JPH05367B2 - - Google Patents

Description

[Detailed description of the invention]

<Industrial Application Field> The present invention relates to an insulin-containing skin patch having a hypoglycemic effect. More specifically, the present invention comprises a drug carrier containing insulin and a heating body provided on the opposite side of the surface of the drug carrier to be applied to the skin, and the drug carrier and the heating body The present invention relates to an extremely useful insulin-containing heating skin patch that is substantially integrated with the above and is capable of fully exerting the pharmacological action of insulin due to the presence of a heating element. <Prior art and problems to be solved by the inventors> Various insulin injections (quick-acting injections, slow-acting injections, etc.) are used in the medical field for the treatment of diabetes. Frequent injections are required over a period of time, and in many cases diabetic patients administer the injections themselves under the supervision and guidance of a doctor, which not only causes physical pain for the patient, but also leads to insulin overload. The reality is that side effects such as hypoglycemia, induration at the injection site, and bacterial contamination at the injection site cannot be ignored. In order to avoid hypoglycemia due to insulin overdose, the closed-loop method (Yamazaki et al., Drug Delivery System Vo1.2 No.1,
22-27, 1987), but it required a microneedle sensor for continuous blood glucose measurement and an insulin injection needle to be placed in the subcutaneous tissue, and the long-term reliability of the sensor and the need to keep the injection needle in the subcutaneous tissue were considered. It has not yet been put into practical use because it is not sufficiently safe in terms of biological reactions and other factors when left in place for a long period of time. On the other hand, the patient's physical pain, induration at the injection site,
To avoid bacterial contamination, nasal insulin-containing preparations (Nagai, Advance in Drug Delivery
System, 131-134, 1986 Elsivier), but it cannot be ruled out that some of the excipients contained in insulin and the same preparation may pass through the nasal cavity and directly reach the lungs. , has not yet been put into practical use. In addition, insulin-containing suppositories (Ichikawa et al.
J.Pharm.Pharmacol.32, 314, 1980) was also studied, but the bioavailability of insulin was not necessarily satisfactory and it has not yet been put to practical use. Furthermore, as an insulin-containing patch,
WO85/05036 is known, and dimethyl sulfoxide, dimethylacetamide, dimethylformamide, etc. are indicated as absorption enhancers. However, it has been pointed out that these substances are irritating to the skin, and doubts remain from a safety perspective.Furthermore, the blood sugar-lowering effect shown in the examples is extremely weak compared to the amount of insulin used, so it is difficult to put them into practical use. This is considered to be far from the case. As an absorption enhancer for insulin-containing suppositories, polyoxyethylene nonyl phenyl ether, di-2
-Sodium ethylhexyl sulfosuccinate and glycolic acid are effective (New formulation development system comprehensive technology 225-226, R&D planning 1985)
It is known. However, since the rectal mucosa is part of the digestive tract, it is highly absorbent and is the ideal organ for drug absorption, whereas the skin is an organ with a strong barrier layer to prevent foreign substances from entering. Therefore, it is clear from the difference in physiological function and anatomical structure between the two organs that it is not necessarily the best absorption site for drugs. Furthermore, since the physical properties of the base used in insulin-containing suppositories and insulin-containing skin patches differ, the dispersion state of insulin in the base differs. The composition of tissue components at the application site (rectal mucosa and skin) is different, and the physical properties of the base used are different, so the distribution rate of insulin between the application site and the base is different. It is clear that the application of the former absorption enhancer to the latter cannot be expected to give satisfactory results since these are markedly different. In addition, regarding insulin absorption enhancers,
There was no prior knowledge that examined the relationship between heating temperature and absorption promotion effect. On the other hand, as preparations that are expected to be more effective by transdermally administering drugs and heating them for a predetermined period of time, there are thermal poultices (for example, Japanese Patent Publication No. 60-12831) and thermal plasters (for example, Japanese Patent Publication No. 61-93114). Publication No.) is known. The former uses salicylic acid, methyl salicylate, and glycol salicylate as exemplary drugs, and the latter uses methyl salicylate, l-menthol, dl-camphor,
It lists salokol, thymol, vitamin E acetate, etc. However, as stated in the 11th revised Japanese Pharmacopoeia General Rules for Preparations in the "Commentary" section for cataplasms, preparations containing the above ingredients may cause bruises, sprains, and
These are preparations that are expected to have local effects such as stiff shoulders and muscle pain.Moreover, if a preparation containing a volatile drug is applied to the patch under heat for a specified period of time, the drug will volatilize and transfer to the skin, increasing the local pharmacological effect. This can be easily imagined from the statement in the ``Explanation'' section that ``Originally, poultices are warmed before use, and the drug is allowed to act in the presence of water and heat...'' However, insulin cannot be expected to be as volatile as the above-mentioned analgesic and anti-inflammatory drugs. This is a preparation that is expected to have a systemic effect (hyperglycemic lowering effect) through the absorbed drug. In this respect, they are completely different in terms of the physical properties of the drugs and the expected pharmacological effects. As described below, nothing was known about the pharmacological effects of drugs that are not expected to be volatile, especially insulin, when the drug is contained in a skin patch and applied to the skin after heating. The present inventors focused on insulin skin patches due to their ease of use, and in view of the problems of the prior art as described above, the inventors of the present invention have developed an insulin patch that can sustainably and sufficiently exert the pharmacological action of insulin. As a result of extensive research in order to obtain a formulation that is highly effective and clinically useful, we have arrived at the present invention. <Means for Solving the Problems> As a result of intensive studies by the present inventors, it has been found that in the case of insulin-containing warming skin patches, when a specific absorption enhancer is used in combination, the absorption of insulin is significantly promoted. In addition, a new finding was obtained that the degree of pharmacological effect of insulin varies depending on the absorption enhancer added. That is, the present invention comprises: (1) a drug carrier containing insulin and a temperature-dependent absorption enhancer; and (2) a heating element disposed on the opposite side of the drug carrier to the surface to be applied to the skin. This is an insulin-containing warming skin patch in which the drug carrier and the warming body are substantially integrated. In the present invention, the amount of insulin absorbed from the drug carrier is increased by integrating the drug carrier and the heating body.
Fully exhibits pharmacological effects. Furthermore, when a self-temperature-controlled heating element is used as the heating element, a preparation can be obtained that allows the diabetic patient to absorb the optimal dose according to his or her blood sugar level. It is possible to achieve extremely useful properties in terms of formulation. Examples of the drug support of the present invention include those in which a base layer containing insulin is provided on a flexible support. Such carriers are particularly suitable if they are flexible enough not to cause a significant discomfort when applied to the skin, and are stable against heat when integrated with the heating element. There are no material restrictions. Examples of such carriers include synthetic resin films such as polyolefin, polyester, polyurethane, polyvinyl alcohol, vinylidene chloride, and polyamide, rubber films, nonwoven fabrics, woven and knitted fabrics, papers, metal foils, and laminates of these. Film is an example. In some cases, such carriers may cause itching or irritation on the skin surface to which they are applied, so carriers that have substantially no moisture permeability, air permeability, or flexibility should be provided with holes or cuts. Appropriate breathability and flexibility can be imparted. Also, as a base material for the base layer, commonly used pressure sensitive adhesives such as alkyl ether, poly(meth)
Acrylate, polyurethane, polyester, polyamide, ethylene-vinyl acetate copolymer, styrene-isobutylene-styrene block copolymer rubber, styrene-butadiene block copolymer rubber, polybutene rubber, polyisopropylene rubber, butyl rubber, silicone rubber, Examples include synthetic resins selected from natural rubber and rubber-based substances. In addition to these, polymers that are soluble in water and/or lower alcohols are preferred as the base material for the base layer, since insulin is easily soluble in water and/or lower alcohols and is difficult to denature. Examples of polymers soluble in water and/or lower alcohols include cellulose-based polymers such as hydroxypropylmethylcellulose and hydroxypropylcellulose, and polyacrylic acid-based polymers such as carboxyvinyl polymer and sodium polyacrylate. However, among these, carboxyvinyl polymer and/or sodium polyacrylate are more preferred. When a polymer soluble in water and/or lower alcohol is used as the base, it is preferable to include a humectant. The amount of insulin added is 0.05 to 5
A range of 0.3 to 2% by weight is desirable because the effects of the present invention are clearly exhibited. The temperature-dependent absorption enhancer of the present invention refers to one that promotes the absorption of insulin through the skin by heating. Such absorption enhancers include, for example, glycerin monostearate, diethyl sebatate, sodium deoxycholate, dipotassium glycyrrhizate, linoleic acid, sodium polyoxyethylene cetyl ether phosphate,
Examples include one or more selected from the group consisting of sodium oleyl phosphate and sodium hyaluronate. Those that do not promote the absorption of insulin by heating, such as polyoxyethylene (7.5)-nonylphenyl ether, sodium di-2-ethylhexyl sulfosuccinate, etc., are not temperature-dependent absorption enhancers of the present invention. . The amount of such absorption enhancer is 1 to 10% by weight, preferably 1 to 5% by weight, based on the base. Examples of the humectant of the present invention include glycerin,
Diols and/or triols of lower hydrocarbons such as propylene glycol are commonly used as humectants, and include insulin,
There are no particular limitations on the material as long as it does not cause undesirable reactions with the polymer, absorption enhancer, etc. used as the base material in the present invention. The amount of such a humectant is preferably 100 to 150% by weight based on the base because the effects of the present invention are clearly exhibited. The drug carrier of the present invention has 5 to
It is obtained by providing the above-mentioned base layer having a thickness of 300 μm and entirely or partially containing insulin. The heating element of the present invention is, for example, a heating element such as a wood ash warmer, a platinum catalyst warmer, or a heating element whose main component is iron powder, an alkali metal sulfide or polysulfide, or a hydrated salt thereof. , a so-called chemical heating element that generates heat by contacting with air or oxygen, or by mixing a substance that generates oxygen through a chemical reaction; a heating element made of a conductive heating substance such as nichrome wire or carbon black; Examples include self-temperature-controlled heating elements such as these, and preheated heat storage bodies (such as ice cubes) in which a material with a large heat capacity is placed in a suitable container as required. In order for the heating element of the present invention to efficiently absorb insulin from the drug carrier and exert the necessary and sufficient pharmacological effects, the heating element described above must be heated at a temperature of 35°C.
It is desirable to use a heating element that can variably maintain any temperature between 60°C and 60°C for 6 to 16 hours, especially between 35°C and 50°C for 8 to 24 hours or more. Among the above-mentioned heating elements, chemical heating elements and self-temperature control type heating elements are preferable as such heating elements. Examples of methods for controlling the temperature of a self-temperature-controlled heating element include (1) a power supply section that has a temperature control circuit that conducts electricity when it is below a certain set temperature and cuts off electricity when it is above a certain set temperature, and a temperature sensor attached thereto; To maintain a heating element at an arbitrary set temperature by keeping the heating element constant. (2) A heating element using a constant temperature heater that utilizes the transfer phenomenon of emulsion, which maintains the set temperature constant depending on the type of constant temperature heater. etc. The insulin-containing warming skin patch of the present invention includes:
It consists of the above-mentioned drug carrier and a heating element located on the opposite side of the surface of the drug carrier to be applied to the skin, and these are substantially integrated. Such integration of the drug carrier and the heating member is achieved by (1) adhering the opposite side of the drug carrier to the side to be applied to the skin and one side of the heating member (for example, providing an adhesive layer on the drug carrier: double-sided tape); , magic tape, etc.),
Or, a method of joining (e.g., hook, chuck, snap, etc.) (2) A method of making a bag-shaped molded product on the back of the drug carrier and inserting a heating element into the molded product (3) A method of folding and layering when used Connect one end of the heating body and one end of the drug support body to a flexible structure (e.g., soft plastic film, fabric, etc.).
Method (4) of bonding can be achieved by a method of forming a drug carrier having an insulin-containing layer by laminating on one side of the heating element. One major feature of insulin skin patches (unlike other administration methods) is that even if hypoglycemia occurs due to an insulin overdose, it can be easily avoided by peeling off the patch from the skin. It is. In addition to the general characteristics of the above-mentioned patch, the insulin-containing heating skin patch of the present invention can administer the optimal amount of insulin required by diabetic patients simply by controlling the heating temperature of the heating element. It is an extremely useful formulation because it has the characteristic of being able to The present invention will be explained in more detail below using examples. Example 1 (1) Preparation of insulin-containing drug support 14.8 mg (379 U) of insulin and 90 mg of sodium deoxycholate were mixed with 30 ml of water and 70 ml of methanol.
After dissolving in a mixed solvent consisting of 4 g of glycerin and mixing, add Carbopol-940 (carboxy vinyl polymer manufactured by BF Goodrich) and dissolve by stirring vigorously. 8,000 to 12,000 cp) was added and stirred to form a uniform dope. This dope was coated on release paper with a 600 μm spacer, dried with air at about 40 to 50°C to remove the solvent, and then coated on 3M surgical tape.
1 (manufactured by Takemoto Yushi Co., Ltd.: copolymer of 2-ethylhexyl acrylate, methyl methacrylate, and acrylic acid) about 10 μm thick was backed with a laminated tape and cut into 3×3 cm ^{2 pieces} to obtain drug carriers. The insulin content of this product was 2U/ ^9cm2 . (2) Measurement of blood sugar fluctuation Two domestic rabbits (weighing approximately 3 kg) whose backs had been depilated in advance (fasted from the evening of the previous day) were used, and this drug carrier was attached to them using a heating element with a temperature sensor attached. (sample a), 40
Blood sugar levels were measured over time for 8 hours after application of the samples heated to 10°C (sample b) and 42°C (sample c). As the power source, a power source (manufactured by Tokyo Gijutsu Kenkyu) having a temperature control circuit was used.
Blood sugar level before application, after application 1, 2, 3, 4, 6, 8
After hours, blood was collected and measured using Glucoscan 300 (manufactured by Eiken Chemical). The results are shown in Table 1. The amount of blood sugar fluctuation was calculated as Po−Pi. Po = Measured value before pasting Pi = Measured value after i hours

[Table] From Table 1, it was confirmed that the decrease in blood sugar level was large depending on the temperature from sample a to sample c, and that the amount of insulin absorbed could be controlled by controlling the temperature. Examples 2 to 3 (1) Preparation of insulin-containing drug support In Example 2, 0.5 g of TC-5 (Hydroxypropyl methylcellulose 2910, manufactured by Shin-Etsu Chemical) was used in place of the sodium polyacrylate in Example 1.
In Example 3, 0.25 g of HPC-M (Hydroxypropylcellulose manufactured by Nippon Soda) was used in place of the sodium polyacrylate in Example 1 to create a drug support in the same manner as in Example 1. . The insulin content of Examples 2 and 3 is
It was 2U/ ^9cm2 . (2) Measurement of blood sugar fluctuation Example 1 using the drug carrier obtained in (1) above
It was administered to domestic rabbits in the same manner as above, and blood sugar levels were measured.
However, heating was performed at only one level, 40°C. The results are shown in Tables 2 and 3.

【table】

[Table] As is clear from Tables 2 and 3, in both Example 2 and Example 3, the 40°C heating type application (sample b) was better than the non-heating type application (sample a). The decrease in blood sugar levels was significant, indicating that the amount of insulin absorbed can be controlled by controlling the temperature. However, in Example 3, delayed absorption of insulin was observed. As a result, it was confirmed that among the water-soluble polymer bases, the base made of carboxyvinyl polymer and sodium polyacrylate is the most preferable. Examples 4 to 10 (1) Preparation of insulin-containing drug support Instead of sodium deoxycholate in Example 1, absorption enhancers shown in Table 4 were used. The amount added was 90 mg in each case. The method for preparing the drug support was the same as in Example 1, and the method for administration to rabbits and the method for measuring blood sugar levels were the same as in Example 2. Examples 4 to 10
The insulin content in each case was 2U/ ^9cm2 . The results are shown in Table 4. For each absorption enhancer, when the patch was heated at 40°C, the blood sugar level decreased more than when it was applied without heating, and heating improved the absorption of insulin. This shows that insulin has the property of increasing the amount of insulin, and that the pharmacological effect (pattern of blood sugar fluctuation amount) of insulin differs depending on the absorption enhancer added. Both absorption enhancers have desirable properties for the formulations of the present invention.

[Table] Comparative Examples 1 and 2 In Comparative Examples 1 and 2, the absorption enhancers shown in Table 5 were used in place of sodium deoxycholate. The amount added was 90 mg. The method for preparing the drug support was the same as in Example 1, and the method for administration to rabbits and the method for measuring blood sugar levels were the same as in Example 2. Comparative examples 1-2
The insulin content in each case was 2U/ ^9cm2 . As shown in Table 5, the results are shown in Table 5. All of the absorption enhancers lower blood sugar levels, but the pharmacological effects of insulin (patterns of blood sugar fluctuations) are different. More importantly, none of the absorption enhancers has the property of increasing the amount of insulin absorbed even when heated.

[Table] Comparative Example 3 In Comparative Example 3, the drug was doped using the same formulation as in Example 1 except that sodium deoxycholate was removed. From now on, the method for preparing the drug support was the same as in Example 1, and the administration method to rabbits and blood glucose level measurement were also explained. The method was carried out in the same manner as in Example 2. Insulin content was 2U/ ^9cm2 . As shown in Table 6, no decrease in blood sugar was observed in either the 40°C heating type or the non-heating type, indicating that an absorption enhancer is essential.

[Table] Comparative Examples 4 to 6 In Comparative Examples 4 to 6, the absorption enhancers shown in Table 7 were used in place of sodium deoxycholate. The amount added was 90 mg in each case. In the case of Comparative Example 6, when insulin, glycocholic acid, and glycerin were added to a mixed solvent of water and methanol and stirred, they were once about to dissolve, but insoluble substances gradually precipitated. At the time when carbobol and sodium polyacrylate were added, the precipitate gradually began to aggregate, and since a uniform dope could not be prepared, the experiment after the preparation of the drug carrier was discontinued. In Comparative Examples 4 and 5, the method for preparing the drug support was the same as in Example 1, and the method for administration to rabbits and the method for measuring blood sugar levels were the same as in Example 2. The insulin content of Reference Examples 4 and 5 was 2 U/9 cm ² . As shown in Table 7, the results showed that heating promoted the absorption of insulin, but compared to Examples 1 to 10, it was confirmed that the blood sugar lowering effect was extremely small. Comparative example 4,
All of No. 5 are reported to be effective as absorption enhancers for insulin-containing suppositories.
This fact indicates that satisfactory results cannot be obtained even if the absorption enhancer for insulin-containing suppositories is used as the absorption enhancer for insulin-containing patches.

【table】

Claims (1)

[Scope of Claims] Consisting of 1. a drug carrier containing insulin and a temperature-dependent absorption enhancer; and (2) a heating element located on the opposite side of the drug carrier to the side to be applied to the skin. ,
Further, an insulin-containing heating type skin patch, wherein the drug carrier and the heating body are substantially integrated. 2. The insulin-containing warming skin patch according to claim 1, wherein the warming body is a chemical heating body. 3. The insulin-containing heating type skin patch according to claim 1, wherein the heating element is a self-temperature-controlled heating element. 4 Drug carrier is a polymer soluble in water and/or lower alcohol, insulin, absorption enhancer,
and Claims 1-- containing a moisturizing agent.
The insulin-containing warming skin patch according to any one of Item 3. 5. The insulin-containing warming skin patch according to claim 4, wherein the water and/or lower alcohol-soluble polymer is a water-soluble polyacrylic acid polymer. 6. The insulin-containing warming skin patch according to claim 4 or 5, wherein the water-soluble polyacrylic acid-based polymer contains a carboxyvinyl polymer and/or sodium polyacrylate. 7 Temperature-dependent absorption enhancers include glycerin monostearate, diethyl sebacate, sodium deoxycholate, dipotassium glycyrrhizinate,
Any one of claims 1 to 6 containing one or more selected from the group consisting of linoleic acid, sodium polyoxyethylene cetyl ether phosphate, sodium oleyl phosphate, and sodium hyaluronate. The insulin-containing warming skin patch described above. 8. The insulin-containing warming skin patch according to any one of claims 1 to 7, wherein the humectant is glycerin, lower hydrocarbon diol and/or triol.