CN115252718A

CN115252718A - Transdermal patch containing timolol and preparation method thereof

Info

Publication number: CN115252718A
Application number: CN202110482806.9A
Authority: CN
Inventors: 周小顺; 牟东升; 贺容丽; 李进; 刘文双
Original assignee: Wuhan Conform Pharmaceutical Co ltd
Current assignee: Wuhan Conform Pharmaceutical Co ltd
Priority date: 2021-04-30
Filing date: 2021-04-30
Publication date: 2022-11-01

Abstract

The invention provides a transdermal patch containing timolol active ingredients and a preparation method thereof. The transdermal patch consists of a back lining layer, a medicine layer and a protective layer, the medicine release and skin absorption are promoted by adding a proper penetration enhancer in the medicine layer, the stability of the patch is improved and the irritation to the skin is reduced by adding traditional Chinese medicine components, so that the bioavailability of active medicines and the receiving degree of infants are finally improved, and the administration frequency is reduced.

Description

Transdermal patch containing timolol and preparation method thereof

Technical Field

The invention relates to the field of medicinal preparations, in particular to a patch containing timolol active ingredients, a preparation method of the patch and application of the patch to hemangioma treatment.

Background

Timolol is a non-selective beta-adrenergic receptor blocker, with 8 times the receptor blocking effect of propranolol, but with much less side effects than propranolol. The traditional Chinese medicine composition is widely used for treating diseases such as hypertension, angina pectoris, tachycardia and the like in clinic, but the medicine has great liver first pass effect and low bioavailability of oral administration; and because the biological half-life period is 2.5-4.5 h, the ideal effect can not be achieved by intravenous administration. The preparation absorbed through skin has the advantages of avoiding first pass effect of liver, continuous administration, etc. In 2010, researchers can externally treat the hemangioma of infants by local application, and a better effect is achieved.

Patent application CN201410447231.7 discloses a timolol long-acting transdermal preparation and application thereof in hemangioma. The preparation method of the transdermal preparation comprises the steps of preparing timolol into timolol nano-drugs or micro-powder, and then preparing the timolol nano-drugs or micro-powder into timolol hydrogel transdermal preparations, ointment transdermal preparations or microneedle transdermal preparations. The ointment preparation needs to be administrated for multiple times at fixed intervals, the inorganic silicon microneedle preparation is not safe enough in biocompatibility, and silicon materials are easy to break to cause other health problems in the skin. In addition, no mention is made in this patent application of how to solve the problem of poor bioavailability of timolol caused by photosensitivity to light, nor the problem of poor acceptability of infants caused by discomfort due to irritation of sensitive skin by drugs, regardless of the formulation.

Disclosure of Invention

In order to improve the stability of timolol active ingredients in a preparation, reduce allergy caused by drug stimulation, improve the bioavailability of a drug and facilitate the administration of the drug, the invention provides a timolol transdermal patch, which consists of a back lining layer, a drug layer and a protective layer, wherein the drug layer consists of the following raw materials in percentage by mass: 10-20% of timolol active ingredient, 15-25% of humectant, 2-8% of patch skeleton, 1-2% of cross-linking agent, 1-2% of cross-linking regulator, 30-40% of gel matrix, 1-3% of penetration enhancer, 5-10% of traditional Chinese medicine ingredient, pH regulator and water; the pH value of the medicine layer is 7.0-7.5 by adding the pH regulator, and the sum of the mass ratios of the components of the medicine layer is 100% by using the water.

Preferably, the Chinese medicinal components comprise a first mixture obtained by respectively sieving powders of herba schizonepetae, honeysuckle, fagopyrum cymosum, folium artemisiae argyi, pinellia ternate, rhizoma bletillae, radix astragali and ginseng with a 100-mesh sieve and mixing.

Further preferably, the first mixture is composed of the following raw materials in parts by weight: 20 to 50 parts of herba schizonepetae, 10 to 20 parts of honeysuckle, 10 to 20 parts of wild buckwheat rhizome, 5 to 15 parts of folium artemisiae argyi, 5 to 10 parts of pinellia ternate, 2 to 6 parts of rhizoma bletillae, 10 to 30 parts of astragalus mongholicus and 1 to 10 parts of ginseng.

Preferably, the Chinese medicinal components comprise a second mixture obtained by respectively sieving powders of flos Sophorae Immaturus, coptidis rhizoma, scutellariae radix, folium Isatidis, glycyrrhrizae radix, aloe and rhizoma Polygoni Cuspidati with 100 mesh sieve and mixing.

Further preferably, the second mixture is composed of the following raw materials in parts by weight: 30 to 50 parts of sophora flower bud, 20 to 40 parts of goldthread root, 10 to 25 parts of folium isatidis, 6 to 12 parts of liquorice, 1 to 10 parts of common coltsfoot flower and 1 to 10 parts of giant knotweed rhizome.

Preferably, the penetration enhancer is at least one of azone, sodium dodecyl sulfate, sodium tetradecyl sulfate, hexadecyltrimethylammonium chloride, eucalyptus oil, propylene glycol, farnesol and thiaketone.

Further preferably, the penetration enhancer consists of azone and thiaketone according to the mass ratio of 1 (1-5).

Still further preferably, the penetration enhancer consists of azone and thiaketone in a mass ratio of 1:1.

Preferably, the gel matrix consists of poloxamer P407 and poloxamer P188 in a mass ratio of (1.5-2.1): 1.

Preferably, the patch matrix is sodium polyacrylate NP700; the humectant is at least one of glycerol, polyethylene glycol, butanediol, sorbitol and hyaluronic acid; the cross-linking agent is at least one of dihydroxyaluminum glycinate, aluminum trichloride, aluminum sulfate and aluminum hydroxide; the crosslinking regulator is EDTA and/or EDTA sodium salt.

Preferably, the timolol active ingredient is timolol and/or a pharmaceutically acceptable salt of timolol.

The invention also provides a preparation method of the transdermal patch containing the timolol active ingredient, which comprises the following steps:

s1, adding the cross-linking agent and the cross-linking regulator into the humectant, uniformly stirring, adding the patch framework, and uniformly stirring to obtain a mixture A;

s2, adding the traditional Chinese medicine component, the timolol active component and the penetration enhancer into water, stirring uniformly, adding the gel matrix, and stirring uniformly to obtain a mixture B;

and S3, slowly adding the mixture B into the mixture A, uniformly stirring, adding the pH regulator to regulate the pH value to 7.0-7.5, coating the mixture on the back lining layer, standing and curing at 0-10 ℃, and attaching the protective layer to obtain the transdermal patch.

Preferably, the transdermal patch prepared as described above is used for the treatment of hemangiomas.

Further preferably, the transdermal patch prepared according to the above method is used for treating infantile hemangioma.

Compared with the prior art, the invention has the beneficial effects that: (1) According to the invention, the traditional Chinese medicine components are added into the patch, so that the photostability of the timolol active component can be greatly improved, the irritation of various components in the patch to the skin is reduced, the situation that the bioavailability is not high due to the degradation of the timolol active component when the patch is used for a long time can be prevented, and the discomfort caused by the continuous irritation of the patch to the skin due to the long-time contact of the patch with the skin can be avoided; (2) The patch prepared by the invention does not need to be added with preservative, and can keep the patch stable for a long time by utilizing the anti-inflammatory and antibacterial effects of the traditional Chinese medicine components; (3) The active ingredients in the patch prepared by the invention can be slowly released for a long time, the administration frequency can be reduced, and the patch is particularly suitable for treating infantile hemangioma.

Detailed Description

The technical solution of the present invention is described in detail and fully with reference to the following examples, it is obvious that the described examples are only a part of the examples of the present invention, and not all of the examples. All other embodiments, which can be derived by a person skilled in the art from the embodiments of the present invention without making any creative effort, shall fall within the protection scope of the present invention. Any equivalent changes or substitutions by those skilled in the art according to the following embodiments are within the scope of the present invention.

In the following examples, powders of schizonepeta, honeysuckle, wild buckwheat, artemisia leaf, pinellia tuber, bletilla striata, astragalus root, ginseng, sophora flower bud, goldthread root, isatis leaf, licorice, coltsfoot flower and giant knotweed rhizome are respectively sieved by a 100-mesh sieve, and then mixed according to parts by weight to obtain a first mixture and a second mixture respectively. The composition of the first mixture was as follows: 30 parts of schizonepeta, 20 parts of honeysuckle, 15 parts of wild buckwheat rhizome, 10 parts of folium artemisiae argyi, 6 parts of pinellia ternate, 5 parts of rhizoma bletillae, 30 parts of astragalus membranaceus and 5 parts of ginseng; the composition of the second mixture was as follows: 40 parts of sophora flower bud, 30 parts of goldthread root, 15 parts of folium isatidis, 10 parts of liquorice, 5 parts of flos farfarae and 5 parts of giant knotweed.

Example 1

The transdermal patch containing timolol active ingredient in this example consists of a backing layer, a drug layer, and a protective layer. Wherein the medicine layer consists of the following raw materials in percentage by mass:

15% timolol, 15% glycerin, 2% sodium polyacrylate NP700,1% aluminum hydroxide, 1% edta,40% gel matrix, 1% penetration enhancer, 10% herbal ingredients, pH adjuster citric acid, balance water, adjusted pH =7.0. The gel matrix is composed of poloxamer P407 and poloxamer P188 according to a mass ratio of 1.5. The penetration enhancer is composed of eucalyptus oil and 1,3-propylene glycol according to the mass ratio of 1:1. The traditional Chinese medicine component is a first mixture.

The preparation method of the patch comprises the following steps:

s1, adding aluminum hydroxide and EDTA into glycerol, stirring uniformly, adding sodium polyacrylate NP700, and stirring uniformly to obtain a mixture A;

s2, adding the traditional Chinese medicine components, timolol and the penetration enhancer into water, stirring uniformly, adding the gel matrix, and stirring uniformly to obtain a mixture B;

and S3, slowly adding the mixture B into the mixture A, stirring uniformly, adding citric acid to adjust the pH value to 7.0, coating the obtained medicine layer on the back lining layer, standing and curing at 0-10 ℃, and attaching the protective layer to obtain the transdermal patch.

Example 2

10% timolol, 25% polyethylene glycol, 5% sodium polyacrylate NP700,1.5% aluminum chloride, 1.5% disodium EDTA, 38% gel matrix, 2% penetration enhancer, 5% traditional Chinese medicine components, tartaric acid as a pH regulator, and water as the balance, and adjusting pH =7.5. The gel matrix is composed of poloxamer P407 and poloxamer P188 according to a mass ratio of 1.8. The penetration enhancer is composed of sodium dodecyl sulfate and sodium tetradecyl sulfate according to a mass ratio of 1:1. The traditional Chinese medicine component is a second mixture.

The preparation method of the patch in this example was the same as in example 1 except that the raw material in example 1 was replaced with the raw material in this example.

Example 3

20% timolol maleate, 20% butanediol, 8% sodium polyacrylate NP700,2% aluminum sulfate, 2% EDTA tetrasodium, 30% gel matrix, 3% penetration enhancer, 6% Chinese medicinal components, malic acid as pH regulator, and water as balance, and adjusting pH =7.5. The gel matrix is composed of poloxamer P407 and poloxamer P188 according to a mass ratio of 2.1. The penetration enhancer is prepared from thiaketone and 1,2-propylene glycol according to the mass ratio of 1:2. The Chinese medicinal components are mixture of first mixture and second mixture.

Example 4

The composition of the drug layer of the transdermal patch containing timolol as the active ingredient in this example was substantially the same as in example 1, except that the herbal ingredient was a mixture of the first mixture and the second mixture.

The method of producing the patch in this example was the same as in example 1 except that the raw material in example 1 was replaced with the raw material in this example.

Example 5

The composition of the drug layer of the transdermal patch containing timolol as the active ingredient in this example was substantially the same as that of example 4, except that the permeation enhancer was azone and thiazone in a mass ratio of 1:1.

Comparative example 1

The composition of the drug layer of the transdermal patch containing timolol as an active ingredient in this comparative example was different from that of example 1 in that the drug layer of this comparative example did not contain a traditional Chinese medicine ingredient, i.e., the drug layer of this comparative example did not contain the first mixture.

The preparation method of the patch in this comparative example was the same as in example 1 except that the raw material in example 1 was replaced with the raw material in this comparative example.

Comparative example 2

The composition of the drug layer of the transdermal patch containing timolol as an active ingredient in this comparative example was different from that of example 4 in that the permeation enhancer was not contained in the drug layer in this comparative example.

The preparation method of the patch in this comparative example was the same as in example 4 except that the raw material in example 4 was replaced with the raw material in this comparative example.

Comparative example 3

The composition of the drug layer of the transdermal patch containing timolol as the active ingredient in this comparative example was different from that of example 2 in that the drug layer in this comparative example did not contain the traditional Chinese medicine ingredient, i.e., the drug layer in this comparative example did not contain the second mixture.

The preparation method of the patch in this comparative example was the same as in example 2 except that the raw material in example 2 was replaced with the raw material in this comparative example.

Stability test

The transdermal patches prepared in each example and comparative example were directly placed in a light box, irradiated with fluorescent light at an irradiation intensity of 4000 to 5000lx for 8 hours per day for 7 days, and the purity of timolol active ingredient (API) in the patch was measured using HPLC method at 0, 3, 5, and 7 days, respectively, and the test results are shown in table 1; the HPLC chromatographic conditions were as follows:

a chromatographic column: venusil MP-C18 column (250 mm. Times.4.6 mm,5 μm),

mobile phase: phosphate buffer (0.05 mol/L sodium dihydrogen phosphate, 0.5mL triethylamine per 1000mL, pH adjusted to 3.0 with phosphoric acid) -acetonitrile (85 by volume,

detection wavelength: at the wavelength of 295nm,

flow rate: 1.0mL/min of the reaction solution,

column temperature: at a temperature of 25 c,

sample injection amount: 20 μ L.

TABLE 1 stability test data for transdermal patches containing timolol as active ingredient

As can be seen from the above table, the types and amounts of the ingredients of the Chinese herbal medicines used in examples 4 and 5 are the same, and the degradation rates of the timolol active ingredient in the patch are substantially the same. Example 3 the same kind of the Chinese medicine ingredients as in example 4 was added, but the content of the Chinese medicine in example 3 was lower than that in example 4, and the degradation rate of timolol active ingredient in the patch was faster than that in example 4. In comparative examples 1 and 3, no herbal ingredients were added, and the degradation rate of timolol active ingredient in the patch was much greater than in examples 1 and 2.

Transdermal Performance test

The drug layers prepared in examples 1 to 5 and comparative example 2 were subjected to a transdermal test, and the test results are shown in table 2; the test method is as follows:

the experimental device is characterized in that an improved Franz vertical diffusion cell is adopted for testing, the skin of a rat in vitro is cleaned, the rat is fixed between a supply cell and a receiving cell, 2g of a tested drug layer is uniformly coated on the skin of the rat, physiological saline is added into the receiving cell, a magnetic stirrer is placed in the receiving cell, the stirring speed is 200-300 rpm, and the temperature of the receiving cell is 36.5 ℃. After the test, samples were taken at 1,2, 4, 6, 8 and 12 hours, filtered through a 0.22 μm microporous membrane and then detected by HPLC, and 3mL of the receiving solution was taken, and 3mL of physiological saline was added to the receiving cell immediately after each sample was taken.

TABLE 2 transdermal patch transdermal performance test results containing timolol active ingredient

As can be seen from the test results in the above table, the highest amount of timolol and the highest amount of percutaneous permeation are obtained in example 3, and the lowest amount of timolol and the lowest amount of percutaneous permeation are obtained in example 2, which indicates that the amount of percutaneous permeation of the active drug in the patch prepared according to the present invention is in positive correlation with the content thereof. The timolol content in examples 1, 4 and 5 is the same, and example 5 is different from example 4 in the penetration enhancer, but the transdermal penetration amount of example 5 is the largest, which shows that the penetration enhancer in example 5 has the best penetration enhancing effect. Comparative example 2 has the same timolol content as example 4 except that the transdermal penetration rate is significantly lower than that of example 4 without the addition of a penetration enhancer, which indicates that the penetration enhancer in the present application can significantly increase the release rate of the timolol pharmaceutical active ingredient. As can be seen from the table, the drug release rate was always on the increase in the first 8 hours, and after more than 8 hours, the increase was slow, indicating that the patch prepared according to the present invention can release the pharmaceutically active ingredient for a long period of time.

Cumulative skin irritation test

The back of 8 healthy rabbits were dehaired 24h before the experiment with an electric shaver, and the dehaired area was about 4cm × 6cm. The patches prepared in examples 1 to 5 and comparative examples 1 to 3 were applied to the depilated area of each rabbit, respectively. After 24 hours, all the patches were removed, and then the skin condition of the test site was observed at 1, 24, 48, and 72 hours from the removal of the patches, and erroneous erythema, pimple, edema, and the like were recorded, and the irritation of the patches was evaluated according to the indices listed in table 3, and the evaluation results are shown in table 4.

TABLE 3 skin irritation test Scoring System

Skin irritation response	Score of
		No irritation	0
Slight erythema, barely observable	1
		Marked erythema, macroscopic evidence, mild edema or mild papular response	2
Erythema and papules	3
		Marked edema	4
Erythema, edema and papules	5
		Water bubble	6
Strongly reacting, distribution range is beyond the test part	7

TABLE 4 results of skin irritation test for transdermal patches containing timolol as the active ingredient

Score of	1h	24h	48h	72h
					Example 1	0	0	0.5	0.5
Example 2	0	0.5	1	1
					Example 3	0	0	0	0
Example 4	0	0	0	0
					Example 5	0	0	0	0
Comparative example 1	2	3	3.5	3.5
					Comparative example 2	0	0	0	0
Comparative example 3	1.5	2	2.5	2.5

As can be seen from table 4, in comparative examples 1 and 3, no herbal ingredient was added, and the irritation of the patch to the skin was significantly worse than in example and comparative example 2, in which herbal ingredients were added. Example 2 differs from examples 3 to 5 and comparative example 2 in the kind of the added herbal ingredients, and differs from example 1 in the kind of the added herbal ingredients, and the skin irritation of the patch prepared was slightly worse than in examples 3 to 5, comparative example 2 and example 1. From the comprehensive comparison of the test results of the examples and the comparative example, the traditional Chinese medicine components added in the examples 3-5 and the comparative example 2 simultaneously comprise schizonepeta, honeysuckle, wild buckwheat rhizome, folium artemisiae argyi, pinellia ternate, rhizoma bletillae, astragalus membranaceus, ginseng, sophora flower bud, goldthread root, folium isatidis, liquorice, coltsfoot flower and polygonum cuspidatum, and can effectively eliminate the irritation of the active pharmaceutical ingredients and various auxiliary materials to the skin; the traditional Chinese medicine components in the embodiment 1 comprise schizonepeta, honeysuckle, wild buckwheat rhizome, folium artemisiae argyi, pinellia ternate, rhizoma bletillae, radix astragali and ginseng, the traditional Chinese medicine components in the embodiment 2 comprise sophora flower bud, goldthread root, folium isatidis, liquorice, flos farfarae and polygonum cuspidatum, and compared with the traditional Chinese medicine components in the embodiment 2, the traditional Chinese medicine components in the embodiment 1 can effectively reduce irritation of active pharmaceutical ingredients and various auxiliary materials to skin.

The above description is only a preferred embodiment of the present invention, and is not intended to limit the scope of the present invention. The present invention may take on various modifications and alterations, all as would be apparent to one skilled in the art. Any simple equivalent changes and modifications made in accordance with the protection scope of the present application and the content of the specification are intended to be included within the protection scope of the present invention.

Claims

1. The transdermal patch containing the timolol active ingredient consists of a back lining layer, a medicine layer and a protective layer, and is characterized in that the medicine layer consists of the following raw materials in percentage by mass: 10 to 20 percent of timolol active ingredient, 15 to 25 percent of humectant, 2 to 8 percent of patch skeleton, 1 to 2 percent of cross-linking agent, 1 to 2 percent of cross-linking regulator, 30 to 40 percent of gel matrix, 1 to 3 percent of penetration enhancer, 5 to 10 percent of traditional Chinese medicine ingredient, pH regulator and water; the pH value of the medicine layer is 7.0-7.5 by adding the pH regulator, and the sum of the mass ratios of the components of the medicine layer is 100% by using the water.

2. The transdermal patch containing timolol as an active ingredient according to claim 1, wherein the herbal ingredients comprise a first mixture of powders of Schizonepeta tenuifolia, lonicerae flos, fagopyrum esculentum Moench, artemisiae Argyi folium, pinelliae Tuber, bletilla striata, astragali radix and Ginseng radix, each of which is sieved with 100 mesh sieve and mixed.

3. The transdermal patch containing timolol active ingredient according to claim 2, wherein the first mixture is composed of the following raw materials in parts by weight: 20 to 50 parts of herba schizonepetae, 10 to 20 parts of honeysuckle, 10 to 20 parts of wild buckwheat rhizome, 5 to 15 parts of folium artemisiae argyi, 5 to 10 parts of pinellia ternate, 2 to 6 parts of rhizoma bletillae, 10 to 30 parts of astragalus mongholicus and 1 to 10 parts of ginseng.

4. The transdermal patch containing timolol active ingredient according to claim 1 or 2, wherein the Chinese medicinal ingredient further comprises a second mixture obtained by mixing powders of flos Sophorae Immaturus, rhizoma Coptidis, folium Isatidis, radix Glycyrrhizae, flos Farfarae and rhizoma Polygoni Cuspidati after each passing through a 100 mesh sieve.

5. The transdermal patch containing timolol active ingredient according to claim 4, wherein the second mixture is composed of the following raw materials in parts by weight: 30 to 50 parts of sophora flower bud, 20 to 40 parts of goldthread root, 10 to 25 parts of folium isatidis, 6 to 12 parts of liquorice, 1 to 10 parts of coltsfoot flower and 1 to 10 parts of giant knotweed.

6. The transdermal patch containing timolol as an active ingredient according to claim 1, wherein the penetration enhancer is at least one of azone, sodium dodecyl sulfate, sodium tetradecyl sulfate, cetyltrimethylammonium chloride, eucalyptus oil, propylene glycol, farnesol and thiaketone.

7. The transdermal patch containing the timolol active ingredient according to claim 6, wherein the penetration enhancer consists of azone and thiazone in a mass ratio of 1 (1-5).

8. The transdermal patch containing the timolol active ingredient according to claim 1, characterized in that the gel matrix consists of poloxamer P407 and poloxamer P188 in a mass ratio of (1.5-2.1): 1; the patch skeleton is sodium polyacrylate NP700; the humectant is at least one of glycerol, polyethylene glycol, butanediol, sorbitol and hyaluronic acid; the cross-linking agent is at least one of aluminium glycollate, aluminium trichloride, aluminium sulfate and aluminium hydroxide; the crosslinking regulator is EDTA and/or EDTA sodium salt.

9. The transdermal patch containing a timolol active ingredient according to claim 1, wherein the timolol active ingredient is timolol and/or a pharmaceutically acceptable salt thereof.

10. The method of making a transdermal patch containing a timolol active ingredient of claim 1, comprising the steps of:

and S3, slowly adding the mixture B into the mixture A, uniformly stirring, adding the pH regulator to regulate the pH value to 7.0-7.5, coating the mixture on the back lining layer, standing and solidifying at 0-10 ℃, and attaching the protective layer to obtain the transdermal patch.