the absorption accelerators used in the above known methods have limitations in increasing skin absorption, and in the simple substrate-type transdermal dosage form of steroidal drugs such as testosterone, prevent the formation of crystals over time. The problem is that it is not easy to do.

The present inventors have completed the present invention by discovering a method for producing a formulation that achieves a desired skin absorption rate by selecting an excipient that enhances the solubility of the drug in the drug adhesion layer while assisting the body absorption of the drug, and prevents the formation of crystals in the drug adhesion layer. Was done. Patent related to the prevention of crystal formation is European Patent No. 0304227A2, which is different from the present invention because it is limited to preventing crystalline hydrate when dispersing a solution in a non-aqueous matrix. The present inventors have applied testosterone or salts thereof to the skin. The present invention has been completed by finding a dissolution aid that can contain a drug in a high concentration and an absorption promoter that can increase the amount of absorption.

An object of the present invention is a simple substrate-type transdermal absorption patch containing testosterone, which has no crystallization for a long period of time, enhances transdermal absorption and adheres to general skin under the scrotum, and thus does not have gastrointestinal disorders of the active ingredient. In addition to preventing side effects, testosterone supplements provide a transdermal formulation that can minimize side effects from important and long-term administration.

1A and 1B are cross-sectional views showing the structure of a simple substrate-type transdermal absorbent according to the present invention.

<Description of Symbols for Main Parts of Drawings>

1 support 2 release layer

3 drug storage monolayer or multilayer

The present invention is impermeable to a drug adhesive layer and testosterone comprising 2 to 8% by weight of testosterone or a salt thereof, 25 to 80% by weight of a tacky polymer material, 2 to 5% by weight of a dissolving aid, and 1 to 5% by weight of an absorption accelerator. Provided is a simple substrate-type percutaneous absorption patch including a support and a method for preparing the same. The structure of the percutaneous absorption patch according to the present invention is illustrated by FIG. 1 is a cross-sectional view illustrating the structure of a simple substrate-type transdermal absorbent type according to the present invention. The simple substrate-type transdermal absorbent formulation of the present invention contains an impermeable support (1), a testosterone, a dissolving aid, a surfactant, and an accelerator for adsorbing the skin while imparting adhesion to the skin (3). And, if necessary, a peeling layer 2 that can be easily removed can be added during use while protecting the transdermal administration system from the external environment (FIG. 1A). In addition, as shown in Figure 1b, in order to improve the skin absorption of the drug may be added a drug adhesive layer.

When the effective drug of the transdermal absorption patch according to the present invention is testosterone, the preferred skin absorption rate is usually 2.0 to 12.0 µg / cm ² / hr, and in some cases, the skin absorption rate can be changed by appropriately adjusting the skin absorption regulators. It shows a penetration rate of 4.0 µg / cm ² / hr or more in general human skin.

The present invention relates to a percutaneous absorption patch, specifically, testosterone or salts thereof dissolved in a matrix of adhesive material to enable continuous administration, and attached to the skin to allow transdermal administration of the drug for a certain time, and testosterone and salts thereof. It relates to a transdermal absorption patch containing.

Testosterone or a salt thereof as an active ingredient in the present invention can be administered in the form of a transdermal absorption patch so that the first pass effect can be avoided and the constant administration can be continuously performed while almost preventing side effects in the body.

In particular, as the salt of testosterone usable in the present invention, testosterone propionate, testosterone enanthate, testosterone cypionate, methyltestosterone or dihydroepiandrosterone and the like can be used. In addition, in order to absorb testosterone or its salts into the skin, the drug may be contained in a high concentration or the absorption may be increased by using an absorption accelerator.

The main feature of the present invention is that it can be contained in the base at a high concentration by acting as a solvent to dissolve the drug in the base by using a specific absorption accelerator and a high solubility aid that is compatible with testosterone or salts thereof. It is to increase the skin penetration of the drug.

Hereinafter, the present invention will be described in detail.

The present invention is impermeable to a drug adhesive layer and testosterone comprising 2 to 8% by weight of testosterone or a salt thereof, 25 to 80% by weight of a tacky polymer material, 2 to 5% by weight of a dissolving aid, and 1 to 5% by weight of an absorption accelerator. Provided is a simple substrate-type transdermal absorption patch including a support and a method of preparing the same.

The adhesive polymer used in the present invention may be a water-based or organic solvent-based materials as a pressure sensitive adhesive (PSA) capable of mixing with a medical drug. The polymer material not only functions as a carrier of the active ingredient, but also adheres to the skin, and adheres to the skin to secure the drug storage layer 3 (see FIGS. 1A and 1B). It will play a role in giving diffusion.

The pressure-sensitive adhesive is 1) alkyl acrylate or methacrylate having an alkyl acrylate or methacrylate composition ratio of 50 to 90% having 4 to 12 carbon atoms of the alkyl monomer and having 12 to 26 carbon atoms having many alkyl groups. The ratio of the rate is 10 to 50%. Moreover, in order to raise adhesive strength, the adhesive which introduce | transduced the monomer which has a polar group in the range of 0.1-0.5% as a crosslinking agent is introduce | transduced as a polymeric material of this drug delivery system. As such a polymer material, for example, a copolymer of acrylate may be used, and more specifically, one composed of 2-ethylhexyl acrylate may be used, 2) an adhesive obtained by synthesizing the acrylic monomer in water, and 3) an elastomer. The adhesive which mixed suitably the thing whose molecular weight of polyisobutylene is large and small is used.

Such polymer materials are added in an amount of 25 to 80% by weight based on the total composition. If the amount of the polymer is less than 25% by weight, the transport and storage capacity of the active ingredient is not only low, but also the adhesion and diffusion are poor, and thus the efficiency of use of the skin is reduced. There is a problem that greatly decreases and when the amount is more than 80% by weight, the effect of lowering the transdermal administration effect is lowered because the concentration of the active ingredient is relatively low, there is a problem that the administration effect is worsened because the content of components such as dissolution aids and absorption accelerators is relatively reduced.

In addition, according to the present invention, the testosterone or its salt, which is an active ingredient mixed together in the polymer material, is contained in an amount of 2 to 8% by weight, based on the total drug storage layer. Since the drug remains in the crystalline state in the storage layer, the penetration effect is lowered and side effects such as skin irritation occur.

Meanwhile, as a dissolution aid used in the male hormone transdermal absorption patch of the present invention, an active ingredient such as testosterone or a salt thereof is maintained in a high concentration of dissolution and a solvent that acts as an absorption accelerator is used. When less than%, since the effective ingredient is not completely dissolved, the administration effect is greatly reduced, and an excess of more than 5% by weight is unnecessary because it cannot maintain the form of the matrix. As such a dissolution aid, for example, propylene glycol monolaurate, polyoxyethylene oleyl ether, diethyl toluamide, ethyl alcohol, methyl alcohol, isopropyl alcohol, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, polyethylene glycol, propylene Glycol, polyoxyethylene ester, alkanolamines, alkylamines, diethylene glycol monoethyl ether and N-alkyl pyrrolidone or a mixture of two or more thereof may be used.

In addition, the absorption accelerator used in the male hormone transdermal absorption patch of the present invention is used to enhance the skin penetration effect of the active ingredient, for example, alkylene glycol derivatives, azacycloalkanes, fatty acids and esters thereof, fatty acid alkanols. Amides or polyethylene glycol derivatives, surfactants, alcohols, azones, terpene oils and the like can be used. Specifically, propylene glycol, 1-dodecylazacycloheptan-2-one, 1-[(2-decylthio ) Ethyl] azacyclopentan-2-one (HPE-101), lauricethanolamide or polyethylene glycol 200 monolaurate, polyethylene glycol 300 monolaurate and polyethylene glycol 400 monolaurate, capric acid, oleic acid, linol Rainic acid, lauroylsalcoxine, linolein alcohol, monooleyl-lac-glycerol, mineral oil, polyoxyethylene sorbitan monooleate, sorbitan mono Oleate (SMO), 1-menthol, peppermint oil, d-limonene, azone, diethylene glycol monoethyl ether, dodecylamine, diethyltoluamide (DEET) or a mixture of two or more thereof may be used.

If the absorption accelerator is used in an amount less than 1% by weight, there is no additive effect. When the absorption accelerator is used in an amount greater than 5% by weight, the adhesion decreases and it becomes difficult to maintain the shape of the matrix.

The male hormone transdermal absorption patch according to the present invention preferably further comprises a release layer attached to the drug storage layer so as to be peelable.

Specifically, the male hormone transdermal absorption patch according to the present invention is composed of a drug storage layer (matrix) 3 sandwiched between the support 1 and the release layer 2 as shown in FIG.

According to the present invention, the drug storage layer is composed of a single layer or a multilayer including an active ingredient to control the release rate of the active ingredient, and specifically, contains a tacky polymer material, a dissolution aid and an absorption accelerator in a certain component ratio.

In the transdermal absorbent preparation according to the present invention, the drug storage layer 3, which is substantially the core of the diffusion matrix for transdermal administration of the active ingredient, may have a multi-layer structure as shown in FIG. 1B.

The drug storage layer 3 is formed by applying and drying on the non-permeable support 1, it is possible to form the drug storage layer 3 in a multi-layer if necessary. In this case, for convenience of manufacture, the composition of each layer constituting the drug storage layer 3 is the same, or the composition is changed differently so that the layer located farthest from the support 1 enables the fastest skin penetration. The layers may be formed to overlap each other so that the case where the diffusion penetration rate of the active ingredient is the lowest is located closest to the support 1. At this time, about 3 layers of a multilayer are preferable.

The support that can be used in the transdermal absorbent preparation of the present invention is not particularly limited, but it is preferable to have flexibility such that it does not cause significant discomfort when affixed to the skin surface. For example, polyethylene, polypropylene, polyester, polyvinyl acetate Plastic films such as ethylene-vinyl acetate copolymer, polyvinyl chloride and polyurethane, metal foil such as aluminum foil and tin foil, single-layer films made of nonwoven fabrics, textiles, paper and the like, and laminated films thereof. In addition, it is preferable that these supports be subjected to corona discharge treatment, plasma treatment, oxidation treatment or the like on the base layer formation surface in order to improve the adhesion with the base layer and the adhesiveness. The transdermal absorbent of the present invention is preferably covered with a release liner such as a paper or a plastic film subjected to a release treatment by applying a silicone resin, a fluororesin, or the like to the exposed surface of the base layer until just before adhesion to the skin surface. In the present invention, after forming the drug storage layer (3) in a single layer or a multi-layer on the non-transparent support (1), the release layer (2) is attached, the release layer (2) is the same as a polyethylene film coated with a conventional silicone It is okay if it is used.

When explaining the manufacturing process of the testosterone transdermal absorption patch of the present invention in detail, the active ingredient is prepared and mixed with a dissolution aid and absorption accelerator to make a solution or suspension, and then added to the polymer material for 20 to 30 minutes Mix for 20 to 60 minutes and remove bubbles. The mixture is applied to a transparent polyethylene film prepared as the non-transparent support 1, 100-250 µm and dried at 80-110 ° C. for 10 minutes to form a drug storage layer 3, and then covered with release paper thereon. The size of the patch is preferably 5 to 80 cm ² .

At this time, in order to create a matrix state of a multilayer structure, the mixture is prepared by continuously applying or superimposing the mixture on the first formed matrix in the same manner.

The transdermal absorption patch according to the present invention prepared as described above is applied to the skin by removing the exfoliation layer (2) and attaching the exfoliation of the exposed drug storage layer (3) to the skin drug storage layer by the adhesive polymer material The exfoliation site of (3) is attached to the skin, and then the active ingredient mixed with the polymer material in the state of being dissolved in the dissolution aid in the drug storage layer (3) and dispersed throughout the drug storage layer (3) is released from the matrix. It diffuses with the absorption accelerator and begins to be absorbed into the stratum corneum.

At this time, the absorption promoter promotes percutaneous diffusion into the circulatory system through the skin for the active ingredient.

On the other hand, since the non-permeable film is covered on the support 1 positioned opposite the release layer of the drug storage layer 3, it prevents the drug from leaking or contamination from the outside.

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

<Example 1>

2% by weight of testosterone (TS), 5% by weight of sorbitan monooleate (SMO) as a surfactant, and an absorption accelerator having a composition as shown in Table 1 below were added to a polyacrylate-based pressure-sensitive adhesive AS-923 which is a tacky polymer. Stir well until dissolved or evenly mixed in the tacky polymer solution. The mixed solution was poured onto the Scotch Pack 1109, which is an impermeable support, to coat the substrate layer, and then continuously dried while raising the temperature stepwise from 80 ° C. to 120 ° C. for 10 minutes. At this time, the coating thickness was 100 µm. The final product was obtained by attaching the release paper on the coated adhesive substrate layer and cutting it to 20 cm ^2. The abdominal hair of a male rat weighing about 220 g was cut with an electric hair clipper, and then cut off a portion immediately. It was used for the test. The skin is placed in the middle of the Franz-type diffusion cell with the stratum corneum face up, and then 40% polyethylene glycol (PEG) 400 buffer is added to the bottom space and the temperature of the diffusion cell is 37 Keep the temperature. The receptor solution (buffer solution / polyethylene glycol 400) was adhered to the transdermal absorbent prepared according to the above example by agitating at a constant speed (500 rpm) and fixed with a clip. The transdermal flux of testosterone and its salts was determined by HPLC analysis of the amount of testosterone and its salts absorbed into the diffusion cell through the skin for 48 hours. Meanwhile, crystal formation was observed while preserving at 25 ° C. for 4 months.

<HPLC operating condition>

Column: Cosmosil 5C18, (5㎛, 4mm × 150mm, Nacalai Tasque., Japan)

Mobile phase: Acetonitrile / 50 mM acetic acid buffer solution (pH 4.0), 40: 60

Detector: UV absorbance photometer (wavelength: 242 nm)

Flow rate: 1.0 ml / min

* Degree of crystal formation: 0 to 5 (0: No crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in the above results, the skin absorption rate of testosterone was good in order of oleic acid and capric acid, and some crystals of lauryl acid were observed at 4 months.

<Example 2>

2% by weight of testosterone (TS), 5% by weight of sorbitan monooleate as a surfactant, and an absorption accelerator having a composition as shown in Table 2 below were mixed to a total of 100% by weight of a polyacrylate-based adhesive AS-923 as a tacky polymer material. After the experiment in the same manner as in Example 1 and the results are shown in Table 2.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

The results showed that oleic acid was the best for skin absorption of testosterone.

<Example 3>

100% by weight of 2% by weight of testosterone (TS), 5% by weight of sorbitan monooleate as a surfactant, and an absorption accelerator having a composition as shown in Table 3 were added to the polyacrylate adhesive AS-923 as a tacky polymer. After mixing so as to experiment in the same manner as in Example 1 and the results are shown in Table 3.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

In the above results, testosterone showed an excellent skin absorption rate in the order of lauroyl alkoxin and oleoyl alkoxin, and no crystal was observed in the case of lauroyl alkoxin or oleyl alkoxin.

<Example 4>

2% by weight of testosterone (TS), 5% by weight of sorbitan monooleate as a surfactant, and 100% by weight of a polyacrylate adhesive AS-923, which is a tacky polymer, were added to an absorption accelerator having a composition as shown in Table 4 below. After mixing so as to experiment in the same manner as in Example 1 and the results are shown in Table 4.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

In the above results, dodecylamine and lauroylsalcoxine were found to have excellent skin absorption rate of testosterone, and no crystal was observed in the case of dodecylamine.

<Example 5>

Example 1 after mixing 2% by weight of testosterone (TS), 1% by weight of dodecylamine and a surfactant having a composition as shown in Table 5 to 100% by weight of a polyacrylate-based pressure-sensitive adhesive AS-923 as an adhesive polymer material The experiment was carried out in the same manner as shown in Table 5.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in the above results, when sorbitan monooleate was 10% by weight, the skin absorption rate of testosterone was the best and no crystal was formed.

<Example 6>

After mixing 2% by weight of testosterone (TS) and 10% by weight of span 80 to 1,3,5% by weight of dodecylamine, polyacrylate-based adhesive AS-923, which is a tacky polymer, was mixed to a total of 100% by weight. Experiments were carried out in the same manner as 1, and the results are shown in Table 6.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in the above results, as the weight percent of dodecylamine increased, the skin absorption rate of testosterone was good, but crystals were formed at 5% by weight of dodecylamine and determined as 3% by weight.

<Example 7>

Testosterone (TS) 2% by weight, the absorption accelerator and the dissolution aid having a composition as shown in Table 7 were mixed to a total of 100% by weight of the polyacrylic adhesive AS-923 as an adhesive polymer material and then tested in the same manner as in Example 1 The results are shown in Table 7.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in this experiment, among the various dissolution aids used to increase the solubility of testosterone, the skin absorption promoting effect was good for the skin absorption with high diethyltoluamide and hardened castor oil.

<Example 8>

After mixing testosterone and testosterone propionate gigak 2, 4, 6 and 8% by weight of the absorption accelerator having a composition as shown in Table 8 to 100% by weight of the total polyacrylate pressure sensitive adhesive NS 87-2510 Experiments were carried out in the same manner as in Example 1, and the results are shown in Tables 8 and 9.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in the above results, the highest skin absorption was observed at the testosterone concentration of 8%, but the crystal was precipitated, and at 6%, the skin absorption was high at 6.51㎍ / cm ² / hr and no crystal was precipitated.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

In the case of testosterone propionate, more crystals were precipitated than testosterone, and when the skin absorption rate was 8%, the testosterone propionate dropped to 3.15 µg / cm 2 / hr.

Example 9

Polyacrylate-based adhesive NS 87- which is a tacky polymer material in diethyltoluamide 2, 3.5 and 5% by weight, 6% by weight of testosterone (TS), 10% by weight of sorbitan monooleate, and 3% by weight of dodecylamine. After mixing 2510 to a total of 100% by weight, the experiment was carried out in the same manner as in Example 1 and the results are shown in Table 10.

* Degree of crystal formation: 0 to 5 (0: no crystal is observed during storage

5: quite a lot of decisions are observed during the storage period)

As shown in the above results, when the concentration of diethyltoluamide was 3,5%, it showed the highest skin absorption and no crystal was formed.

<Example 10>

6% by weight of testosterone (TS), 10% by weight of sorbitan monooleate, 3% by weight of dodecylamine, and 3.5% by weight of diethyltoluamide were mixed with a polyacrylate-based adhesive Duro-Tak 87-2510, an adhesive polymer material. After mixing to 100% by weight in total, a patch was prepared in the same manner as in Example 1, and the results of experiments on the penetration of human skin and rat skin were as shown in FIG. The rate of penetration of TS through the skin of rats and humans was 10.44 μg / cm ² / hr and 4.74 μg / cm ² / hr, respectively.

Figure 1. Permeation Pattern of Testosterone Through the Skin of Rats and Humans

If you make a patch of 45 ~ 50cm ² using the above prescription, you can get 5.1 ~ 5.7mg of drug absorption in human skin for 24hr. It will do more than that.

Experimental Example 1

In Example 8, 8-3 patches (A), storage type conventional products (B), and simple matrix type conventional products (C) prepared as shown in Table 8 were attached to the abdomen of white rats, and the tail vein was fixed at regular intervals. The result of measuring the TS concentration in the blood by blood sampling is shown in Figure 2. 8-3 Patch (A) is a simple substrate type, but superior to the existing simple substrate type (C) and can be seen to show an excellent blood concentration even when compared to the existing product (B) of the storage type. As a result of this experiment, it seems that 8-3 patch (A) has both advantages of simple substrate type with low manufacturing cost and attachment to whole body skin.

Figure 2. Comparison of Plasma Testosterone Concentrations with Existing Products after Attaching to Rat Abdomen

Experimental Example 2

Sixty male volunteers were evaluated for skin irritation according to the Examples, 10 for each transdermal absorption preparation.

The transdermal absorption agent was attached to the back of the volunteer for 24 hours, and then removed. The change of erythema, edema and more skin condition was observed after 12, 24, and 48 hours. The results according to the main example showed skin irritation (erythema or mild edema) when 15 wt% of surfactant (span 80) was used in the case of 5-3 prescription as shown in Table 11, and as a dissolution aid in the case of 7-8 prescription. When 5% by weight of cured castor oil was used, mild erythema appeared only at the beginning (12 hours) of application, and other prescriptions did not show skin irritation.

When the male hormone transdermal absorption patch containing testosterone or a pharmaceutically acceptable salt thereof according to the present invention is used as an active ingredient, it is applicable to extra-scrotum skin by inhibiting drug crystallization and increasing transdermal absorption. Easy to use and less skin irritation.

Claims (10)

A transdermal absorption patch comprising a drug storage layer containing testosterone or a salt thereof on a support impermeable to testosterone or a salt thereof, wherein the drug storage layer comprises from 2 to 8% by weight of testosterone or a salt thereof, 67 to 80% by weight. With a sticky polymeric material of 5 to 15% by weight of sorbitan monooleate, 2 to 5% by weight of diethyltoluamide, and 1 to 5% by weight of dodecylamine, lauroylsalcoxine and oleoylsaloxin A male hormone transdermal absorption patch containing an absorption accelerator selected from the group consisting and applicable to extra-scrotum skin. The testosterone transdermal patch according to claim 1, wherein the salt of testosterone is testosterone propionate. delete delete delete The male hormone transdermal absorption patch according to claim 1, wherein the tacky polymer material is a copolymer of alkylacrylate or methacrylate. The testosterone transdermal absorption patch of claim 1, further comprising a release layer attached on the drug storage layer. The testosterone transdermal absorption patch of claim 1, wherein the drug storage layer is composed of a single layer. The testosterone transdermal absorption patch of claim 1, wherein the drug storage layer is formed of a multilayer. delete