CN102218074B - A transdermal patch containing paeoniflorin and glycyrrhetinic acid and its preparation method - Google Patents

Abstract

The invention discloses the composition and preparation method of a peony-licorice transdermal patch. The transdermal patch is composed of a backing layer, a drug-loaded pressure-sensitive adhesive layer and an anti-adhesive layer. The drug-loaded pressure-sensitive adhesive layer contains 1 to 20 parts by weight of paeoniflorin and glycyrrhetinic acid, or 5 to 30 parts by weight of paeoniflorin extract and glycyrrhetinic acid extract, and also contains an organic base, a transdermal penetration enhancer and butanol. The contents of paeoniflorin and glycyrrhetinic acid in the peony and licorice extracts are 20% to 90% respectively. The main active ingredients of peony and licorice in the transdermal patch can penetrate into the skin and subcutaneous tissue through the skin, effectively relieving and inhibiting the spasm and pain symptoms of local tissues.

Description

A transdermal patch containing paeoniflorin and glycyrrhetinic acid and its preparation method

technical field

The invention relates to the technical field of medicine, and provides a transdermal drug delivery system capable of suppressing local spasm and pain, specifically a transdermal patch containing paeoniflorin and glycyrrhetinic acid and a preparation method.

Background technique

Shaoyao Gancao Decoction comes from the book "Treatise on Febrile Diseases", which is formulated by Zhongjing for the acute syndrome of typhoid fever, sweating and death of yang, and leg spasms after yang recovery. In recent years, according to modern pharmacological research, Shaoyao Gancao Decoction has been widely used in internal medicine, surgery, gynecology and various pain syndromes. It is used in syndrome differentiation and has satisfactory curative effect.

Shaoyao Gancao Decoction is traditionally administered orally. Its curative effect is definite. It has pharmacological effects on uterine smooth muscle and gastrointestinal tract. Large doses can lead to adverse reactions such as gastrointestinal irritation, hypertension and pseudoaldosteronism, and the bioavailability is low. Theoretically, transdermal administration can avoid the first-pass effect of the stomach and liver. The active ingredients can not only directly reach the deep local target tissue under the skin to exert their local direct effect, but also enter the blood circulation through the subcutaneous capillary to exert a systemic effect. Therefore, for Shaoyao Gancao Decoction, transdermal administration is more advantageous than oral administration.

Long-term clinical practice has proved that Shaoyao Gancao Decoction has therapeutic effects on various muscle spasms and local pains. However, although the prescription is simple in composition, traditional extracts are used as raw materials, the active ingredients are too complicated, the quality is difficult to control, and the curative effect mechanism is difficult to explain. The active ingredients of traditional Chinese medicine are the material basis for exerting the medicinal effect, and the premise and basis for further in-depth research and development of traditional Chinese medicine. The use of active ingredients or effective component combination research on traditional Chinese medicine can ensure the accuracy of clinical dosage of traditional Chinese medicine, reduce toxicity and increase efficacy, and deeply reveal its mechanism of action.

A large number of studies have proved that the main components of Shaoyao Gancao Decoction are paeoniflorin and glycyrrhizic acid. After oral administration, glycyrrhizic acid is metabolized into glycyrrhetinic acid in the body to play a role. Oral formulations of peony and licorice extracts have been available for a long time, and there are many reports on the pharmacodynamic studies of the active ingredients of peony and licorice and different combinations of active ingredients. Although the conclusions are different, the synergistic effect has been confirmed. Patent CN101926815A discloses a composition of paeoniflorin and glycyrrhetinic acid, which is used to make various oral dosage forms to treat rheumatoid arthritis and eczema; CN 200810135364.5 discloses a preparation for transdermal administration of paeoniflorin and a preparation method. CN101433529A discloses a glycyrrhizic acid transdermal preparation and its preparation process, but does not provide any data that can explain the transdermal penetration and absorption of glycyrrhizic acid, and is only used to treat skin diseases. Patent CN101920017A discloses a composition for promoting the transdermal penetration of glycyrrhetinic acid, and this technology can improve the transdermal absorption of glycyrrhetinic acid. Whether Shaogan Decoction, a classic prescription of traditional Chinese medicine, can exert the same or even better medicinal effect than oral administration through skin administration requires the establishment of percutaneous penetration of active ingredients and the compatibility of active ingredients and active components. The synergistic drug effect is proved, and the composition and process are optimized.

Contents of the invention

The purpose of the present invention is to provide a transdermal drug delivery system containing active ingredients of peony and licorice and capable of effectively inhibiting local spasm and pain and a preparation method thereof.

The technical problem to be solved by the present invention is to improve the transdermal permeation rate and stability of active ingredients of Paeoniae officinalis and Glycyrrhizae in the pressure-sensitive adhesive matrix, and provide a Paeoniae Paeoniae Alba with good spasmolytic and analgesic activities Gan patch, effective prevention and treatment of local tissue spasm and pain and other diseases.

The peony-sweet transdermal patch provided by the present invention is composed of a backing layer, a drug-loaded pressure-sensitive adhesive layer and a release layer, and is characterized in that: the drug-loaded pressure-sensitive adhesive layer adopts one of the following formulations:

(1) Composed of pressure-sensitive adhesive, paeoniflorin, and glycyrrhetinic acid, the specific composition is as follows: the drug-loaded pressure-sensitive adhesive layer contains 6% to 30% by weight of paeoniflorin and 6% to 30% by weight of glycyrrhetinic acid, and at the same time Containing 3%-10% by weight of organic base, 2%-15% by weight of transdermal penetration enhancer, 5%-15% by weight of butanol and 40%-70% by weight of pressure-sensitive adhesive;

(2) Composed of pressure-sensitive adhesive, peony extract containing paeoniflorin and licorice extract containing glycyrrhetinic acid, the specific composition is as follows: the drug-loaded pressure-sensitive adhesive layer contains 6% to 30% by weight of peony extract and 6 %-30% by weight of licorice extract, simultaneously containing 3%-10% by weight of organic base, 2%-15% by weight of transdermal penetration enhancer, 5%-15% by weight of butanol and 40%-70% by weight Compared with the pressure-sensitive adhesive; wherein the peony extract contains 20% to 90% by weight of paeoniflorin, and the licorice extract contains 20% to 90% by weight of glycyrrhetinic acid.

Described organic base is diethylamine, diethanolamine, triethylamine, triethanolamine.

The skin penetration enhancer is selected from the group consisting of higher fatty alcohols containing 10 to 18 carbon atoms, fatty acid esters containing 3 to 16 carbon atoms, menthone, menthol, azone, borneol, camphor or these substances A combination of two or more, but dimethyl sulfoxide is not included in the combination; the higher aliphatic alcohols containing 10 to 18 carbon atoms refer to decyl alcohol, myristyl alcohol, palmityl alcohol, stearyl alcohol, etc.; containing 3 to 16 Fatty acid esters with two carbon atoms refer to ethyl propionate, isopropyl myristate, isopropyl palmitate and the like.

87-4098、87-9301)或含有羟基基团(如

87-2510、87-2287、

87-2516)的丙烯酸酯压敏胶。为了调整压敏胶中芍药苷、甘草次酸的载药量和经皮渗透速率可以将含有羟基基团压敏胶或不含有功能性基团压敏胶进行混合。The pressure-sensitive adhesive is selected from acrylate pressure-sensitive adhesive, polyisobutylene pressure-sensitive adhesive, silicone rubber, natural rubber, styrene-isoprene-styrene hot-melt pressure-sensitive adhesive (SIS type), styrene-butadiene Acrylic-styrene hot-melt pressure-sensitive adhesive (SBS type) and its blend of two or more, preferably without functional groups (such as

87-4098, 87-9301) or containing hydroxyl groups (such as

87-2510, 87-2287,

87-2516) acrylate pressure sensitive adhesive. In order to adjust the drug loading of paeoniflorin and glycyrrhetinic acid and the transdermal penetration rate in the pressure-sensitive adhesive, the pressure-sensitive adhesive containing hydroxyl groups or the pressure-sensitive adhesives without functional groups can be mixed.

In order to improve the transdermal penetration and stability in the matrix of the active ingredients of Paeoniae Alba-Glycyrrhetinic patch (especially glycyrrhetinic acid), a cosolvent is added to the matrix to promote the solubility and stability of the active ingredients or corresponding extracts in the matrix. For skin permeability, the co-solvent is selected from non-volatile butanol and organic base, and the total amount added does not exceed 25% by weight.

In order to further improve the transdermal penetration rate of active ingredients, a transdermal penetration enhancer with certain compatibility with the skin was added to the pressure-sensitive adhesive. The total amount does not exceed 15% by weight.

The drug-loaded pressure-sensitive adhesive layer of the peony-sweet transdermal patch provided by the invention has a thickness of 50 microns to 500 microns and an area of 10 to 200 cm2.

The preparation method of peony root transdermal patch provided by the invention is as follows:

Add paeoniflorin and glycyrrhetinic acid or their extracts to butanol and organic base, stir and dissolve for later use, add the liquid medicine into the pressure-sensitive adhesive and stir evenly, then add the transdermal penetration enhancer and continue stirring evenly. The glue is coated on a coating machine, and the thickness of the drug-loaded pressure-sensitive adhesive layer is 50 microns to 500 microns. After the coating is dried or cooled, it is pressed onto the backing layer, cut and punched, and sealed in bags for storage.

In the present invention, the patch prescription is screened with the in vitro transdermal penetration amount and the drug crystallization in the matrix as indicators, and the patch prescription is optimized with the animal analgesic activity experiment, by increasing the transdermal penetration rate of the drug and improving the patch efficacy. The formulation was optimized for transdermal analgesic activity.

The in vitro percutaneous penetration test method provided by the invention is as follows:

The in vitro transdermal absorption device adopted is a horizontal diffusion cell with an effective diffusion area of 0.627cm2. The skin used is the skin of depilated mice. Receiving tank, the volume of the receiving tank is 5.0ml, continuous magnetic stirring is carried out during the permeation process, the stirring speed is 600-800rpm, and the temperature of the receiving tank is maintained at 37°C by using a peripheral circulating water bath.

In vitro test results show that the combination of organic base and butanol and other acrylate pressure-sensitive adhesives without carboxyl groups can increase the cumulative penetration rate of glycyrrhetinic acid through rat skin for 24 hours compared with that of ordinary transdermal patches. 40 times, the transdermal penetration of glycyrrhetinic acid and paeoniflorin can reach about 1000 μg/cm2 in 24 hours. Gan transdermal drug delivery system and a carboxyl group-containing pressure-sensitive adhesive system.

The present invention provides two analgesic tests of acetic acid-induced writhing and dysmenorrhea in mice, the purpose of which is to explain the antispasmodic and analgesic effect of peony root patch, but it does not mean that the peony root transdermal patch is only suitable for dysmenorrhea pain inhibition.

1. Analgesic activity of Shao-gan patch on mice writhing caused by acetic acid

The experimental mice were randomly divided into: negative control group; blank matrix group; meloxicam positive control group; peony root patch A group (active ingredient) and paeonin patch B group (extract), 10 in each group .

24 hours before the experiment, the abdomen of the mice was depilated using a depilatory agent. In the blank matrix group, a blank patch (compared with the drug-administered group, with the same ingredients except no drug) was pasted on the abdomen of the mouse, and the patch was fixed with adhesive tape, and the experiment was carried out after 12 hours; Mice were fed with 0.5 mg/mL meloxicam 0.2 mL, and the experiment was carried out 3 hours after gavage; in the peony root patch group, the drug-containing patch was pasted on the abdomen of the mice, and the experiment was carried out 12 hours later. After reaching the specified time, the mice were intraperitoneally injected with 0.6% acetic acid 0.2mL, and the number of writhing reactions occurred in the mice within 20 minutes was observed (that is, the behavioral reactions of the mice appeared concave in the abdomen, the trunk and hind legs were stretched, and the buttocks were raised), and the writhing reactions were recorded. body times, and calculate the pain suppression rate of the drug. Inhibition rate (%)={(average number of writhing times in the negative control group-average number of writhing times in the treatment group)/average number of writhing times in the control group}×100%. The experimental results are shown in Table 1.

The experimental results show that both the paeoniae officinalis patches A and B provided by the invention and the positive drug meloxicam can significantly reduce the number of writhing in mice induced by glacial acetic acid, and have a significant inhibitory effect on pain. The analgesic effect of the positive control group and the peony root patch group on mice writhing caused by acetic acid was similar, and paeoniflorin-glycyrrhetinic acid or their extracts were compatible in different ratios (5:1, 3:1, 1:1, 1: 3) Paeoniae-Garris patch group (total content is determined to be 36%) pain suppression rate is respectively 74.7% and 83.4%, 62.8% and 70.3%, 53.3% and 55.6%, 43.5% and 45.2% (experimental result See Table 1). The above experimental results suggest that the peony-sweet patch has a better inhibitory effect on inflammatory pain, and the greater the proportion of paeoniflorin in the patch, the better the analgesic effect. After 12 hours of application of the transdermal patch, no redness and swelling was seen on the skin, indicating that the two patches prepared in this experiment had no obvious irritation to the skin.

2. Analgesic activity of Shao-gan patch on writhing mice caused by dysmenorrhea

The experimental mice were randomly divided into: negative control group; blank matrix group; meloxicam positive control group; peony-sweet patch A group and paeony-glucoside patch B group, 10 in each group. Mice were fed with diethylstilbestrol once a day, 2 mg/kg each time (volume 5 mL/kg), for 12 consecutive days. From the 10th day, the positive control group was given meloxicam (0.5mg/mL, 0.2mL/monkey) by intragastric administration every day for 3 consecutive days; the blank matrix and peony patch group were applied once a day for continuous administration 3 days. One hour after the last administration of diethylstilbestrol, 20 U/kg of oxytocin was injected intraperitoneally, and the writhing latency and times of writhing of the mice were recorded within 30 minutes.

The experimental results show that the peony root patch group and the positive drug meloxicam have a significant inhibitory effect on the writhing of mice caused by dysmenorrhea, and the number of writhing in mice is significantly reduced. Paeoniflorin-glycyrrhetinic acid or their extracts in different proportions (5:1, 3:1, 1:1, 1:3) of the peony-sweet patch group (total content determined to be 36%) had good Pain suppression rate of dysmenorrhea mice, among which the 1:1 group was the best, and the analgesic effect was even better than that of the positive drug control group of meloxicam, which was very significantly different from the negative control group (P<0.01) (the experimental results are shown in Table 2 ).

Paeoniflorin is a traditional Chinese medicine ingredient with strong analgesic activity. The higher the proportion of paeoniflorin, the better the analgesic effect. This was also verified in the above acetic acid-induced writhing experiment in mice. In the dysmenorrhea model test, we found that compared with the single paeoniflorin patch, the Paeoniflorin patch group had a higher pain suppression rate. With the increase of glycyrrhetinic acid content, the pain inhibition rate of Paeoniflorin patch group on dysmenorrhea mice increased, and when the ratio of paeoniflorin: glycyrrhetinic acid reached 1:1, the inhibitory effect on dysmenorrhea-induced writhing in mice reached the best , further increasing the proportion of glycyrrhetinic acid, the effect decreased instead, this study proves that the compatibility of paeoniflorin and glycyrrhetinic acid has a good therapeutic effect on dysmenorrhea caused by uterine spasm, and shows the synergistic effect of peony and licorice percutaneous administration. effect. Animal efficacy tests have proved that the peony-gan transdermal patch prepared by this technology can be used to relieve and inhibit local tissue spasm and pain symptoms.

The invention provides a peony root transdermal drug delivery transdermal patch, which enables the active ingredients or active ingredients of the two medicinal materials, peony and licorice, to permeate continuously and effectively, and more effectively play their role in local analgesia and anti-inflammation. , antispasmodic and other aspects of synergistic drug effect.

Attached content

Fig. 1a The in vitro permeation curve of paeoniflorin in Paeoniflorin patch with different functional groups.

Fig. 1b In vitro permeation curves of glycyrrhetinic acid in the pressure-sensitive adhesive Shaogan patch with different functional groups.

Fig. 2a Comparison of the effects of different solvents on percutaneous penetration of paeoniflorin in peoniflorin patch in vitro.

Fig. 2b The comparative effect of different solvents on the in vitro percutaneous penetration of glycyrrhetinic acid in Shao-gan patch.

87-4098)芍药苷体外透过曲线图。Fig. 3a Shao-Gan patch with different drug loads (

87-4098) in vitro permeation curve of paeoniflorin.

Figure 3b Shao-Gan patch with different drug loads ( 87-4098) in vitro penetration curve of glycyrrhetinic acid.

Detailed ways

The following will be described in detail in conjunction with specific examples, but they do not limit the present invention. In the examples, the content of active ingredients or active ingredient extracts and other components is based on weight percentage.

Example 1

Paeoniflorin 6, glycyrrhetinic acid 30, diethanolamine 10, azone 2, butanol 5

87-2287)47Hydroxyl group-containing acrylate pressure sensitive adhesive (

87-2287)47

Example 2

Paeoniflorin 30, Glycyrrhetinic Acid 6, Triethylamine 3, Lauryl Alcohol 10, Butanol 5, Silicone Rubber Pressure Sensitive Adhesive 46

Example 3

Paeoniflorin 18, Glycyrrhetinic acid 18, Triethanolamine 6, Isopropyl myristate 10, Butanol 8, Natural rubber pressure-sensitive adhesive 40

Example 4

Paeoniflorin 8, glycyrrhetinic acid 8, triethanolamine 3, stearyl alcohol 6, butanol 5,

Acrylic pressure sensitive adhesives containing hydroxyl functional groups ( 87-2516)70

Example 5

Paeoniflorin 27, glycyrrhetinic acid 9, diethylamine 3, decanol 15, butanol 5,

SIS/SBS Blended Hot Melt Pressure Sensitive Adhesive 41

Example 6

Paeoniflorin 12, glycyrrhetinic acid 24, triethanolamine 7, azone 2, butanol 15,

87-4098)40Non-functional acrylate pressure sensitive adhesive (

87-4098)40

Example 7

Paeoniflorin Extract 15, Glycyrrhetinic Acid Extract 15, Triethylamine 5, Borneol 10, Butanol 15,

SIS Hot Melt Pressure Sensitive Adhesive 40

Example 8

Paeoniflorin Extract 6, Glycyrrhetinic Acid Extract 30, Triethanolamine 10, Azone 2,

87-4098)47Butanol 5, acrylate pressure sensitive adhesive containing hydroxyl group (

87-4098)47

Example 9

Paeoniflorin Extract 30, Glycyrrhetinic Acid Extract 6, Triethanolamine 3, Ethyl Propionate 7, Menthol 3, Butanol 10, Polyisobutylene Pressure Sensitive Adhesive 41

Example 10

Paeoniflorin Extract 24, Glycyrrhetinic Acid Extract 12, Triethylamine 4, Isopropyl Myristate 10,

Butanol 10, non-functional acrylate pressure sensitive adhesive ( 87-4098)40

Example 11

Paeoniflorin Extract 10, Glycyrrhetinic Acid Extract 10, Diethylamine 3, Isopropyl Palmitate 15,

87-9301混合物)57Butanol 5, acrylate pressure sensitive adhesive ( 87-4098 and

87-9301 mixture) 57

Example 12

Paeoniflorin extract 8, glycyrrhetinic acid extract 12, diethanolamine 3, menthone 2, butanol 5, polyisobutylene pressure-sensitive adhesive 70

Example 13

Add 10g of paeoniflorin and 15g of glycyrrhetinic acid into 10g of butanol and 5g of triethanolamine and stir until dissolved for later use, and add the liquid medicine to the acrylate pressure-sensitive adhesive ( 87-4098) 143g (solid content 38.5%) and stir evenly, then add 5g of azone and continue stirring to dissolve. The glue is coated on a coating machine with a thickness of 120 μm, and the coating is dried at 70-90°C and then pressed to cover the backing layer, cut and punched to form a peony-sweet patch with a thickness of 50 μm, which is sealed in bags and stored at room temperature.

Example 14

Add 10g of paeoniflorin extract and 10g of glycyrrhetinic acid extract into 5g of butanol and 5g of triethylamine and stir until dissolved for later use, add 7g of borneol to 63g of molten SIS hot-melt pressure-sensitive adhesive at 120°C and seal it Stir, add the above standby medicinal solution at 90°C and continue to stir evenly. The glue solution is coated on a coating machine, and after the coating is cooled, it is pressed to cover the backing layer, cut and punched to form a peony-sweet patch with a thickness of 500 μm, which is sealed in bags and stored at room temperature.

As shown in Figure 1a, Figure 1b, Figure 2a, Figure 2b, Figure 3a, Figure 3b.

Table 1 Analgesic activity of Shao-Gan patch on mice writhing caused by acetic acid

Note: A: Paeoniflorin (PF)-glycyrrhetinic acid (GA) group;

B: paeoniflorin extract (PE) (paeoniflorin 70%wt)-glycyrrhetinic acid extract (GE) (glycyrrhetinic acid 70%wt) z group;

Compared with the negative control group, *P<0.05, **P<0.01.

Table 2 Analgesic activity of Shao-Gan patch on writhing mice caused by dysmenorrhea

Note: A: Paeoniflorin (PF)-glycyrrhetinic acid (GA) group;

B: paeoniflorin extract (PE) (paeoniflorin 70%wt)-glycyrrhetinic acid extract (GE) (glycyrrhetinic acid 70%wt) z group;

Compared with the negative control group, *P<0.05, **P<0.01.

Claims (5)

1. transdermal patch that contains peoniflorin and enoxolone by being formed by lining, medicine carrying pressure-sensitive adhesive layer and adherent layer, is characterized in that: said medicine carrying pressure-sensitive adhesive layer adopts a kind of in the following prescription:

(1) forms by pressure sensitive adhesive, peoniflorin, enoxolone; The concrete composition as follows: contain 6%～30% weight ratio peoniflorin and 6%～30% weight ratio enoxolone in the medicine carrying pressure-sensitive adhesive layer; Contain 3%～10% weight ratio organic base simultaneously; 2%～15% weight ratio transdermal penetrating agent, 5%～15% weight ratio butanols and 40%～70% weight ratio pressure sensitive adhesive;

(2) form by pressure sensitive adhesive, the Radix Glycyrrhizae extract that contains the Radix Paeoniae Alba extract of peoniflorin and contain enoxolone; The concrete composition as follows: contain 6%～30% weight ratio Radix Paeoniae Alba extract and 6%～30% weight ratio Radix Glycyrrhizae extract in the medicine carrying pressure-sensitive adhesive layer; Contain 3%～10% weight ratio organic base simultaneously; 2%～15% weight ratio transdermal penetrating agent, 5%～15% weight ratio butanols and 40%～70% weight ratio pressure sensitive adhesive; Wherein contain 20%～90% weight ratio peoniflorin in the Radix Paeoniae Alba extract, contain 20%～90% weight ratio enoxolone in the Radix Glycyrrhizae extract;

Described organic base is diethylamine, diethanolamine, triethylamine, triethanolamine;

Described transdermal penetrating agent is selected from: contain the high fatty alcohol of 10～18 carbon atoms, the fatty acid ester that contains 3～16 carbon atoms, menthone, menthol, azone, Borneolum Syntheticum, Camphora or the combination of these materials more than two kinds, but do not comprise dimethyl sulfoxide and higher fatty acids;

Pressure sensitive adhesive is selected from acrylate pressure-sensitive adhesive, Polyisobutylene PSA, silicone rubber, natural rubber, SIS type styrene-isoprene-phenylethene hot-fusible pressure-sensitive adhesive, SBS type s-B-S hot melt pressure sensitive adhesive and the blend more than two kinds thereof.

2. a kind of transdermal patch that contains peoniflorin and enoxolone according to claim 1 is characterized in that the high fatty alcohol that contains 10～18 carbon atoms is meant decanol, myristyl alcohol, palmityl alcohol, stearyl alcohol; The fatty acid ester that contains 3～16 carbon atoms is meant ethyl propionate, isopropyl myristate, isopropyl palmitate.

3. a kind of transdermal patch that contains peoniflorin and enoxolone according to claim 1 is characterized in that acrylate pressure-sensitive adhesive is meant the acrylate pressure-sensitive adhesive that does not contain carboxylic group.

4. the method for preparing of claim 1,2 or 3 said transdermal patches; It is characterized in that; It is subsequent use with the organic base stirring and dissolving that peoniflorin and enoxolone or their extract are added butanols, and medicinal liquid is added the back adding transdermal penetrating agent and continue to stir of stirring in the pressure sensitive adhesive; Glue is filmed on coating machine, and the thickness of medicine carrying pressure-sensitive adhesive layer is 50 microns～500 microns, covers backing layer after coating drying or the cooling, cutting and punch forming, and packed sealing is preserved.

5. the application of claim 1,2 or 3 said transdermal patches is characterized in that this transdermal patch is used to prepare the medicine of alleviating and suppressing local organization spasm and pain.

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