CN112826809B

CN112826809B - Stable tulobuterol percutaneous absorption preparation

Info

Publication number: CN112826809B
Application number: CN201911153062.5A
Authority: CN
Inventors: 李萍; 高莹; 呼瑞; 李厚全; 赵媛媛; 李之韬; 宋士霞; 陈胜飞
Original assignee: Beijing Tide Pharmaceutical Co Ltd
Current assignee: Beijing Tide Pharmaceutical Co Ltd
Priority date: 2019-11-22
Filing date: 2019-11-22
Publication date: 2023-01-10
Anticipated expiration: 2039-11-22
Also published as: CN115054590A; CN112826809A; CN115054590B

Abstract

The invention provides a tulobuterol percutaneous absorption preparation which has good application performance, small change of adhesive force of a patch after application and can maintain a certain drug release degree for a long time. The amine compound is added into the adhesive layer in the preparation, so that the stability of the tulobuterol is effectively improved, the precipitation of the tulobuterol medicine crystal is inhibited, a small amount of medicine in the tulobuterol patch can be fully absorbed in the body, and the medicine absorbability and bioavailability are improved.

Description

Stable tulobuterol percutaneous absorption preparation

Technical Field

The present invention relates to a stable percutaneous absorption preparation containing tulobuterol, which enables the tulobuterol to be absorbed into the skin for a long time by controlling the drug release rate.

Background

Tulobuterol has been used for the treatment and prevention of chronic bronchitis, bronchial asthma, etc. The tulobuterol oral drug has short drug effect time, and causes various adverse reactions due to the instantaneous rise of the drug concentration in blood. In order to maintain a certain concentration of tulobuterol in blood for a long time, a patch is prepared by coating a drug-containing adhesive on the surface of a backing, so that tulobuterol is absorbed into the skin. However, the percutaneous absorption preparations produced by the conventional methods have problems in terms of quality, drug efficacy, and the like. Therefore, it is difficult to obtain a good quality patch preparation.

Tolobuterol percutaneous absorption preparations have been reported in patent document 1 (Japanese patent application laid-open No. Hei 4-99720), patent document 2 (Japanese patent application laid-open No. Hei 5-194202), patent document 3 (Japanese patent application laid-open No. Hei 7-285854), patent document 4 (Japanese patent application laid-open No. 3260765), and the like. In the above-mentioned literature, tulobuterol having a solubility higher than the saturation level is added to the binder so that a part of the tulobuterol is dispersed in the paste layer in a crystalline form. However, this method of preparation causes the solid drug crystals present in the paste to reduce the adhesion between the patch and the skin, and the drug crystals are easily detached from the skin surface.

In the percutaneous absorption preparation of tulobuterol disclosed in patent document 5 (japanese patent application laid-open No. 11-228395), the tulobuterol in the paste is dissolved in the paste not in a crystal form but in an amount of 5 wt% or more, but this preparation has a disadvantage that the bioavailability of the drug in the patch is generally lower than that in the preparation having a crystal precipitation type, although a large amount of tulobuterol is contained.

In order to solve the problems, the invention provides the tulobuterol transdermal absorption preparation which has good sticking performance, small change of sticking force of a sticking agent after sticking, overcomes the defects of low drug concentration and incapability of keeping good drug effect in vivo caused by crystallization precipitation of main drug components in the prior art, and can maintain a certain drug release degree for a long time.

Disclosure of Invention

After repeated studies, the inventors found that when the content of tulobuterol dissolved in the paste is 3.0 to 5.0 wt%, the tulobuterol transdermal absorption preparation has not only good adhesion but also low irritation.

The preparation contains a bonding agent capable of dissolving tulobuterol, and can be acrylic acids, synthetic rubbers, natural rubbers, silica gels and the like. Acrylic adhesives are selected for use in the present invention. Acrylic adhesives have high polarity, have water absorption, and are easily ventilated even after being attached to the skin. On the other hand, adhesives such as rubbers and silicones are nonpolar, have poor water absorption and ventilation properties, and are easily reddened at the site of application and easily shed from the skin surface upon sweating. The patch preparation is to be used for children patients in the future, and an acrylic adhesive is preferable as a base material in view of skin irritation.

Acrylic adhesives are widely varied. One of the most widely used is a polar group containing hydroxyl or carboxyl and the like, and has stronger cohesive force. However, the matrix binder used in the present preparation is an acrylic binder containing no polar molecular chain such as hydroxyl group or carboxyl group. The inventors have unexpectedly found that a polar bond and tulobuterol can react with each other during the course of research, and when an adhesive containing a polar molecular chain such as a hydroxyl group or a carboxyl group is used, the polar groups of the tulobuterol and the acrylic adhesive react with each other, so that the tulobuterol is in a stable state in the adhesive and is not easily absorbed subcutaneously, and the percutaneous absorbability of tulobuterol is finally reduced. The percutaneous absorption preparation of the invention is characterized in that an adhesive layer is coated on the surface of a backing which is not permeable by a medicament, the adhesive is an acrylic adhesive which does not contain polar molecular chains such as hydroxyl or carboxyl, the adhesive is composed of (methyl) acrylic acid alkyl ester polymer, wherein the monomer forming the (methyl) acrylic acid alkyl ester polymer is methacrylic acid alkyl ester or acrylic acid alkyl ester, such as 2-ethylhexyl methacrylate, dodecyl methacrylate, tetradecyl methacrylate, hexadecyl methacrylate, octadecyl methacrylate or 2-ethylhexyl acrylate, and the adhesive is further polymerized by 2-ethylhexyl methacrylate, 2-ethylhexyl acrylate and dodecyl methacrylate.

In the preparation process of the tulobuterol patch, the drug is easily decomposed when being heated. In order to solve this problem, researchers have found that the stability of tulobuterol in the formulation can be effectively improved by adding an amine compound while selecting a binder consisting of an alkyl (meth) acrylate polymer as a matrix.

Researches show that the amine compound protects secondary amine with a base structure with the strongest reactivity in the tulobuterol molecule, reduces the reactivity of the secondary amine of the tulobuterol and effectively enhances the stability of the tulobuterol. Research confirms that besides ammonia water and salts thereof, diethanolamine and ethylenediamine also have an enhancing effect on the stability of tulobuterol. Moreover, the protective effect of the amine compound on tulobuterol is a property shared by these compounds.

Therefore, the present invention selects amine compounds capable of reducing the reactivity of the secondary amine of tulobuterol as the stability of the transdermal absorption preparation of tulobuterol, such as ammonia water and its salts, or compounds in which the hydrogen atom of ammonia water is replaced by a hydrocarbon group, such as ammonia water, diethanolamine, ethylenediamine, ammonium acetate, ammonium chloride, etc., and further, ammonia water and its salts, such as ammonia water, ammonium acetate, ammonium chloride, are preferable as the amine compounds. The amount of the amine compound is 0.02 to 5.0 wt%, preferably 0.02 to 3.0 wt%, and more preferably 0.02 to 0.1 wt%.

According to the above results, the percutaneous absorption preparation of tulobuterol according to the present invention is prepared by dissolving tulobuterol in an alkyl (meth) acrylate polymer and adding an amine compound, particularly ammonia water. The tulobuterol concentration and the amount of ammonia added are determined by adjusting the tulobuterol or ammonia concentration to evaluate the transdermal absorption, skin irritation, skin adhesion, long-term stability, and other indicators. In addition to the amine compound, other excipients, such as an antioxidant and a surfactant, may be further added to improve the adhesiveness and long-term stability of the patch. Wherein the surfactant can be selected from span 80, polysorbate, stearic acid, glyceryl monostearate, sodium lauryl sulfate or sodium fatty alcohol polyoxyethylene ether sulfate, and span 80 can be further preferably selected. The oxidizing agent may be DL-alpha-tocopherol, butyl p-hydroxyanisole, dilauryl thiomalonate (DLTDP), sodium thiosulfate, dibutylphenol, and in some embodiments the oxidizing agent is DL-alpha-tocopherol.

The above-mentioned polymer is prepared by solution polymerization (radical polymerization). For example, a reaction vessel is charged with a mixture containing the above-mentioned 3 kinds of alkyl (meth) acrylates, and a polyfunctional monomer and a solvent as required. Then azo is reactedThe compound and peroxide are used as catalyst, and the polymerization reaction is carried out under the nitrogen environment at the temperature of 60-80 ℃. In the present invention, the substrate is an acrylic adhesive composition obtained by mixing a (meth) acrylic polymer and an amine compound such as ammonia. Wherein the tulobuterol concentration is 3.0 to 5.0 wt%, more preferably 3.5 to 4.8 wt%, and the preferable concentration is 3.5 to 4.5 wt%. When the tulobuterol content is less than 3.0 wt%, the percutaneous absorption rate is too small. In order to achieve an effective blood drug concentration, it is necessary to enlarge the area of the transdermal absorption preparation. In addition, when the tulobuterol content is more than 5.0 wt%, the percutaneous absorption rate is too high. In order to maintain an appropriate blood concentration, it is necessary to reduce the area of the percutaneous absorption preparation to 1 cm ² Left and right. If the area of the preparation is too small, it is inconvenient for the patient to use. To maintain the drug effect of tulobuterol for 24 hours after percutaneous absorption, 1 patient needs to continuously absorb 0.3 to 3mg of tulobuterol through the skin. In order to ensure the absorption of the desired amount of tulobuterol, the transdermal preparation of the present invention should contain at least 0.5-5 mg of tulobuterol. The thickness of the adhesive layer and the patch area were selected and the tulobuterol content was adjusted by the following method. The adhesive layer is preferably 30 to 60 μm thick. When the thickness of the adhesive layer is less than 30 μm, insufficient adhesion occurs, resulting in easy detachment of the percutaneous absorption preparation from the skin surface. On the contrary, if the thickness is more than 60 μm, the solvent needs to be removed at a high temperature for a long time during the preparation, which may result in a large volatilization of tulobuterol, resulting in a decrease in the drug content of the formulation.

The area of the transdermal preparation is determined according to the amount of tulobuterol contained in the adhesive layer and the thickness of the adhesive layer, and the target amount of tulobuterol. In order to reduce discomfort at the time of application and skin irritation at the application site, the smaller the area of the transdermal absorption preparation, the better. However, the patch has an excessively small area, and is inconvenient for patients to use. Therefore, the optimum area is 1.0 to 10cm ² . The backing of the percutaneous absorption preparation of the present invention may be made of a material impermeable to a drug, particularly a film or sheet having a gas barrier function. Suitable backing materials may be polyester fiber, polyvinylidene chloride, etc. or polyester fiber nonwoven fabric compounded on these filmsThe material of (2). The surface of the adhesive layer of the percutaneous absorption preparation is protected with a release film as necessary. The release film can be polyester fiber, polyvinylidene chloride film, high-quality film compounded with polyolefin, etc.

The percutaneous absorption preparation of the present invention is prepared by dissolving a mixture of the above polymer, ammonia water and tulobuterol in an organic solvent, coating the resulting solution on the surface of a backing, and drying the coating. Or coating the coating liquid on the surface of the release film according to a common preparation method, drying, and then attaching and compounding the coating liquid on a backing.

The adhesive layer is prepared by applying the coating liquid and then drying the coating liquid, wherein the drying temperature is controlled to about 50 to 90 ℃ in order to reduce volatilization of tulobuterol.

The adhesive preparation of the present invention has a drug impermeable backing coated with an adhesive layer. The adhesive is an acrylic adhesive composition prepared by mixing 91.0 to 97.0 wt% of an alkyl (meth) acrylate polymer, 3.0 to 5.0 wt% of tulobuterol, and 0.02 to 5.0 wt% of ammonia water.

A patch preparation containing tulobuterol, wherein an adhesive layer is coated on the surface of a drug impermeable backing. The adhesive is an acrylic adhesive composition prepared by mixing 91.15 to 96.48 wt% of an alkyl (meth) acrylate polymer, 3.5 to 4.5 wt% of tulobuterol, and 0.02 to 5.0 wt% of ammonia water. Further the above alkyl methacrylate polymer is a copolymer containing 8 moles of 2-ethylhexyl methacrylate, 1 mole of dodecyl methacrylate, and 1 mole of 2-ethylhexyl acrylate.

The tulobuterol percutaneous absorption preparation is prepared by adding 3.0-5.0 wt% of tulobuterol and 0.02-5.0 wt% of ammonia water into acrylic adhesive, mixing, heating and uniformly mixing, and removing solvent from the adhesive.

A percutaneous absorption preparation containing tulobuterol in an amount of 3.0 to 5.0 wt% is prepared by dissolving and mixing an acrylic adhesive, tulobuterol and ammonia water in a solvent to prepare an adhesive composition solution, wherein the amount of ammonia water added is 0.02 to 3.0 wt%. Then, the adhesive composition solution is heated to remove the solvent.

The preparation method of the tulobuterol transdermal absorption preparation comprises a process of adding 3.0-5.0 wt% of tulobuterol and 0.02-0.10 wt% of ammonia water into an acrylic adhesive for mixing, and a process of removing a solvent from the adhesive after heating and uniform mixing.

The method for preparing a percutaneous absorption preparation containing 3.5 to 4.5 wt% of tulobuterol comprises a process for preparing a solution of a binder composition by dissolving and mixing an acrylic binder, tulobuterol and aqueous ammonia in a solvent, wherein the amount of aqueous ammonia added is 0.02 to 0.1 wt%. And then, heating the adhesive composition solution to remove the solvent.

The invention provides a percutaneous absorption preparation of tulobuterol, which has stable drug release speed and can obtain sufficient drug effect for a long time. A patch having a small area can obtain a sufficient medicinal effect and reduce the unpleasant feeling caused by an excessively large area of the patch. The percutaneous absorption preparation of the present invention has excellent adhesiveness and is closely attached to the skin surface for a long period of time. The percutaneous absorption preparation is prepared by coating a single adhesive on the surface of a release film, and has the advantages of simple structure, single preparation method, low cost and easy preparation in a short time.

Drawings

FIG. 1 skin transmittance profiles of tulobuterol transdermal formulations and marketed products of examples 6 and 7;

FIG. 2 skin transmittance profiles of the tulobuterol transdermal formulation of example 8 and marketed products;

fig. 3 is a skin transmittance spectrum of the tulobuterol transdermal absorption preparation in example 10 and comparative example 5 and marketed products.

Detailed Description

Evaluation of stability of drug

Examples 1 to 5, comparative examples 1 to 4

2-ethylhexyl methacrylate 39 parts by weight, dodecyl methacrylate 6.5 parts by weight, 2-ethylhexyl acrylate 4.5 parts by weight, and ethyl acetate 30 parts by weight were uniformly mixed, and after 0.6 part by weight of azobisisobutyronitrile was added, polymerization was performed under a nitrogen gas stream atmosphere at 65 ℃ to prepare an alkyl (meth) acrylate polymer (referred to as adhesive a). The drug-containing coating solution is prepared by adding a predetermined amount of tulobuterol and an amine compound (ammonia, diethanolamine, ethylenediamine, ammonium acetate, ammonium chloride) to a predetermined amount of the polymer ethyl acetate solution. The coating solution was applied to a release film and dried at 70 ℃ for 8 minutes to give an adhesive layer having a thickness of about 46 μm. Compounding polyethylene terephthalate film on the surface of the adhesive layer to obtain the tulobuterol percutaneous absorption preparation. As a comparative example, a tulobuterol transdermal absorption preparation containing no amine compound was prepared. Tables 1 and 2 show the formulations (by weight) of examples 1 to 5 and comparative examples 1 to 4, respectively.

[ TABLE 1 ]

[ TABLE 2 ]

After preparation, the sample was stored at room temperature for 1 week, and then the decomposition product (related substance) was detected.

The largest related species appear around 60.4 minutes in the liquid chromatogram. The content of the relevant substances is calculated after detecting the relevant substances in the percutaneous absorption preparation. The content of the relevant substances below 0.3% is considered to meet the standard.

Table 3 results:

as can be seen from table 3, the addition of the amine compound inhibited the substances involved in the patch of the example.

Evaluation of percutaneous absorbability of drug

Examples 6 to 10, comparative example 5 and reference example (marketed product)

Adding 4.0-4.8 parts by weight of tulobuterol, 0.05 part by weight of ammonia water, 1.0 part by weight of span-80 and 3.0 parts by weight of DL-alpha-tocopherol into a determined amount of ethyl acetate solution of the adhesive A, and mixing to obtain the medicine-containing coating liquid. The coating liquid was applied to the surface of a release film and dried at 70 ℃ for 8 minutes to give an adhesive layer having a thickness of about 46 μm. Compounding polyethylene glycol terephthalate film on the surface of the adhesive layer to obtain the percutaneous absorption preparation of tulobuterol. As a comparative example, a tulobuterol transdermal absorption preparation was prepared using an acrylic adhesive containing a carboxyl group. Tables 4 and 5 show the formulations (by weight) of examples 6 to 10 and comparative example 5.

[ TABLE 4 ]

[ TABLE 5 ]

The transdermal absorption test was carried out using the above patch preparation. Meanwhile, a commercially available product (Hokunalin, ritong electrical corporation) was also evaluated as a reference example.

Test method

Human skin permeability test: a circular patch with a diameter of 1.3cm was cut, attached to human skin, and placed in a Franz diffusion cell for transdermal testing. The receiver was collected periodically and checked using HPLC. And calculating the cumulative permeation quantity of the tulobuterol according to the analysis and detection result. The results are shown in tables 6 and 7, and in FIG. 1, FIG. 2 and FIG. 3.

[ TABLE 6 ]

[ TABLE 7 ]

As is clear from FIGS. 1 to 3, all the preparations in the examples showed percutaneous absorbability equivalent to those of the marketed products.

As can be seen from fig. 3, the preparation of comparative example 5, which was prepared using a polar group (carboxyl group) -containing adhesive, had significantly lower drug transdermal absorbability than the other preparations.

Evaluation of skin adhesion of the preparation: examples 8,9

Test method

Test of skin adherence to human

A transdermal preparation having a diameter of 1.3cm was applied to the skin of the upper arm of a human, and after 24 hours, the applied part was evaluated for the presence of residual gum and exfoliation and feeling upon peeling.

Evaluation results

Example 8: the sticking part has no adhesive residue phenomenon, the periphery of the sticking piece does not fall off, and the peeling strength is weak;

example 9: the patch had no adhesive residue, no peeling-off around the patch, and a peel strength greater than that of example 8, and had stable skin attachment properties, and thus it was found that the addition of span 80 and DL- α -tocopherol could further improve the skin attachment properties of the preparation, as shown in table 8.

[ TABLE 8 ]

Claims

1. A stable tulobuterol-containing transdermal preparation comprising:

(1) 3.0 to 5.0% by weight of tulobuterol or a pharmaceutically acceptable salt thereof;

(2) 0.02 to 5.0% by weight of an amine compound,

wherein the amine compound is selected from ammonia;

(3) 91.0 to 97.0 wt.% of an acrylic binder,

wherein the acrylic adhesive is a (methyl) acrylic acid alkyl ester polymer without hydroxyl or carboxyl polar molecular chains.

2. The percutaneous absorption preparation containing tulobuterol according to claim 1, wherein the amine compound is used in an amount of 0.02 to 3.0% by weight.

3. The percutaneous absorption preparation according to claim 1, which contains tulobuterol, wherein the amine compound is used in an amount of 0.02 to 0.1% by weight.

4. The tulobuterol-containing transdermal absorption preparation according to claim 1, wherein the alkyl (meth) acrylate polymer is polymerized from monomers of 2-ethylhexyl methacrylate, dodecyl methacrylate, and 2-ethylhexyl acrylate.

5. The tulobuterol-containing transdermal absorption preparation according to claim 1, wherein the acrylic adhesive is used in an amount of 91.15 to 96.48 wt.%.

6. Tulobuterol containing transdermal formulations according to any of claims 1-5, characterized in that the content of tulobuterol or its pharmaceutically acceptable salt is 3.5-4.5% by weight.

7. Tulobuterol-containing transdermal preparation according to any of claims 1-6, wherein the content of relevant substances is less than 0.3% after 1 week of storage of the preparation at room temperature.

8. A percutaneous absorption preparation containing tulobuterol, which contains 91.15-96.48 wt% of acrylic adhesive, 3.0-5.0 wt% of tulobuterol and 0.02-5.0 wt% of ammonia water, wherein the acrylic adhesive is (methyl) acrylic acid alkyl ester polymer without hydroxyl or carboxyl polar molecular chains.