CN108451934B

CN108451934B - Transdermal patch containing rotigotine and preparation method thereof

Info

Publication number: CN108451934B
Application number: CN201710588689.8A
Authority: CN
Inventors: 蒲晓蕾; 卢迪; 张运; 杨旸; 田莉莉
Original assignee: Beijing Tide Pharmaceutical Co Ltd
Current assignee: Beijing Tide Pharmaceutical Co Ltd
Priority date: 2017-07-19
Filing date: 2017-07-19
Publication date: 2020-11-10
Anticipated expiration: 2037-07-19
Also published as: CN108451934A

Abstract

The invention discloses a composition for preparing a transdermal patch containing rotigotine, the transdermal patch containing rotigotine and a preparation method thereof, wherein the composition comprises effective dose of rotigotine and a self-adhesive matrix, and the self-adhesive matrix comprises the following components: polyisobutylene pressure sensitive adhesives and colloid softeners. The transdermal patch containing the rotigotine adopts the polyisobutylene pressure-sensitive adhesive, the C-H skeleton of the transdermal patch is longer and straight, only the end group has an unsaturated bond, and the double bonds are few, so the transdermal patch containing the rotigotine is very stable, and has good weather resistance, heat resistance and ageing resistance, low cost, easily obtained materials and strong operability. The colloid softener is added, so that the stability of the patch is improved, and the precipitation of active pharmaceutical ingredients from the preparation is avoided; furthermore, the transdermal patch is added with an adhesive force regulator, so that the transdermal patch has better permeability.

Description

Transdermal patch containing rotigotine and preparation method thereof

Technical Field

The invention belongs to the technical field of preparation of medicaments for treating Parkinson's disease symptoms, and particularly relates to a rotigotine-containing transdermal patch and a preparation method thereof.

Background

Parkinson's disease is a disease that occurs primarily in the middle-aged and elderly, and affects both men and women as well. The highest incidence of Parkinson's disease occurs in people over the age of 70 years, with Parkinson's disease present in 1.5-2.5% of these people. The mean age at onset is 58-62 years, with the majority of patients who develop Parkinson's disease between 50-79 years of age. In the united states alone, approximately 800,000 people suffer from parkinson's disease. Early motor deficits in parkinson's disease can be traced to the degeneration of nigral dopamine-releasing cells. This neuronal degeneration can produce defects in the dopamine pathway connecting the substantia nigra with the striatum.

Rotigotine is one of the dopamine receptor agonists used to treat symptoms of parkinson's disease. Rotigotine is the international non-proprietary name (INN) for the compound (-) -5, 6, 7, 8-tetrahydro-6- [ propyl- [2- (2-thienyl) ethyl ] -amino ] -1-naphthol. At present, various Transdermal Therapeutic Systems (TTS) for the administration of rotigotine are available, for example WO99/49852, which describes an acrylate-or silicone-based transdermal delivery system containing rotigotine. The adhesive used in the system is acrylate or siloxane, which are separately combined with the active agent to form a system using a single adhesive. The system which is composed of acrylate as the adhesive has low drug release rate; the system which is composed of siloxane as the adhesive has smaller drug loading amount, and the initial release amount of the drug of the product is lower.

WO2002/089778 describes the use of a silicone-based transdermal therapeutic system for the preparation of an anti-Parkinson's disease agent. The transdermal therapeutic system contains rotigotine as active ingredient. However, the slow release rate of the drug from this system, especially the long time to reach the effective dose, causes two problems: 1. in order to achieve effective blood concentration, the transdermal patch must be replaced frequently, for example, once in 24 hours or less, which is not favorable for bringing the advantage of convenience for patients; 2. the transdermal patch has a relatively low initial permeation rate, which results in an excessively long period of time from application of the patch to onset of drug action, often resulting in a delay in patient control. In a word, rotigotine has low skin penetration rate and poor stability in the existing transdermal therapeutic system, and cannot achieve good therapeutic effect.

Disclosure of Invention

The invention aims to provide a composition for preparing a transdermal patch containing rotigotine, which is used for solving the technical problems that the prior rotigotine has low penetration rate in acrylic pressure-sensitive adhesives, low skin penetration rate, no treatment effect and poor stability. Another object of the present invention is to provide a transdermal patch containing rotigotine and a method for preparing the same.

In order to achieve the purpose, the invention adopts the following technical scheme that:

a composition for the preparation of a transdermal patch containing rotigotine, comprising an effective amount of rotigotine and a self-adhesive matrix comprising a polyisobutylene pressure sensitive adhesive and a colloidal softener.

The composition as above, preferably, the polyisobutylene pressure-sensitive adhesive comprises high molecular polyisobutylene with molecular weight of 45 to 210 ten thousand and low molecular polyisobutylene with molecular weight of 1000 to 45 ten thousand in a weight ratio of 1:10 to 10:1 and a viscosity modifier, the colloid softener is liquid paraffin, light liquid paraffin, low molecular polyisobutylene, lanolin, lubricating grease, preferably liquid paraffin, light liquid paraffin, more preferably light liquid paraffin, and the viscosity modifier is selected from: the adhesive comprises polybutene, low-molecular polybutene, an acrylic adhesive, an acetic acid/vinyl acetate copolymer (EVA) and other substances capable of adjusting the adhesive force, wherein the polybutene and the low-molecular polybutene are preferred, the low-molecular polybutene is more preferred, the molecular weight of the low-molecular polybutene is 500-1500, and the adhesive force adjusting agent is used in an amount of less than 55%, preferably 5-44% of the weight ratio of the polyisobutylene pressure sensitive adhesive.

The composition as above, preferably, the weight ratio of the polyisobutylene-based polymer in the self-adhesive matrix is 20% to 99%, preferably 40% to 77%; the weight ratio of the colloid softener in the self-adhesive matrix is less than 55%, preferably less than 44%, further preferably less than 33%, and more preferably 1-22%; the weight ratio of the rotigotine in the composition is 5-20%, preferably 8-15%, and the dosage of the viscosity modifier is less than 55%, preferably 5-44%, of the weight ratio of the polyisobutylene polymer.

The composition as above, preferably, the self-adhesive matrix further comprises silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesive, and the mass percentage of the silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesive in the self-adhesive matrix is 0-20%, preferably 0-15%.

The composition as above, preferably, the self-adhesive matrix further comprises a penetration enhancer in a weight ratio of 0% to 15%, preferably 0.5% to 7%, in the self-adhesive matrix, the penetration enhancer may be laurocapram and its analogues, such as Azone; long chain saturated or unsaturated fatty acids such as oleic acid, lauric acid, and the like.

The composition as above, preferably, the self-adhesive matrix further comprises surfactant substances, such as tween, span, sodium lauryl sulfate and the like; alcohols and polyols such as propylene glycol, glycerol, etc., amines and amides such as urea, etc.

The composition preferably further comprises tackifying resin, which is a substance for improving interfacial adhesion and plasticizing performance of the pressure-sensitive adhesive and can be used for adjusting the adhesion of the patch, wherein the tackifying resin is rosin derivatives, cyclopentadiene or isoprene, and the weight ratio of the tackifying resin to the self-adhesive matrix is 5-25%.

The composition as above, preferably, the self-adhesive matrix further comprises a stabilizer, wherein the weight ratio of the stabilizer in the self-adhesive matrix is 0% -15%, preferably 0.5% -7%, and the stabilizer is polyvinylpyrrolidone, poloxamer, polyethylene glycol.

The composition as above, preferably, the self-adhesive matrix further comprises other fillers, the weight ratio of the other fillers in the self-adhesive matrix is 0% to 15%, preferably 0.5% to 7%, and the other fillers are starch, silicon dioxide, colloidal silicon dioxide or micropowder silica gel.

The composition as above, preferably, the self-adhesive matrix layer further comprises an antioxidant, the antioxidant is one or a mixture of more of ascorbyl palmitate, sodium metabisulfite, DL-a-tocopherol or dibutyl hydroxy toluene, and the dosage of the antioxidant is 0.01% -2% of the self-adhesive matrix layer.

A transdermal patch containing rotigotine comprises the composition as described above.

Specifically, the composition comprises the composition, a support layer which is not chemically reactive with the composition, and a protective film or a release film which is required to be removed before use.

The release film used in the patch of the present invention plays a role of protecting the adhesive layer, and before the patch is used, the release film is peeled off, and the patch is applied to the used site. Wherein the thickness of the release film is generally 50-150 μm, the material is generally non-permeable material coated with special coating, such as PET, PP or metal film, the surface of the film is generally treated by fluoride coating or silicone coating;

the support layer material used in the patch of the present invention mainly functions to attach the colloid system, and is not particularly limited as long as it can provide sufficient adhesive force of the colloid to the support layer and is comfortable to the skin upon application. Thus, the article should have some flexibility, i.e. the support layer material is able to follow the curvature and movements of the skin to a certain extent, and does not cause significant discomfort when it is adhered to the skin surface. The support may be a single layer structure, such as: the film may be a laminate structure of a support film having a single-layer structure, a layer or a film obtained by laminating a plastic film such as polyethylene or polyurethane and a metal film.

The method for preparing the rotigotine-containing transdermal patch as described above comprises preparing the composition, coating the composition on a protective film or a release film using a coater, drying in an oven to volatilize the organic solvent, coating a supporting layer coating film, and finally slicing and packaging.

Specifically, rotigotine and an antioxidant (such as DL-alpha-tocopherol) are dissolved in a high molecular polymer mainly containing polyisobutylene, the mixture is uniformly mixed and coated by a coating machine, so that a medicine-containing colloid is uniformly covered on a protective film or a release film, then drying is carried out in an oven, an organic solvent is volatilized, a supporting layer is coated by a roller, and finally, the supporting layer is sliced by a die and packaged.

The invention has the beneficial effects that:

the transdermal patch containing rotigotine adopts polyisobutylene pressure-sensitive adhesive, has long and straight C-H skeleton and unsaturated bonds only in the end group, and has the advantages of stable colloid system, good weather resistance, heat resistance and ageing resistance, low cost, easily obtained materials and strong operability due to few double bonds and few reaction positions. In addition to the polyisobutylene skeleton material, other materials can be added to adjust the property of the patch, such as a viscosity regulator and a polybutene material, and in addition, some additives can be added to achieve unexpected effects, such as a colloid softener, the initial purpose is to reduce the viscosity of the pressure-sensitive adhesive, facilitate the dispersion and processing of multiple components and improve the wetting performance of the pressure-sensitive adhesive, and improve the initial adhesion and the hand feeling performance. In conclusion, the transdermal patch of rotigotine prepared on the basis of the preparation method has the characteristics of excellent drug release property from the patch and excellent skin permeability on the premise of meeting some conventional properties of the patch.

Drawings

Fig. 1 is a schematic structural diagram of a preferred embodiment of the present invention.

Fig. 2 is a graph of cumulative permeation per unit area versus time for compositions 1-1, 1-2 patches.

Fig. 3 is a plot of cumulative permeation per unit area versus time for a patch of composition 11 versus a patch of control 1.

Fig. 4 is a plot of cumulative permeation per unit area versus time for a patch of composition 12 versus a patch of control 1.

Fig. 5 is a graph of cumulative permeation per unit area versus time for a patch of composition 13 versus a patch of control 1.

Figure 6 is a plot of cumulative permeation per unit area versus time for a patch of composition 1 versus control 1, control 2, and control 3.

Fig. 7 is a graph of cumulative permeation per unit area versus time for the patches of composition 1, composition 5, and comparative example 1.

Fig. 8 is a graph of cumulative permeation per unit area versus time for the patches of composition 1, composition 2, composition 3 and comparative example 1.

FIG. 9 is a graph showing the results of a stability test for composition 1.

FIG. 10 is a graph showing the results of the stability test in comparative example 2.

FIG. 11 is a graph showing the results of stability experiments for blank control.

Detailed Description

Through a great deal of research by the inventor, the invention discovers that the patch containing rotigotine is prepared by dissolving/dispersing rotigotine medicine in polyisobutylene pressure-sensitive adhesive prepared from high molecular polyisobutylene with the molecular weight of 45-210 ten thousand and low molecular polyisobutylene with the molecular weight of 1000-45 thousand and viscosity regulator with the dosage of less than 50%, preferably 5-40% (w/w), and has good permeability, wherein the viscosity regulator can be selected from: polybutylene, low molecular polyisobutylene, acrylic binder, acetic acid/vinyl acetate copolymer (EVA) and other substances capable of adjusting viscosity, wherein polybutylene and low molecular polybutene are preferred, and low molecular polybutene is more preferred. Wherein the passing property of the rotigotine in the colloid is improved by adjusting the proportion of the viscosity regulator in the colloid.

In addition, the viscosity modifier described in the polyisobutylene polymer system may also be added with other substances that help to modify viscosity, such as tackifiers, plasticizers, thermoplastic resins, which are a common type of substances that modify initial viscosity: the softening point of the resin is 50-250 ℃, preferably 50-150 ℃, and the resin comprises natural resin such as rosin and derivatives thereof, terpene resin, terpene phenol resin and the like, and synthetic resin comprises petroleum resin, xylene resin and the like. The use ratio of the polyisobutylene polymer is less than 50 percent by weight, preferably 5-40 percent (W/W) of the polyisobutylene polymer is added into the synthetic colloid component.

The composition of the present invention is prepared by adding a colloid softener, such as liquid paraffin, light liquid paraffin, low molecular weight polyisobutylene, lanolin, lubricating grease, etc., preferably liquid paraffin, light liquid paraffin, more preferably light liquid paraffin. The addition of colloid softener can improve the stability of the patch and avoid the precipitation of active ingredients of the medicine from the preparation. In addition, the addition of the colloid softener can improve the fluidity of the medicine in the matrix, so that the medicine can be separated from the matrix more easily, thereby increasing the transdermal performance of the medicine and enhancing the curative effect of the medicine. In addition, the invention has multiple advantages, and because the materials used in the formula are different from the commercially available products in structure, the problem of possible instability of the commercially available products is avoided.

Other fillers such as starch and silica gel micropowder can also be added. These components can improve wettability of the patch when it is used by sticking, and improve the state of adhesion and comfort when it is applied, by virtue of their hydrophilic properties.

The following description of the present invention is provided in connection with specific examples and should not be construed as limiting the invention. Modifications or substitutions to methods, procedures, or conditions of the invention may be made without departing from the spirit and scope of the invention.

Unless otherwise indicated, the technical means used in the examples are conventional means well known to those skilled in the art, and the reagents used are not specifically indicated and are all conventional commercially available reagents.

Example 1 preparation of transdermal patch composition for the preparation of rotigotine

Adding rotigotine and DL-alpha-tocopherol in the amounts specified in Table 1 into a suitable amount of absolute ethanol solution in a suitable glass container, and stirring until the mixture is completely dissolved. The polyisobutylene B100, the polyisobutylene B10 and the low molecular weight polybutene with the prescription amount in the table 1 are taken and stirred and mixed uniformly to form the polyisobutylene pressure sensitive adhesive, and the colloidal silica and the light liquid paraffin are added into the pressure sensitive adhesive and stirred and mixed uniformly; adding the medicinal solution while stirring until a uniform dispersion system is obtained, and vacuum degassing to obtain compositions 1-1 and 1-2.

The obtained compositions 1-1 and 1-2 were coated on a release film using a small laboratory coater (Elcometer, UK) at a thickness such that the content of the drug per unit area in the dried patch was constant, i.e., per 10cm²Patch with adhesive tapeAnd 4.5mg of tegaserod. Forming a uniform thin layer, drying for 30 minutes at 80 ℃, and covering a supporting layer. Fig. 1 shows a schematic structural diagram of the patch of the present invention, wherein 1 is a support layer, and 2 is a self-adhesive matrix layer containing rotigotine as an active ingredient.

TABLE 1 comparative testing of patch matrices

Detecting the release amount of rotigotine in the transdermal patch of each composition, and adopting an improved FRANZ transdermal diffusion apparatus (LOGAN, ACS-100 type transdermal diffusion apparatus); the experimental carrier adopts purchased dead skin (after subcutaneous fat layer of human breast skin within 2 hours after operation is removed, the skin is washed by normal saline and then refrigerated at minus 30 ℃ for standby); the transdermal actual area of the patch in the experiment is 1.98cm²The temperature of the water bath is 32 ℃, the stirring speed is 500rpm, the volume of the receiving pool is 14ml, and the pH6.8 phosphate buffer solution is used as a receiving medium. The patch is adhered to the stratum corneum of the skin, fixed on a receiving pool, and sampled for 4.5ml at regular time, and then a blank receiving solution with constant temperature of 32 ℃ is supplemented. The sample is analyzed by high performance liquid chromatography (Shimadzu LC-20A type), the cumulative permeation amount of the medicine per unit area is calculated according to the permeation amount, and the sample number is as follows: 2-6 samples are selected from the test article of each patch of the embodiment or the control example; because the transdermal data of the sample are influenced by the skin source and the skin state, the skin from the same source at the same part is selected for experimental investigation in each test. Experimental method an in vitro transdermal experiment was carried out with reference to the experimental method described in "New dosage form for transdermal administration" (Zheng Junmin, people's health Press, 2006, 12 months, Press page 265).

The results are shown in Table 2. The cumulative permeation per unit area versus time for the patches of compositions 1-1 and 1-2 is shown in figure 2.

TABLE 2

According to the past experience, the permeation property of the API in the gel can be improved by increasing the proportion of the low molecular weight polyisobutylene component in the formulation. The invention improves the proportion of the polyisobutylene with low molecular weight in the polyisobutylene and inspects the in vitro percutaneous release behavior. As a result, it was found that increasing the ratio of the low-molecular-weight polyisobutylene, on the contrary, exerts the effect of suppressing the drug release in the patch.

Example 2 comparative testing of different softeners

The type of the softener is screened, so that the transparent behavior of the softener is improved by changing the softener, and the softener is screened for three different softeners: the components and amounts used are shown in table 3, and the preparation method was the same as that described in example 1.

TABLE 3 Components used and amounts

Wherein the Polyisobutylene pressure sensitive adhesive is prepared by uniformly mixing 30.7 parts by weight of Polyisobutylene (isopanol B100, viscosity average molecular weight of 1,000,000)), 30.7 parts by weight of Polyisobutylene (isopanol B10, viscosity average molecular weight of 30,000)), and 5 parts by weight of low molecular polybutene (HV-300, viscosity average molecular weight of 1,260).

Transdermal patches were prepared for the above-prepared compositions 11, 12, and 13, and the release amount of rotigotine in the transdermal patches of the above-prepared compositions was measured by the method described in example 1 while using commercially available rotigotine patch product NEUPRO (UCB, rotigotine)The content of the extract is 0.45mg/cm²) The detection was performed as in comparative example 1.

And f2 factor comparison is carried out on the detection result, wherein,

calculation formula of f 2:

where Rt and Tt represent the average cumulative flux per unit area at time t for the reference and test formulations, respectively, and n is the number of test points, a greater factor f2 indicates greater similarity between the two curves, generally considered consistent when the factor f2 is greater than 50.

The results of testing compositions 11, 12 and 13 prepared from different softeners and comparing the f2 factors are shown in tables 4, 5 and 6.

TABLE 4

TABLE 5

TABLE 6

The results of comparative example 1 in tables 4, 5 and 6 show that the skin selected each time has different drug permeability due to different positions, and the cumulative permeation amount per unit area-time curve graphs are drawn according to the data in the tables, and particularly as shown in fig. 3, 4 and 5, the results show that the light liquid paraffin has the best effect.

Example 3 preparation of transdermal patch composition for the preparation of rotigotine

Composition 1:

the rotigotine, ascorbyl palmitate and all-rac-a-tocopherol, in the amounts prescribed in table 7, were added to an appropriate amount of absolute ethanol solution in a suitable glass container and stirred until the mixture was completely dissolved.

Adding liquid paraffin into the polyisobutylene pressure-sensitive adhesive in the amount prescribed in the table 1, and stirring and mixing the mixture uniformly; adding the medicinal solution while stirring to obtain uniform dispersion system, and vacuum degassing. Coating the obtained colloid system on a release film by using a small laboratory coater (UK, Elcometer) to a thickness of a certain amount per unit area of the dried patch, that is, every 10cm²The patch contains rotigotine 4.5 mg. Forming a uniform thin layer, drying for 30 minutes at 80 ℃, and covering a supporting layer.

Composition 2:

the difference from composition 1 was that the materials were added as in Table 7 with the addition of silicone pressure sensitive adhesive and without the addition of liquid paraffin.

Composition 3:

the difference from composition 1 was that the substances were added as in Table 7 with the addition of acrylic pressure sensitive adhesive and without the addition of liquid paraffin.

Composition 4:

the difference from composition 1 is that the substances are added according to table 7, liquid paraffin and aerosil are added, stirred and mixed until uniform, and then the drug solution is added thereto.

Composition 5:

the difference from composition 1 is that the substances are added according to table 7, liquid paraffin and starch are added, stirred and mixed until homogeneous, and the drug solution is added thereto.

Composition 6:

the difference from composition 1 is that the substances are added according to table 7, lanolin and aerosil are added, mixed until homogeneous, and the drug solution is added thereto.

Composition 7:

the difference from composition 1 is that the substances are added according to table 7, polyvinylpyrrolidone, ascorbyl palmitate, all-rac-a-tocopherol and rotigotine in the amounts specified in table 1 are added to an appropriate amount of absolute ethanol solution, and the mixture is stirred until the mixture is completely dissolved.

Composition 8:

the difference from composition 1 is that the substances are added as in Table 7.

Comparative example 1

Is commercially available as NEUPRO (UCB, content of rotigotine is 0.45 mg/cm)²)。

Comparative examples 2 to 3

The patches of comparative examples 2 and 3 were prepared according to the method of composition 1, according to the components in the drug reservoir layer and the contents thereof (parts by weight) given in table 7. Wherein the comparative example 2 did not contain a softener liquid paraffin; in comparative example 3, only the polyacrylic pressure sensitive adhesive was used instead of the polyisobutylene pressure sensitive adhesive, compared to comparative example 2.

TABLE 7 amounts of the components in the examples

Note: all examples and controls (experimental samples including NEUPRO of control 1) contained the same amount of rotigotine (0.45 mg/cm)²) So as to ensure the comparability of the experimental results.

The compositions prepared above were subjected to in vitro transdermal tests using the test method described in example 1. The experimental results of the permeation rate of the patches prepared from the composition 1 and the patches of the comparative examples 1,2 and 3 through the human ex vivo skin are shown in table 8, fig. 6 is a graph (n is 2) of the permeation rate of the patches prepared from the composition 1 and the patches of the comparative examples 1,2 and 3 through the human ex vivo skin versus time, and according to the data in the graph, the in vitro transdermal permeation amount of the composition 1 is much higher than that of the patches prepared from other systems (comparative example 3), and compared with the prescription (comparative example 2) without the softener, the composition 1 also shows a significant transdermal advantage and also has a significant advantage compared with the currently marketed silicone system prescription.

The results of the factor f2 comparison on the transdermal curves are shown in Table 8.

TABLE 8

Because the comparison example 1 adopts the patch prepared by the expensive silicone pressure-sensitive adhesive on the market at present, and the transdermal value of the patches prepared by using other pressure-sensitive adhesives (comparison examples 2 and 3) is too low to meet the requirement, the composition 1 mentioned in the application is improved on the basis of the comparison example 2, and the same in-vitro transdermal release effect as the comparison example 1 is achieved by adding other substances, so that further clinical research can be carried out, and the corresponding treatment effect can be achieved.

The graphs (n-2) of permeation rate of the patch prepared from the compositions 1 and 4 and the patch prepared from the control example 1 through the skin in vitro and the time are shown in fig. 7, and on the basis of the composition 1, partial fillers such as aerosil are added to further improve the adhesive force state of the patch. The transdermal condition of the composition 4 and the composition 1 is examined, and the transdermal condition can be adjusted without influencing the transdermal effect after partial filling.

The results of the in vitro transdermal permeabilities of the compositions 1,2 and 3 and the comparative example 1 are shown in table 9, and the results show that the in vitro transdermal permeabilities of the compositions 1,2 and 3 and the comparative example 1 are not statistically different, so that the colloid system is not limited to the polyisobutylene matrix, but also comprises a mixture system of polyisobutylene, silicone and acrylic matrix.

TABLE 9

All of the factors f2 were compared with comparative example 1, and the results are shown in FIG. 8, which shows that the transdermal results of the compositions 1-3 of the present invention are significantly better than those of comparative example 1. The comparative example 1 is a commercially available sample, is widely used in clinic and has a good treatment effect, and the prepared compositions 1 to 3 have good transdermal property and can completely meet the requirements in clinical treatment.

Example 4 stability experiment

The composition 1, the comparative example 2 and a blank control (the blank control selected in the example is a release film, whether impurities exist on the release film is observed by a microscope, and the test is prevented from being interfered, the release film is made of PET), are placed at the temperature of 40 +/-2 ℃ and the humidity of 75 +/-5 percent for 2 months, and are subjected to crystallization condition investigation. Such a phenomenon is often referred to as an aging phenomenon in pharmacy. Wherein the conversion of the drug from the amorphous state to stable drug crystals, the degree of dispersion is reduced, and this conversion reduces the thermodynamic activity of the drug. The reduction of the thermodynamic activity of the drug may cause the reduction of the dissolution rate of the drug and the reduction of the transdermal performance of the drug, thereby reducing the treatment effect of the drug. The crystallization condition of the sample was observed by using a microscope, the sample was directly observed by using the microscope (model BX51, Olympus, Japan) with the microscope magnification of 10X 10, and photographed, and the results are shown in FIGS. 9, 10 and 11, wherein FIG. 1 shows that the product prepared by the composition 1 has no crystal precipitation and the sample is relatively stable, FIG. 2 shows that the product prepared by the comparative example 2 has crystal precipitation, wherein the upper part is crystal and the lower part is a common sample, which indicates that the sample of the comparative example 2 is unstable; in the blank comparison example in fig. 3, because the PET is used as the release film for the observation of the sample, the interference caused by the impurities on the release film in the experimental process can be avoided for the surface observation of the release film.

Claims

1. A composition for the preparation of a transdermal patch containing rotigotine, characterised in that it comprises an effective amount of rotigotine and a self-adhesive matrix comprising a polyisobutylene pressure-sensitive adhesive and a colloidal softener;

the polyisobutylene pressure-sensitive adhesive comprises macromolecular polyisobutylene with the molecular weight of 45-210 ten thousand and low molecular polyisobutylene with the molecular weight of 1000-45 ten thousand according to the weight ratio of 1: 10-10: 1, and a viscosity regulator, wherein the colloid softener is liquid paraffin or light liquid paraffin; the adhesive force regulator is low-molecular-weight polybutylene, the molecular weight of the low-molecular-weight polybutylene is 500-1500, and the amount of the adhesive force regulator is 5-44% of the weight ratio of the polyisobutylene pressure-sensitive adhesive;

the weight ratio of the polyisobutylene pressure-sensitive adhesive to the self-adhesive matrix is 20-99 percent; the weight ratio of the colloid softener to the self-adhesive matrix is less than 55 percent; the weight ratio of the rotigotine in the composition is 5-20%.

2. The composition according to claim 1, wherein the self-adhesive matrix further comprises silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesive, and the silicone pressure-sensitive adhesive or acrylic pressure-sensitive adhesive accounts for 0-16.5% by mass of the self-adhesive matrix.

3. The composition according to claim 1, wherein the self-adhesive matrix further comprises a penetration enhancer, the weight ratio of the penetration enhancer in the self-adhesive matrix is 0.5 to 7%, and the penetration enhancer is laurocapram, oleic acid or lauric acid.

4. The composition according to claim 1, characterized in that the self-adhesive matrix further comprises a surfactant, which is tween, span or sodium lauryl sulfate.

5. The composition according to claim 1, characterized in that the self-adhesive matrix further comprises a tackifying resin, which is rosin, cyclopentadiene or isoprene, in a proportion of between 5% and 25% by weight of the self-adhesive matrix.

6. The composition according to claim 1, wherein the self-adhesive matrix further comprises a stabilizer, the weight ratio of the stabilizer in the self-adhesive matrix is 0.5 to 7%, and the stabilizer is polyvinylpyrrolidone, poloxamer or polyethylene glycol.

7. The composition according to claim 1, wherein the self-adhesive matrix further comprises other fillers, the weight ratio of the other fillers in the self-adhesive matrix is 0.5-7%, and the other fillers are starch, silica, colloidal silica or silica micropowder.

8. The composition as claimed in claim 1, wherein the self-adhesive matrix layer further comprises an antioxidant, the antioxidant is one or a mixture of several of ascorbyl palmitate, sodium metabisulfite, DL-alpha-tocopherol or dibutyl hydroxy toluene, and the amount of the antioxidant is 0.01-2% of the self-adhesive matrix layer.

9. A transdermal patch comprising a composition according to any one of claims 1 to 8.

10. The method for preparing a transdermal patch according to claim 9, wherein the composition is prepared by coating the composition on a protective film or a release film using a coater, drying in an oven to evaporate an organic solvent, coating a supporting layer coating film, and finally slicing and packaging.