CN101843608B - Buboo preparation for treating cardiovascular diseases and preparation method thereof - Google Patents

Abstract

The invention belongs to the field of medicaments and relates to an external Buboo formulation of a compound medicament of paeonol, ferulic acid and borneol for treating cardiovascular diseases. The Buboo preparation for treating the cardiovascular diseases consists of a back lining layer, an ointment-containing body and a cover lining layer. The ointment-containing body, namely the kernel part, is prepared from the paeonol, the ferulic acid and the borneol, and auxiliary materials such as adhesives, filler, transdermal enhancer, humectant and the like in certain ratio. The conventional medicaments such as the paeonol, the ferulic acid and the borneol are in oral formulation and injection formulation, but the conventional formulations have some shortages. The Buboo preparation can avoid first-pass effect of oral administration, reduce systemic blood concentration, reduce toxic and side effect, and maintain constant and effective blood concentration. The medicament has the advantages of moisture preservation, high permeability, comfortable and convenient use, less acrimony and irritability to skin, capability of being repeatedly torn off and stuck, and high compliance of patients.

Description

A cataplasm for treating cardiovascular diseases and its preparation method

Technical field:

The invention belongs to the field of medicines, and relates to an external cataplasm dosage form of compound medicine paeonol, ferulic acid and borneol which can be used for treating cardiovascular diseases.

Background technique:

Catalysts refer to external preparations prepared by mixing medicinal extracts, drugs and suitable hydrophilic substrates, and then coating them on the backing material. The earliest mud-like cataplasms appeared in Japan and were called poultices. Since the 1970s, Japan has made several improvements to poultice, and modern industrial materials have been introduced into the poultice matrix, which avoids the shortcomings of poultry such as insufficient stability, poor cohesion, and easy contamination of clothing. It is called shaped poultice. Formed poultice is a mixture of drugs and polymer materials as the main matrix, coated on the backing made of non-woven fabric, the surface of the ointment is covered with a layer of anti-sticking film, cut into different sizes according to the requirements of use, and packed into In plastic film, aluminum foil or paper bags, because the shaped cataplasms are easy to store and easy to apply, they play a major role in the research and application of cataplasms. Therefore, a large number of shaped cataplasms have been launched in developed countries such as Europe, America and Japan, and are well received by doctors and patients. Our country began to study this dosage form in the 1980s, but its development was relatively slow, and only a very small amount of products have come to the market up to now. In the "Appendix" of the 2000 edition of the Pharmacopoeia of the People's Republic of China, the cataplasm ointment is officially recorded, and its adhesion test, excipient test, ointment content, etc. are clearly regulated. Provides a statutory basis for quality control. With the continuous development of the pharmaceutical industry, this new dosage form has developed in my country in recent years. According to the prediction of the World Health Organization, in the next 20-30 years, more than 30% of the drugs will be changed to transdermal drug delivery preparations. This will surely set off a new upsurge in internal and external treatment. Compared with traditional external plasters, cataplasms have the following advantages: large drug loading capacity, especially suitable for large dosage of traditional Chinese medicine extracts; good biocompatibility, affinity, air permeability and sweat resistance to the skin , and not prone to allergies; good drug release performance, due to good moisturizing performance, can improve skin hydration, which is conducive to drug transdermal absorption; easy to use, does not pollute clothes, and can still maintain the original viscosity after repeated application. It does not affect the curative effect; there is no organic solvent pollution in the production, which meets the requirements of green environmental protection.

Cardiovascular disease is a common disease that seriously threatens the health of human beings, especially middle-aged and elderly people over 50 years old. Even with the most advanced and perfect treatment methods, more than 50% of survivors of cardiovascular accidents still cannot take care of themselves completely . The number of people who die from cardiovascular disease is as high as 15 million every year in the world, ranking first among various causes of death. Cardiovascular disease has become the number one killer with the highest cause of death in humans. However, the prevalence, incidence and risk factors of cardiovascular disease in our country are on the rise. The death toll of cardiovascular disease accounts for about 40% of the total death toll in the population. Every year, 200 people die from this disease nationwide. How many people. With the acceleration of my country's population aging trend, cardiovascular diseases have become increasingly prominent, and have become the number one cause of disability and death. At the same time, the pressure from work, society, and life in modern society is huge, coupled with irregular life, unscientific diet, and lack of exercise, etc., which promote the incidence of cardiovascular diseases among young and middle-aged people aged 30 to 40 Also rising, the age span of onset is expanding.

Paeonol has anti-myocardial ischemia-reperfusion injury, anti-arrhythmia, anti-atherosclerosis, anti-hypertension, thrombosis and microcirculation promotion. Ferulic acid is a non-peptide endothelin receptor antagonist, which can antagonize endothelin-induced vasoconstriction, pressurization and vascular smooth muscle cell proliferation. It has the functions of relaxing vascular smooth muscle, inhibiting platelet aggregation, anticoagulation, and improving hemorheology. And so on. It can also inhibit the synthesis of cholesterol, lower blood lipids, scavenge free radicals, prevent lipid peroxidation damage, and enhance immune function. Borneol can increase the coronary sinus blood flow, slow down the heart rate, reduce myocardial oxygen consumption, and at the same time can promote the skin penetration rate of drugs and improve the distribution of drugs in the blood.

Therefore, the combined application of paeonol, ferulic acid, and borneol through scientific prescriptions can enhance pharmacological effects, enhance curative effect, and reduce toxic and side effects. At present, the clinically used dosage forms of paeonol, ferulic acid and borneol are mainly injections and oral preparations (tablets, capsules and oral liquids). Oral administration generally causes gastrointestinal irritation, and some patients also experience nausea, vomiting, abdominal pain and other reactions, which can cause convulsions, loss of consciousness, convulsions, and even death due to respiratory failure in severe cases, which limits their clinical application to some extent. wide application. Compared with oral administration preparations, injection administration has quick onset of action and remarkable curative effect. However, due to the high peak blood concentration of injection administration, it is not conducive to the control of toxic and side effects. In addition, it also has severe muscle irritation, pain, redness and swelling at the injection site, and inconvenience in use. The patient's compliance is poor. In order to make paeonol, ferulic acid, and borneol more effective in clinical practice, a new type of preparation with high safety, convenient use and good compliance is urgently needed clinically.

content of the invention;

The object of the present invention is to provide a safe and effective catarrh formulation for external use for treating cardiovascular diseases, which has long action time and small side effects.

Another object of the present invention is to provide a preparation method of compound drug paeonol, ferulic acid and borneol catarrh.

The advantage of the invention is that the preparation process is simple, and the cataplasm is prepared by scientifically combining paeonol, ferulic acid and borneol with definite curative effects. Administration via transdermal route, the transdermal administration method is simple, the incidence of toxic and side effects is low, and it can also avoid the gastrointestinal tract irritation and liver first-pass effect of oral administration, and the administration can be controlled by adjusting the administration area. The dose can be interrupted at any time as required. In addition, it also reduces the shortcomings of various ointments and plasters in the past that are easy to contaminate clothes and fall off. At the same time, this also reduces the number of medications and prolongs the duration of action.

The cataplasm of the present invention is made of a certain amount of paeonol, ferulic acid, borneol medicine and matrix, and described matrix is made of adhesive, filler, cross-linking agent, humectant, transdermal accelerator, pH Regulators are prepared. Each cataplasm contains 20.0-300.0 mg of paeonol, 50.0-400.0 mg of ferulic acid and 10.0-100.0 mg of borneol.

Described tackiness agent is selected from gelatin, sodium alginate, gum arabic, starch, methyl cellulose, carboxymethyl cellulose and sodium salt thereof, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, carbomer, polyvinyl One or any combination of two or more of acrylic acid and its sodium salt has a content of 20.0-40.0% by weight, preferably 30.0%. The filler is selected from one or any combination of two or more of zinc oxide, micropowder silica gel, calcium carbonate, diatomaceous earth, and titanium dioxide, and its content is 10.0-35.0% by weight, preferably 20.0%. The moisturizing agent is selected from any one or a combination of two or more of glycerin, propylene glycol, sorbitol and polyethylene glycol, and its content is 10.0-60.0% by weight, preferably 40.0%. The crosslinking agent is selected from any one or a combination of two or more of calcium hydroxide, aluminum trichloride, aluminum glycinate, disodium edetate, and its content is 0.0-3.0% by weight, 1.5% is preferred. The skin penetration enhancer is selected from one or a combination of azone, oleic acid, propylene glycol, dimethyl sulfoxide, peppermint oil, etc., and its content is 2.0-10.0% by weight, preferably 3.0%.

The preparation method of the cataplasm of the present invention is as follows: take the adhesive, add water to fully swell; add the filler and mix evenly, and heat it in a water bath to about 90°C; add a humectant while keeping warm; add paeonol, ferulic acid, The borneol is fully stirred and mixed evenly; then add a cross-linking agent and a transdermal accelerator, and knead evenly for 15 minutes to 45 minutes. Cut into appropriate size to get shaped poultice.

Detailed ways:

Embodiment 1: A kind of preparation method of cataplasm for treating cardiovascular disease

Drug: paeonol 2.0g ferulic acid 3.0g borneol 0.5g

Excipients: Gelatin 2.0g Sodium Alginate 2.0g

Polyvinyl alcohol 10.0g Sodium polyacrylate 2.0g

Zinc Oxide 5.0g Glycerin 5.0g

Propylene Glycol 1.5g Azone 1.5g

  Aluminum Glycinate 0.3g

Preparation method: Weigh gelatin and sodium alginate according to the prescription amount, add appropriate amount of distilled water to fully swell, heat in a water bath to about 90°C, add the prescribed amount of polyvinyl alcohol, stir to dissolve and mix evenly, and then mix sodium polyacrylate and glycerin , Propylene Glycol Zinc Oxide is added in above-mentioned glue solution, stirs and mixes evenly. Cool down to 60°C, add paeonol, ferulic acid, and borneol in the prescribed amount, stir and mix evenly; then add aluminum glycinate and azone, and stir evenly for 30 minutes. The refining temperature is 60°C, apply while it is hot, and stand , cooled, dried and solidified, cut into a suitable size to obtain cataplasms, the amount of paeonol contained in each cataplasm is 200.0mg, the amount of ferulic acid is 300.0mg, and the amount of borneol is 50.0mg.

Embodiment 2: A kind of preparation method of cataplasm for treating cardiovascular disease

Drug: paeonol 2.0g ferulic acid 3.0g borneol 0.5g

Excipients: gelatin 2.0g sodium carboxymethylcellulose 2.0g

Polyvinylpyrrolidone 10.0g Sodium polyacrylate 3.0g

Diatomaceous earth 5.0g Glycerin 5.0g

Macrogol-400 2.5g Azone 1.5g

Oleic acid 1.5g Aluminum glycinate 0.5g

Preparation method: Weigh gelatin and sodium carboxymethyl cellulose according to the prescription amount, add appropriate amount of distilled water to fully swell, heat in a water bath to about 90°C, add the prescription amount of polyvinylpyrrolidone, stir to dissolve and mix evenly, and then polyacrylic acid Add sodium, glycerin, polyethylene glycol 400, and diatomaceous earth into the above-mentioned glue solution, stir and mix evenly. Cool down to 60°C, add paeonol, ferulic acid, and borneol in the prescribed amount, stir and mix evenly; then add aluminum glycinate, azone, and oleic acid, and stir evenly for 45 minutes. The refining temperature is 70°C, and coat while it is hot , stand still, cool, dry and solidify, cut into suitable size, namely get cataplasm, the amount of paeonol contained in each cataplasm is 200.0mg, the amount of ferulic acid is 300.0mg, the amount of borneol is 50.0 mg.

Embodiment 3: A kind of preparation method of cataplasm for treating cardiovascular disease

Drug: paeonol 2.0g ferulic acid 3.0g borneol 0.5g

Excipients: Gum Arabic 2.0g Sodium Carboxymethyl Cellulose 2.0g

Polyvinylpyrrolidone 10.0g Sodium polyacrylate 3.0g

Calcium Carbonate 5.0g Glycerin 5.0g

Propylene Glycol 1.5g Azone 2.5g

  Calcium Hydroxide 0.8g

Preparation method: Weigh Arabic gum and sodium carboxymethyl cellulose according to the prescription amount, add appropriate amount of distilled water to fully swell, heat in a water bath to about 90°C, add the prescription amount of polyvinylpyrrolidone, stir to dissolve and mix evenly, and then polyvinylpyrrolidone Add sodium acrylate, glycerin, propylene glycol, and calcium carbonate into the above glue, and stir to mix evenly. Cool down to 60°C, add paeonol, ferulic acid, and borneol in the prescribed amount, stir and mix evenly; then add calcium hydroxide and azone, stir evenly for 45 minutes, and the refining temperature is 65°C, apply while it is hot, static place, cool, dry and solidify, and cut into suitable size to obtain cataplasms. Each cataplasm contains 200.0 mg of paeonol, 300.0 mg of ferulic acid, and 50.0 mg of borneol.

Embodiment 4: the in vitro transdermal test of this cataplasm

The in vitro transdermal test adopts an improved Franz diffusion cell with a diffusion area of 1.5cm2. The prepared isolated skin is fixed in the middle of the two chambers of the diffusion cell, so that the horny layer faces the supply cell, and different ingredients are added according to the ratio of the ingredients in the prescription in Example 1. A cataplasm made of a transdermal enhancer (azone, oleic acid, propylene glycol, dimethyl sulfoxide) was pasted on the isolated skin, and 10% ethanol was used as a receiving fluid to carry out an isolated skin penetration test. The circulating water temperature in the constant temperature jacket of the diffusion cell is 37±0.5°C, and the magnetic stirring is performed at a constant speed of 300r/min. The timing was started after 15 minutes of equilibration, and 1 ml of skin permeate was taken out at 2, 4, 6, 8, 10, and 12 hours respectively, and an isothermal and equal volume of 10% ethanol was added at the same time. The receiving liquid was filtered with a 0.45 μm microporous membrane, the primary filtrate was discarded, the secondary filtrate was collected, and the contents of ferulic acid and paeonol were determined by HPLC. Calculate the cumulative infiltration, and the results are shown in Table 1 and Table 2. It can be seen that compared with the cataplasms without a penetration enhancer, the cataplasms with azone, oleic acid, propylene glycol, and dimethyl sulfoxide as penetration enhancers have significant penetration-enhancing effects on ferulic acid and paeonol , of which Azone has the best permeability-enhancing effect.

Embodiment 5: the adhesion test of this cataplasm

1. Initial adhesion test of this cataplasm

Using "Chinese Pharmacopoeia" 2005 edition "Part One" appendix ⅫE plaster adhesion determination. Respectively get three pieces of cataplasms made according to embodiment 1, 2, 3, all can stick to the largest steel ball (10#), and the initial adhesion test is qualified.

2. The sticking force test of this cataplasm

Using "Chinese Pharmacopoeia" 2005 edition "Part One" appendix ⅫE plaster adhesion determination. Three tablets of cataplasms prepared according to Examples 1, 2, and 3 were respectively taken, which could move 1.5 cm after 1 hour under the action of a weight of 3000 g, and the adhesion force test was qualified.

Embodiment 6: other quality evaluations of this cataplasm

Other quality evaluation tests of this cataplasm were to paste the formed cataplasm on the back of the wrists of 10 volunteer subjects, and to evaluate the spread and softness, film residue, skin followability, paste uniformity, skin discomfort and pain. Make an evaluation. The evaluation criteria are as follows:

Spreading and softness: When the paste is applied, the anchoring property is good, the paste is even and continuous, and it is best to feel soft and not greasy when touched lightly with hands.

Film residue: Take the shaped poultice and peel it off at 180°, the less the amount left on the film, the better.

Skin followability: This indicator draws on the Japanese method of evaluating cataplasms, stick the shaped patch on the back of the hand bowl, and shake it vigorously for 10 times without falling off.

Uniformity of the paste: The prepared paste is uniform and has a suitable consistency. It is best to apply the paste on the lining layer without granular micelles, fine and consistent in thickness.

Skin discomfort and pain: It is best to stick it on the skin without itching, allergies, ulcers and painless when peeling off.

Each of the above five items is 20 points. Each of the cataplasms of the present invention made according to Embodiment 1, 2, and 3 is scored by 10 volunteers according to each standard, and each score is averaged and then added up to obtain total score. The results are shown in Table 3. The results show that the product of the present invention, a cataplasm for treating cardiovascular diseases, has a comprehensive score of more than 90 points, is good for spreading, softness, film residue, skin followability, and paste uniformity, and has no skin discomfort. And pain, can be repeatedly pulled and applied. The results reveal that the product of the present invention, a cataplasm for treating cardiovascular diseases, has good biocompatibility, affinity, air permeability, and sweat resistance to the skin, and is not prone to allergies.

Table 1 Cumulative penetration of ferulic acid in cataplasms containing different penetration enhancers (n=6)

Table 2 Cumulative penetration of paeonol in cataplasms containing different penetration enhancers (n=6)

Table 3 Scores of different prescription cataplasms

Claims (11)

1. A cataplasm for the treatment of cardiovascular disease is characterized in that the medicated ointment is made of paeonol, ferulic acid, borneol and matrix of therapeutically effective dose, and described matrix comprises adhesive, humectant, filler , crosslinking agent, transdermal accelerator, pH regulator, the drug content in each paste is paeonol 20-200mg, ferulic acid 50-300mg, borneol 10-50mg, matrix by weight percentage, the content of adhesive 20- 40%, the content of moisturizing agent is 10-60%, the content of filler is 10-35%, the content of cross-linking agent is 0-3%, and the content of skin penetration accelerator is 2-10%. 2. the cataplasm for the treatment of cardiovascular disease according to claim 1 is characterized in that by weight percentage, the content of adhesive in the medicated ointment is 20-40%, and described adhesive is selected from gelatin, sodium alginate , gum arabic, starch, methylcellulose, carboxymethylcellulose and its sodium salt, polyvinyl alcohol, polyethylene glycol, polyvinylpyrrolidone, carbomer, polyacrylic acid and its sodium salt Any combination of the above. 3. the cataplasm for the treatment of cardiovascular disease according to claim 1, is characterized in that by weight percentage, the content of humectant in the medicated ointment is 10-60%, and described humectant is selected from glycerin, propylene glycol , sorbitol, polyethylene glycol, any one or a combination of two or more. 4. the cataplasm for treating cardiovascular disease according to claim 1, is characterized in that by weight percentage, the content of filler in the medicated plaster is 10-35%, and described filler is selected from zinc oxide, One or any combination of two or more of micronized silica gel, calcium carbonate, diatomaceous earth, and titanium dioxide. 5. the cataplasm for treating cardiovascular disease according to claim 1 is characterized in that by weight percentage, the content of cross-linking agent in the ointment containing medicine is 0-3%, and described cross-linking agent is selected from hydrogen Any one or a combination of two or more of calcium oxide, aluminum trichloride, aluminum glycinate, and disodium edetate. 6. the cataplasm for the treatment of cardiovascular disease according to claim 1, is characterized in that by weight percentage, the content of transdermal enhancer in the medicated ointment is 2-10%, and the transdermal enhancer is selected from azone , oleic acid, propylene glycol, dimethyl sulfoxide, peppermint oil, etc., or a combination of two. 7. the cataplasm for the treatment of cardiovascular disease according to claim 1 is characterized in that the medicated ointment is made of paeonol, ferulic acid, borneol and matrix of following therapeutically effective dose: Paeonol 2.0g Ferulic acid 3.0g Borneol 0.5g Gelatin 2.0g Sodium alginate 2.0g Polyvinyl alcohol 10.0g Sodium polyacrylate 2.0g Zinc oxide 5.0g Glycerin 5.0g Propylene glycol 1.5g Azone 1.5g Aluminum Glycinate 0.3g. 8. the cataplasm for the treatment of cardiovascular disease according to claim 1, is characterized in that the medicated ointment is made of paeonol, ferulic acid, borneol and matrix of following therapeutically effective dose: Paeonol 2.0g Ferulic acid 3.0g Borneol 0.5g Sodium carboxymethylcellulose 2.0g Gelatin 2.0g Diatomaceous earth 5.0g Polyvinylpyrrolidone 10.0g Sodium polyacrylate 3.0g Glycerin 5.0g Macrogol-400 2.5g Oleic acid 1.5g Azone 1.5g Aluminum glycinate 0.5g. 9. The cataplasm for the treatment of cardiovascular disease according to claim 1, characterized in that the medicated ointment is made from paeonol, ferulic acid, borneol and matrix of the following therapeutically effective dose: Paeonol 2.0g Ferulic Acid 3.0g Borneol 0.5g Gum Arabic 2.0g Sodium Carboxymethylcellulose 2.0g Polyvinylpyrrolidone 10.0g Sodium polyacrylate 3.0g Calcium carbonate 5.0g Glycerin 5.0g Propylene glycol 1.5g Azone 2.5g Calcium hydroxide 0.8g. 10. The preparation method of the cataplasm for the treatment of cardiovascular disease described in any one of claims 1-9, it is characterized in that comprising the following steps: take adhesive, add water and fully swell; After filler is added, mix evenly, water bath is heated to 90°C; add humectant under heat preservation; add paeonol, ferulic acid, borneol and mix well; then add cross-linking agent and transdermal accelerator, stir evenly and knead for 15 to 45 minutes, kneading temperature is 50 ℃-70℃, apply while it is hot, let it stand, cool, dry and solidify to obtain a shaped poultice. 11. The use of the cataplasm for treating cardiovascular diseases according to any one of claims 1-9 in the preparation of medicines for treating cardiovascular diseases.