JPH0676321B2 - Clonidine transdermal formulation - Google Patents

Description

TECHNICAL FIELD The present invention relates to a clonidine transdermal preparation suitable for sustained release of clonidine.

[Prior Art] As a percutaneous absorption preparation using clonidine, which is a transdermally absorbable systemic drug, is disclosed in JP-A-54-20129 and JP-A-54-20129.
57-150614, the drug storage layer, which is seen in the public relations, provides controlled release of the drug through the pressure-sensitive adhesive layer that comes into contact with the skin and, in some cases, through the drug permeation control membrane. From the viewpoint of controlling the release rate of the drug and the pharmacological effect, the purpose can be sufficiently satisfied. However, in the case of long-term administration or continuous administration, side effects such as irritation due to drugs, redness due to swelling due to sweating, and touch may occur. Further, the pressure-sensitive adhesive layer that comes into contact with the skin serves as a barrier for the initial release of the drug, and the onset of the drug effect tends to be delayed.

Therefore, the present inventors have sufficiently endured long-term administration and continuous administration, reduce side effects such as redness due to drug irritation, rash due to sweating, touch, etc., and further, a clonidine transdermal preparation excellent in initial drug efficacy expression. For the purpose of providing
As a result of intensive studies, the present invention has been achieved.

[Means for Solving Problems] That is, the clonidine transdermal preparation of the present invention comprises a support, a drug storage layer laminated on the support, a drug permeation control membrane laminated on the drug storage layer, and It is composed of a pressure sensitive adhesive layer laminated on a drug permeation control membrane, the drug is clonidine, and the pressure sensitive adhesive layer is (AB) nX or (AB).
n-A type elastic polymer [wherein, A is a substantially monovinyl-substituted aromatic compound polymer block, B is a substantially conjugated diolefin copolymer block, n is an integer of 3 to 7, and X is n.
It represents a residue derived from a polyfunctional compound to which individual polymer chains (AB) are bound], a water-absorbing polymer, a natural gum, and a higher fatty acid ester as essential components.

By the clonidine transdermal preparation of the present invention, the ideal release of the contained drug clonidine was obtained, and it was succeeded in significantly reducing the side effects such as redness and feeling in long-term administration and continuous administration. .

Clonidine used in the present invention has a general name of 2,6-dichloro-N-2-imidazolidinylidenebenzenamine and is represented by the following structural formula.

The content of this clonidine is 6 to 20% by weight, preferably 8 to 15% by weight in the drug storage layer, and 1 to 10% by weight, preferably 2 to 6% by weight with respect to the pressure-sensitive adhesive layer. .

(AB) nX or (AB) n- used in the present invention
Specific examples of the A-type elastic polymer include styrene-butadiene-styrene block copolymer (Califlex TR-1101) manufactured by Shell Chemical Co., Ltd., which is easily available as a commercial product, and styrene-isoprene-styrene block copolymer (Califlex). TR-1107, Califlex TR-1111) and the like, and Sorprene 418 manufactured by Flip Petroleum Co., Ltd., and the like, and a styrene-isoprene-styrene block copolymer is particularly preferably used. This (AB) nX or (AB)
By using the n-A type elastic polymer in the pressure-sensitive adhesive layer, the initial release of clonidine is excellent and the drug effect is very rapidly exhibited, as described in the test examples described later.

The water-absorbing polymer used in the present invention is one which is supplied with 10 times or more of its own weight of water to cause gelation and swelling. For example, a water-soluble polymer having a slight cross-linking introduced therein is used. Sanyo Chemical Co., Ltd. Sunwet (IM-300, IM-300
MPS, IM-1000, IM-1000MPS, etc.), Aqua Keep (4S, 4SH, etc.) made by Steel Chemical Co., Ltd., Sumika Gel (SP-520, SP-540, N-100, NP-) made by Sumitomo Chemical Co., Ltd. 1020, NP-1040, etc.),
Ara soap (800, 800F, etc.) manufactured by Arakawa Chemical Co., Ltd. is used.

The natural gum is a resin secreted from a special natural plant. For example, gum arabic, tragacanth gum, guar gum, karaya gum, benzoin gum and the like are used, and karaya gum, guar gum and the like are particularly preferably used.

The higher fatty acid ester is a compound produced by dehydration from an acid and an alcohol, preferably a saturated fatty acid ester, more preferably a linear fatty acid ester, such as isopropyl myristate, isopropyl palmitate, butyl stearate, lauryl. Hexyl acid, myristyl myristate and the like.

In the pressure-sensitive adhesive layer according to the present invention, preferable contents of the (AB) nX or (AB) nA type elastic polymer, the water-absorbing polymer, the natural gum, and the higher fatty acid ester are as follows. Is.

That is, the total content of the essential components consisting of (AB) nX or (AB) nA type elastic polymer, water-absorbing polymer, natural gum, higher fatty acid ester is the pressure-sensitive adhesive layer. It is 20 to 99% by weight, more preferably 30 to 60% by weight. Further, the content of each component, the pressure-sensitive adhesive layer,
(AB) nX or (AB) nA type elastic polymer 5
20% by weight, more preferably 8-10% by weight, water-absorbing polymer 1-7% by weight, more preferably 2-5% by weight, natural gum substance 0.5-5% by weight, further preferably 1-3% by weight, The higher fatty acid ester content is 0.1 to 4% by weight, more preferably 0.5 to 2% by weight, and the combination within this range is most effective for the present invention.

In the pressure-sensitive adhesive layer of the present invention, in addition to the above-mentioned essential components, conventionally well-known softening agents such as liquid paraffin, tackifying resins, antioxidants, absorption accelerators and the like are appropriately contained.

As the support used in the transdermal preparation of clonidine of the present invention, various conventionally known plastic films, non-woven fabrics, multilayer films in which aluminum is laminated, and the like are used.

Further, a mixture of polyisobutylene and mineral oil is used together with the drug in the drug storage layer. Specifically, polyisobutylene (trade name Vistanex) manufactured by Exxon Corporation is used.
Further, mineral oil having a temperature of 40 ° C. and 5 cSt to 100 cSt is used, and specifically, liquid paraffin (trade name: Cristol) manufactured by Esso Co. is used. The compounding ratio of polyisobutylene and liquid paraffin is 30 to 60 parts by weight of polyisobutylene and 40 parts of liquid paraffin to 100 parts by weight of the drug storage layer excluding the drug.
˜70 parts by weight is preferred.

A polypropylene membrane (trade name: Duraguard) manufactured by Polyplastics Co., Ltd. is used as the drug permeation control membrane.

Next, a method for producing the clonidine transdermal preparation of the present invention will be described.

First, dissolve the base component and drug (clonidine) in a solvent such as hexane, heptane, methylene chloride, chloroform,
After being coated on a suitable support or a film which has been once subjected to a release treatment, it is transferred and pressure-bonded to a suitable support to obtain a product. More specifically, as shown in FIG. 1, a drug permeation control membrane 3 previously saturated with liquid paraffin is laminated on a drug storage layer 2 spread on a support 1, and a liner 5 is used.
It is laminated with the pressure-sensitive adhesive layer 4 spread over and cut into a desired size to obtain a product.

The clonidine transdermal preparation of the present invention thus obtained comprises: 1) a support, a drug storage layer laminated on the support, a drug permeation control membrane laminated on the drug storage layer, and a drug permeation control membrane. A laminated preparation comprising a pressure-sensitive adhesive layer laminated on the above, and 2) a constituent component of the pressure-sensitive adhesive layer is (AB) nX or (AB) nA type elastic polymer Polymers Natural gums Higher fatty acid ester, A) Excellent initial release of clonidine, which accelerates the onset of drug effect [Effect of 2)] B) Prolongs drug effect for a long time [1) and 2) Action] C) It is a truly ideal transdermal preparation for clonidine, which is the stimulation of the drug by long-term administration, the reduction of side effects such as redness due to stuffiness such as sweat, and the touch [the above 2)-[]]. Is.

[Examples] Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples and the like. In the examples, comparative examples and reference examples, "part" means "part by weight".

Example 1 (; Preparation of Drug Storage Layer) Polyisobutylene (Brand Name Vistanex MML-100) 5.36 Parts Polyisobutylene (Brand Name Vistanex LM-MS) 6.69 Parts Liquid Paraffin (Brand Name Cristol) 10.71 Parts Hexane 77.24 Parts A total of 100 parts of was placed in a separable flask equipped with a reflux condenser, and heated and dissolved at 60 ° C. Then clonidine
After adding 3.13 parts dissolved in 6 parts of heavy ethanol and thoroughly mixing and dispersing, it was spread on a polyester film with a thickness of 11μ to a dry thickness of 50μ and dried overnight at room temperature. It was dried at 50 ° C for 15 minutes to form a drug storage layer.

(; Adjustment of drug permeation control membrane) A polypropylene membrane (Duraguard 2400, made by Polyplastics Co., Ltd.) is immersed in liquid paraffin and vacuum pumped to 2
Degassed for hours.

(; Preparation of pressure-sensitive adhesive layer) Styrene-isoprene-styrene block copolymer (trade name Califlex TR-1107) 10.39 parts Butylhydroxytoluene 0.52 parts Liquid paraffin (trade name Cristol) 7.27 parts Tackifying resin (fat) Aromatic saturated hydrocarbon) (Brand name Alcon P-100) 20.78 parts Isopropyl myristate 0.95 parts Hexane 60 parts A total of 100 parts was placed in a separable flask equipped with a reflux condenser and heated and dissolved at 60 ° C. Then the above solution
Water-absorbent polymer (polyacrylate polymer) (trade name Arassorb 800F) 4.27 parts Karaya gum 1.90 parts to 100 parts, and then 3 parts ethanol in which 1.37 parts clonidine was dissolved, and mixed and dispersed well. Then, it was spread on a silicone-treated polyester film so that the thickness after drying was 50 μm, in the same manner as in the procedure for preparing the storage layer.

Then, on the adhesive layer surface of the pressure-sensitive adhesive layer prepared above, the drug permeation control membrane prepared above is laminated, and further on the drug storage layer surface of the drug storage layer-polyester support composite prepared above, the drug The clonidine transdermal preparation of the present invention was prepared by laminating the permeation control membrane so that the permeation control membrane was in contact.

Comparative Examples 1 to 3 Preparation of the drug storage layer and preparation of the drug permeation control membrane were performed in the same manner as in Example 1, and preparation of the pressure-sensitive adhesive layer was carried out using isopropyl myristate, a water-absorbing polymer (polyacrylate polymer, Arasorb 800F) and karaya gum were added as shown in Table 1 and carried out in the same manner as in Example 1.

Using these drug storage layer, drug permeation control membrane and pressure-sensitive adhesive layer, a clonidine transdermal preparation was obtained in the same manner as in Example 1.

Comparative Example 4 The drug storage layer was prepared and the drug permeation control membrane was prepared in the same manner as in Example 1, and the pressure-sensitive adhesive layer was prepared as follows.

Polyisobutylene (Brand Name Vistanex MML-100) 8.20 parts Polyisobutylene (Brand Name Vistanex LM-MS) 10.20 parts Liquid paraffin (Brand name Cristol) 16.38 parts Isopropyl myristate 0.85 parts Hexane Remainder 100 parts in total The mixture was placed in a separable flask equipped with a condenser and heated to dissolve at 60 ° C. Then the above solution
To 100 parts, water-absorbent polymer (polyacrylate polymer) (Brand name Arasorb 800F) 3.85 parts Karaya gum 1.71 parts was added, and then clonidine 1.54 parts ethanol 2.6 parts was added and mixed well and dispersed. Then, it was spread on a silicone-treated polyester film so that the thickness after drying was 50 μm, in the same manner as in the procedure for preparing the storage layer.

Then, on the adhesive layer surface of the pressure-sensitive adhesive layer prepared above, the drug permeation control membrane prepared above is laminated, and further on the drug storage layer surface of the drug storage layer-polyester support composite prepared above, the drug A clonidine transdermal preparation was laminated so that the permeation control membrane was in contact.

Reference Example 1 The preparation of the drug storage layer and the preparation of the drug permeation control membrane were performed in the same manner as in Example 1, and the preparation of the pressure sensitive adhesive layer was carried out as follows.

Polyisobutylene (brand name Vistanex MML-100) 5.36 parts Polyisobutylene (brand name Vistanex LM-MS) 6.69 parts Liquid paraffin (brand name Cristol) 10.71 parts Hexane 77.24 parts Separa with a reflux condenser It was put in a bull flask and heated to dissolve at 60 ° C. Then clonidine
After adding 1.5 parts of ethanol in which 0.85 parts were dissolved, and thoroughly mixed and dispersed, it was spread on a silicone-treated polyester film so that the thickness after drying would be 50 μ, and after overnight room temperature drying, It was dried at 50 ° C for 15 minutes to form a pressure-sensitive adhesive layer.

Then, on the adhesive layer surface of the pressure-sensitive adhesive layer prepared above, the drug permeation control membrane prepared above is laminated, and further on the drug storage layer surface of the drug storage layer-polyester support composite prepared above, the drug A clonidine transdermal preparation was laminated so that the permeation control membrane was in contact.

Test Example 1 (Water Release Test) Using the clonidine transdermal preparations of Example 1, Reference Example 1 and Comparative Example 4, a water release test was conducted at 37 ° C. The results are shown in FIG.

As shown in FIG. 2, the clonidine transdermal preparation of Example 1 clearly has a higher initial release property than the clonidine transdermal preparations of Comparative Example 4 and Reference Example 1. There is. This is because the pressure-sensitive adhesive layer of Example 1 uses an elastic polymer (styrene-isoprene-styrene block copolymer). That is, it supports the usefulness of the present invention.

Test Example 2 (Water Absorption Test, Surface pH Measurement, and Skin Irritation Test) The clonidine transdermal preparations of Example 1, Comparative Examples 1 to 3 and Reference Example 1 were each immersed in 0.62% physiological saline for 24 hours,
The water absorption force per pressure-sensitive adhesive layer was measured. Further, the pH of the plaster surface of each Example, Comparative Example and Reference Example was measured separately.
In addition, each preparation was applied to the depilated dorsal skin of 12 hypertensive rats by 1
After application for a week, the state of the skin after peeling was observed and the correlation between water absorption, pH value and skin irritation was examined.

The results are shown in Table 2. The skin irritation criteria are as follows.

No change; -Weak redness; ± Clear redness; + Severe feel; As is clear from Table 2, the clonidine transdermal preparation of Example 1 contains a water-absorbing polymer, natural gum, and higher fatty acid ester as essential components, and Comparative Example 1 lacking one component thereof 3, moreover, the water absorption power more remarkable than that of Reference Example 1 was exhibited. Furthermore, by blending a natural gum substance (karaya gum), it synergizes with its pH buffering power and greatly reduces skin irritation. (See comparison of Example 1 and Comparative Example 3).
This greatly supports the usefulness of the present invention.

Test Example 3 (Pharmaceutical efficacy test) The clonidine transdermal preparation of Example 1 and Reference Example 1 (clonidine amount 5 mg / person) was administered to adult males with the same hypertension to conduct a pharmacological efficacy test. The results are shown in FIG.

As is clear from FIG. 3, the transdermal preparation for clonidine of Example 1 exerts its therapeutic effect within 24 hours after application,
In Reference Example 1, the drug effect is exhibited after 24 hours. In addition, the clonidine transdermal preparation of Example 1 had remarkably weak side effects such as redness and feeling compared to Reference Example 1 (see Table 2).

[Advantages of the Invention] As described above, a support, a drug storage layer laminated on the support, and a drug permeation control membrane laminated on the drug storage layer,
Further, the pressure-sensitive adhesive layer is composed of a pressure-sensitive adhesive layer laminated on the drug permeation control film, and the pressure-sensitive adhesive layer is (AB) nX or (A-).
B) The clonidine transdermal preparation of the present invention containing an n-A type elastic body, a water-absorbing polymer, a natural gum, and a higher fatty acid ester is excellent in initial release of clonidine and promotes rapid onset of drug effect. Moreover, since it is sufficiently safe without causing redness or feeling, it is a formulation that is a marked advance over conventional clonidine transdermal preparations, and is extremely useful industrially.

[Brief description of drawings]

FIG. 1 is a schematic diagram showing the structure of the clonidine transdermal preparation of the present invention, FIG. 2 is a diagram showing the time change of the release rate (%) in the water release test, and FIG. 3 is the blood pressure value with respect to the application time. The figure which shows the result of the drug efficacy test. 1: Support, 2: Drug storage layer, 3: Drug permeation control membrane, 4: Pressure-sensitive adhesive layer, 5: Liner.

 ─────────────────────────────────────────────────── ─── Continuation of the front page (56) References JP 60-59209 (JP, B2) JP 54-16566 (JP, B2) JP 62-42886 (JP, B2)

Claims (1)

[Claims] 1. A suspension comprising a support, a drug storage layer laminated on the support, a drug permeation control film laminated on the drug storage layer, and a pressure-sensitive adhesive layer laminated on the drug permeation control film. In the dermal preparation, the drug is clonidine and the pressure-sensitive adhesive layer is (AB) nX or (AB) nA type elastic polymer [wherein A is substantially a monovinyl-substituted aromatic group]. Compound polymer block, B is substantially a conjugated diolefin copolymer block, n is an integer of 3 to 7, X is derived from a polyfunctional compound to which n polymer chains (AB) are bound. The present invention represents a residual residue], a water-absorbent polymer, a natural gum, and a higher fatty acid ester.