CN116531426B - Sulfur-containing protamine pharmaceutical composition for preventing and treating leucopenia caused by chemotherapy and preparation method thereof - Google Patents
Sulfur-containing protamine pharmaceutical composition for preventing and treating leucopenia caused by chemotherapy and preparation method thereof Download PDFInfo
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- CN116531426B CN116531426B CN202310631973.4A CN202310631973A CN116531426B CN 116531426 B CN116531426 B CN 116531426B CN 202310631973 A CN202310631973 A CN 202310631973A CN 116531426 B CN116531426 B CN 116531426B
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Abstract
The invention relates to a medicine composition containing sulfur and pronin for preventing and treating leucopenia caused by radiotherapy and a preparation method thereof, belonging to the technical field of medicine compositions. In order to solve the problems of large side effect and slow effect of the existing medicines for treating leucopenia caused by chemotherapy, the invention provides a medicine composition containing sulfur-containing protamine for preventing and treating leucopenia caused by chemotherapy, which comprises the components of tioprotamine, astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract. The invention combines the traditional Chinese medicine extract on the basis of the tiopronin, the western medicine has quick effect, the traditional Chinese medicine has the effects of strengthening body resistance and consolidating constitution, and has the effects of tonifying qi and blood and replenishing vital essence and producing marrow, the combination of the traditional Chinese medicine extract and the western medicine can enhance the effects of preventing and relieving leucopenia after chemotherapy, and the traditional Chinese medicine can also enhance the physical function of a patient through conditioning the traditional Chinese medicine, so that the body can promote the absorption and utilization of the tiopronin, and simultaneously reduce the adverse reaction possibly caused by taking the tiopronin.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compositions, and particularly relates to a pharmaceutical composition containing sulfur and pronin for preventing and treating leucopenia caused by radiotherapy and a preparation method thereof.
Background
In the course of malignant tumor chemotherapy, the chemotherapeutic medicine has low selectivity to tumor cells, and can kill cancer cells and damage normal cells. The most common side effect is bone marrow suppression, the hematopoietic function of bone marrow is inhibited, the number of newly increased leucocytes is reduced, the number of peripheral blood leucocytes is reduced, the immune function of the organism is reduced, and the clinical examination can show that the leucocyte value is lower. After chemotherapy has been shown to have a decrease in leukocytes, the physician will take various measures depending on the degree of leukocyte decrease. If the white blood cells are slightly reduced, continuing the treatment; if the leucocyte is reduced more, the treatment is interrupted, and the treatment can be continued after the leucocyte is increased. The time intensity of chemotherapy is closely related to the curative effect, and the treatment effect is greatly affected by discontinuing the treatment. Therefore, prevention of a substantial decrease in peripheral blood leukocyte count, and improvement of immunity in tumor patients are important for enhancing clinical benefit of tumor chemotherapy.
When bone marrow depression reaches a level of II or above after chemotherapy, a white blood ascending needle is often used clinically to cope with the problem of serious deficiency of white blood cells after chemotherapy. The active ingredient of the white blood lifting needle is recombinant human granulocyte colony stimulating factor, which can stimulate bone marrow hematopoietic cells to generate white blood cells, thereby achieving the purpose of white blood lifting. The ascending white needle can be classified into a short ascending white needle and a long ascending white needle according to the duration of the medicinal effect. Wherein the long-acting white needle is used for preventive treatment, can be used on the second or third day of chemotherapy, and has effect for two weeks without frequent injection. However, the long-acting white needle is expensive, and has adverse reactions such as fever, muscle, bone, joint pain and the like after use.
Oral leukorrhagia treating preparation is cheaper than long-acting leukorrhagia treating needle, and has slow acting, and is applied before bone marrow suppression is II degree. The resequencing in the oral preparation is one of the western medicines with higher effective rate, the effective rate reaches 60-70%, but allergic dermatitis can be caused; batyl alcohol has similar effectiveness as inosine, which is reported to cause pharyngitis after administration, and inosine, which can occasionally cause stomach discomfort and allergic reactions. Therefore, developing a highly effective, low side effect and low cost whitening drug is still a urgent problem in the art.
Disclosure of Invention
The invention provides a drug composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof, which aims to solve the problems of large side effect and slow effect of the existing drug for treating leucopenia caused by chemotherapy.
The technical scheme of the invention is as follows:
a pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which comprises the following components in parts by mass: 1 to 5 parts of tiopronin, 20 to 30 parts of astragalus extract, 15 to 25 parts of American ginseng extract, 10 to 15 parts of poria extract, 10 to 15 parts of licorice extract and 20 to 25 parts of malaytea scurfpea extract.
A pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which comprises the following components in parts by mass: 1 to 10 parts of tiopronin and 1 to 300 parts of drug-loaded liposome; the medicine carried by the medicine-carrying liposome is astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract, and the mass ratio of the medicine carried by astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract is 20-30:15-25:10-15:10-15:20-25.
Further, the preparation method of the drug-loaded liposome comprises the following steps:
accurately weighing astragalus extract, american ginseng extract, poria cocos extract, licorice root extract, fructus psoraleae extract, egg yolk lecithin and cholesterol;
dissolving astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract in purified water to obtain a traditional Chinese medicine extract aqueous solution, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained traditional Chinese medicine extract aqueous solution, removing the solvent by rotary evaporation, drying overnight in vacuum to obtain a lipid film, dissolving and hydrating the lipid film, carrying out ultrasonic treatment on the obtained hydration system to enable the liposome to be fully dispersed in the hydration system, and carrying out film treatment on the hydration system after ultrasonic treatment to obtain the drug-loaded liposome with the particle size of 100-150 nm.
Further, the composition also comprises the following components in parts by mass: 1-100 parts of whey protein polypeptide.
Further, the preparation method of the antioxidant whey protein polypeptide comprises the following steps:
dissolving whey protein powder in water to obtain whey protein water solution, regulating pH of the obtained whey protein water solution to 8, adding alkaline protease, performing enzymolysis at 50deg.C for 2h, inactivating at 95deg.C for 10min, centrifuging to collect supernatant, dialyzing the supernatant, concentrating, purifying, lyophilizing, and pulverizing to obtain whey protein polypeptide with molecular weight of 2 kDa.
A pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which is oral enteric particles, wherein the oral enteric particles comprise the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 300 parts of drug-loaded liposome, 200 to 300 parts of starch, 100 to 200 parts of microcrystalline cellulose, 200 to 300 parts of isolation layer coating and 450 to 550 parts of enteric layer coating;
or the oral enteric particles comprise the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 250 parts of drug-loaded liposome, 1 to 50 parts of whey protein polypeptide, 200 to 300 parts of starch, 100 to 200 parts of microcrystalline cellulose, 200 to 300 parts of isolation layer coating and 450 to 550 parts of enteric layer coating.
A method for preparing a sulfur-containing prothrombin pharmaceutical composition for preventing and treating leucopenia caused by chemotherapy, comprising the following steps:
step I, mixing tiopronin and drug-loaded liposome with starch and microcrystalline cellulose, bonding with a proper amount of 5% starch slurry, granulating to obtain particles with the particle size of 20 meshes, and drying at 50 ℃ for later use;
or mixing tiopronin, drug-loaded liposome and whey protein polypeptide with starch and microcrystalline cellulose, bonding with appropriate amount of 5% starch slurry, granulating to obtain particles with particle diameter of 20 mesh, and drying at 50deg.C;
step II, placing the particles obtained in the step I in a fluidized bed, spraying an isolating layer coating liquid at room temperature, and drying completely to obtain particles with isolating layer coating on the surfaces;
and III, placing the particles with the isolation layer coating on the surface obtained in the step II in a fluidized bed, spraying enteric coating liquid at room temperature, and drying completely to obtain the oral enteric particles with the enteric coating on the surface.
The medicine composition for preventing and treating leucopenia caused by chemotherapy comprises a sulfur-containing protamine, wherein the medicine composition is an oral liquid preparation, and the oral liquid preparation comprises the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 300 parts of drug-loaded liposome and 300 to 500 parts of prebiotic aqueous solution;
or the oral liquid preparation comprises the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 250 parts of drug-loaded liposome, 1 to 50 parts of whey protein polypeptide and 300 to 500 parts of prebiotic aqueous solution;
or the oral liquid preparation comprises the following components in parts by mass: 1 to 300 parts of oral enteric particles and 300 to 500 parts of prebiotic water solution.
Further, the oral enteric particles comprise the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 300 parts of drug-loaded liposome, 200 to 300 parts of starch, 100 to 200 parts of microcrystalline cellulose, 200 to 300 parts of isolation layer coating and 450 to 550 parts of enteric layer coating;
or the oral enteric particles comprise the following components in parts by mass: 1 to 10 parts of tiopronin, 1 to 250 parts of drug-loaded liposome, 1 to 50 parts of whey protein polypeptide, 200 to 300 parts of starch, 100 to 200 parts of microcrystalline cellulose, 200 to 300 parts of isolation layer coating and 450 to 550 parts of enteric layer coating.
Further, the prebiotics are one or a combination of more of tremella polysaccharide, ganoderma lucidum polysaccharide, medlar polysaccharide, agaric polysaccharide, lentinan or aloe polysaccharide; the concentration of the prebiotics in the prebiotic water solution is 1-20wt%.
The invention has the beneficial effects that:
the invention combines the traditional Chinese medicine extracts of astragalus, american ginseng, fructus psoraleae, poria cocos and liquorice on the basis of tiopronin, the western medicine has quick response, the traditional Chinese medicine has the effects of strengthening body resistance and consolidating constitution, and has the effects of tonifying qi and blood and replenishing vital essence and producing marrow, the combination of the two can enhance the effects of preventing and relieving bone marrow depression after chemotherapy, and the body function of a patient can be enhanced through the conditioning of the traditional Chinese medicine, so that the body can be promoted to absorb and utilize the tiopronin, and the adverse reaction possibly generated by taking the tiopronin can be reduced. The invention also prepares the traditional Chinese medicine extract into nano-scale drug-loaded liposome, thereby further promoting the absorption of the traditional Chinese medicine extract and exerting the drug effect.
The invention further combines whey protein polypeptide and prebiotics on the basis of tiopronin and traditional Chinese medicine extracts. The whey protein polypeptide can rapidly supplement nutrition for organisms, and can provide sufficient material basis for the organisms to synthesize white blood cells when tiopronin and active ingredients of traditional Chinese medicines activate marrow hematopoietic function. The prebiotics can stimulate the growth of beneficial bacteria in the intestinal tract, and promote the recovery of hematopoietic function by improving intestinal microecology of patients after chemotherapy; meanwhile, the intestinal function is enhanced, and the absorption of the intestinal tract to the effective medicinal components is further promoted, so that the effect of the medicinal composition on preventing and treating leucopenia caused by chemotherapy as a whole is enhanced.
The invention further prepares the pharmaceutical composition into an oral enteric-coated particle preparation, the enteric-coated dosage form does not disintegrate in the stomach, and the medicine is released in the intestinal tract, so that the stability and bioavailability of tiopronin, medicine-carrying liposome and whey protein polypeptide can be improved, the irritation of the medicine to the stomach of a patient with chemotherapy is reduced, and the medication compliance is increased.
Detailed Description
The following embodiments are used for further illustrating the technical scheme of the present invention, but not limited thereto, and all modifications and equivalents of the technical scheme of the present invention are included in the scope of the present invention without departing from the spirit and scope of the technical scheme of the present invention. The process equipment or apparatus not specifically noted in the following examples are all conventional equipment or apparatus in the art, and the raw materials and the like used in the examples of the present invention are commercially available unless otherwise specified; unless specifically indicated, the technical means used in the embodiments of the present invention are conventional means well known to those skilled in the art.
Example 1
This example provides a pharmaceutical composition containing sulfur and protamine for the prevention and treatment of chemotherapy-induced leukopenia.
The pharmaceutical composition in this embodiment comprises the following components in parts by mass: 5 parts of tiopronin, 30 parts of astragalus extract, 25 parts of American ginseng extract, 15 parts of poria extract, 10 parts of licorice extract and 20 parts of fructus psoraleae extract.
The extraction methods of astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract in the embodiment are as follows:
step 1, respectively crushing astragalus, american ginseng, poria cocos, liquorice and fructus psoraleae to 10 meshes to obtain astragalus particles, american ginseng particles, poria cocos particles, liquorice particles and fructus psoraleae particles;
step 2, respectively soaking the astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles obtained in the step 1 in clear water for 6 hours, taking out, rapidly freezing at the temperature of minus 30 ℃, and taking out after freezing for 30 minutes;
and 3, respectively adding 10 times of pure water into the frozen astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles in the step 2 for decoction for 3 hours, collecting decoction, respectively adding 5 times of pure water into the rest Chinese medicinal residues for decoction for 3 hours, respectively collecting and combining the decoction, respectively freeze-drying at-40 ℃ and respectively crushing to 100 meshes to obtain astragalus extracts, american ginseng extracts, poria cocos extracts, licorice extracts and fructus psoraleae extracts.
In the embodiment, astragalus extract has the effects of benefiting qi and nourishing blood, tonifying deficiency and strengthening weakness, american ginseng extract has the effects of tonifying lung and qi, tonifying without dryness, and the two medicines are combined to regulate the hematopoietic function of bone marrow, and the fructus psoraleae extract has the effects of warming kidney and tonifying yang, tonifying kidney and replenishing essence, nourishing yin and supplementing blood, promoting the proliferation of hematopoietic stem cells and improving hematopoietic microenvironment; the poria cocos extract has the functions of promoting diuresis, removing dampness, strengthening spleen, soothing nerves, harmonizing spleen and stomach and enhancing the absorption capacity of small intestines; licorice root, radix Glycyrrhizae Praeparata extract, with the effects of regulating the middle warmer, moistening lung, removing toxic substances, and harmonizing the drugs. The traditional Chinese medicine extract provided by the embodiment has the effects of tonifying qi and blood and replenishing vital essence and generating marrow through compatibility of the components, and can prevent and relieve marrow suppression after chemotherapy and promote leucopoiesis.
Tiopronin is used as an amino acid derivative containing free sulfhydryl, and toxic and side effects caused by radiotherapy and chemotherapy are relieved through metabolic detoxification and tissue cell protection. Tiopronin can also prevent leucopenia caused by radiotherapy and chemotherapy, has protective effect on bone marrow, and can promote hematopoietic function recovery.
The invention combines the traditional Chinese medicine extract on the basis of the tiopronin, enhances the physical function of a patient through the traditional Chinese medicine extract, and reduces adverse reactions possibly generated by taking the tiopronin while promoting the absorption and utilization of the tiopronin by an organism. The invention exerts the synergistic effect of western medicines with rapid effect, mild and safe drug property through the combination of the western medicines. Compared with single tiopronin, the combined medicine realizes better whitening effect with smaller dosage of the tiopronin, and further reduces side effects of the medicine.
Example 2
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The pharmaceutical composition in this embodiment comprises the following components in parts by mass: 10 parts of tiopronin and 300 parts of drug-loaded liposome.
The medicine carried by the medicine-carrying liposome in the embodiment is astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract, and the mass ratio of the medicine carried by the astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract is 30:25:15:10:20.
The extraction methods of astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract in the embodiment are as follows:
step 1, respectively crushing astragalus, american ginseng, poria cocos, liquorice and fructus psoraleae to 10 meshes to obtain astragalus particles, american ginseng particles, poria cocos particles, liquorice particles and fructus psoraleae particles;
step 2, respectively soaking the astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles obtained in the step 1 in clear water for 6 hours, taking out, rapidly freezing at the temperature of minus 30 ℃, and taking out after freezing for 30 minutes;
and 3, respectively adding 10 times of pure water into the frozen astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles in the step 2 for decoction for 3 hours, collecting decoction, respectively adding 5 times of pure water into the rest Chinese medicinal residues for decoction for 3 hours, respectively collecting and combining the decoction, respectively freeze-drying at-40 ℃ and respectively crushing to 100 meshes to obtain astragalus extracts, american ginseng extracts, poria cocos extracts, licorice extracts and fructus psoraleae extracts.
The preparation method of the drug-loaded liposome in the embodiment comprises the following steps:
firstly, accurately weighing 6 parts of astragalus extract, 5 parts of American ginseng extract, 3 parts of poria extract, 2 parts of licorice extract, 4 parts of fructus psoraleae extract, 500 parts of egg yolk lecithin and 200 parts of cholesterol;
dissolving astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract in purified water to obtain a traditional Chinese medicine extract aqueous solution, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained traditional Chinese medicine extract aqueous solution, removing the solvent by rotary evaporation in a warm water bath at 20 ℃, drying overnight in vacuum to obtain a lipid membrane, dissolving and hydrating the lipid membrane by adding DEPC physiological saline, hydrating for 1h by a shaking table at 20 ℃, treating the obtained hydration system with 500W ultrasonic power for 5min to fully disperse the liposome in the hydration system, carrying out membrane treatment on the hydration system subjected to ultrasonic treatment by a polycarbonate membrane with the pore diameter of 100nm, repeatedly extruding for 15 times, then placing the obtained liposome mixed solution in a dialysis bag with the interception molecular weight of 30kDa, dialyzing for 30min by physiological saline, removing the unencapsulated traditional Chinese medicine extract in a permeate, and collecting liquid in the dialysis bag to obtain the drug-carrying liposome with the particle size of 100-150 nm.
The embodiment further prepares the traditional Chinese medicine extract into nano-scale drug-loaded liposome, and the liposome has good biocompatibility and biodegradability, and is phagocytized by a mononuclear phagocyte system after entering a human body, so that the liposome is enriched in tissues such as liver, spleen, lung, bone marrow and the like in a targeting way, and better exerts the drug effect.
Example 3
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The pharmaceutical composition in this embodiment comprises the following components in parts by mass: 10 parts of tiopronin, 300 parts of drug-loaded liposome and 100 parts of whey protein polypeptide.
The medicine carried by the medicine-carrying liposome in the embodiment is astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract, and the mass ratio of the medicine carried by the astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract is 30:25:15:10:20.
The extraction methods of astragalus extract, american ginseng extract, poria extract, licorice extract and fructus psoraleae extract in the embodiment are as follows:
step 1, respectively crushing astragalus, american ginseng, poria cocos, liquorice and fructus psoraleae to 10 meshes to obtain astragalus particles, american ginseng particles, poria cocos particles, liquorice particles and fructus psoraleae particles;
step 2, respectively soaking the astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles obtained in the step 1 in clear water for 6 hours, taking out, rapidly freezing at the temperature of minus 30 ℃, and taking out after freezing for 30 minutes;
and 3, respectively adding 10 times of pure water into the frozen astragalus particles, the American ginseng particles, the poria cocos particles, the licorice root particles and the fructus psoraleae particles in the step 2 for decoction for 3 hours, collecting decoction, respectively adding 5 times of pure water into the rest Chinese medicinal residues for decoction for 3 hours, respectively collecting and combining the decoction, respectively freeze-drying at-40 ℃ and respectively crushing to 100 meshes to obtain astragalus extracts, american ginseng extracts, poria cocos extracts, licorice extracts and fructus psoraleae extracts.
The preparation method of the drug-loaded liposome in the embodiment comprises the following steps:
firstly, accurately weighing 6 parts of astragalus extract, 5 parts of American ginseng extract, 3 parts of poria extract, 2 parts of licorice extract, 4 parts of fructus psoraleae extract, 500 parts of egg yolk lecithin and 200 parts of cholesterol;
dissolving astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract in purified water to obtain a traditional Chinese medicine extract aqueous solution, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained traditional Chinese medicine extract aqueous solution, removing the solvent by rotary evaporation in a warm water bath at 20 ℃, drying overnight in vacuum to obtain a lipid membrane, dissolving and hydrating the lipid membrane by adding DEPC physiological saline, hydrating for 1h by a shaking table at 20 ℃, treating the obtained hydration system with 500W ultrasonic power for 5min to fully disperse the liposome in the hydration system, carrying out membrane treatment on the hydration system subjected to ultrasonic treatment by a polycarbonate membrane with the pore diameter of 100nm, repeatedly extruding for 15 times, then placing the obtained liposome mixed solution in a dialysis bag with the interception molecular weight of 30kDa, dialyzing for 30min by physiological saline, removing the unencapsulated traditional Chinese medicine extract in a permeate, and collecting liquid in the dialysis bag to obtain the drug-carrying liposome with the particle size of 100-150 nm.
The preparation method of the whey protein polypeptide in the embodiment comprises the following steps:
whey protein powder and water are mixed according to the mass volume ratio of 10g:100mL of the mixture is mixed to obtain whey protein aqueous solution, the pH of the obtained whey protein aqueous solution is adjusted to 8, alkaline protease is added according to 3000U/g, enzymolysis is carried out for 2h at 50 ℃, inactivation is carried out for 10min at 95 ℃, supernatant is collected by centrifugation, and the supernatant is dialyzed, concentrated, purified, freeze-dried and crushed to obtain the whey protein polypeptide with the molecular weight of 2 kDa.
The whey protein polypeptide added in the embodiment is easier to be absorbed and utilized by organisms, can rapidly supplement nutrition for the organisms, can provide sufficient material basis for the organisms to synthesize white blood cells when tiopronin and effective components of traditional Chinese medicines activate marrow hematopoietic function, and solves the problem of lack of nutrition caused by poor digestion and absorption capacity due to vomiting, inappetence and gastrointestinal function injury after chemotherapy of tumor patients.
Example 4
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The pharmaceutical composition in the embodiment is oral enteric particles, and consists of the following components in parts by mass: 10 parts of tiopronin, 300 parts of drug-loaded liposome, 300 parts of starch, 200 parts of microcrystalline cellulose, 300 parts of isolation layer coating and 550 parts of enteric layer coating; wherein the isolating layer coating contains hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide in a mass ratio of 10:1:1; the enteric coating layer contains HPMCP-50, acetin and acetone in the mass ratio of 10:2:88.
The preparation method of the drug-loaded liposome and the extraction method of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2.
The preparation method of the oral enteric microparticles in this example comprises:
step I, mixing tiopronin and drug-loaded liposome with starch and microcrystalline cellulose, bonding with a proper amount of 5% starch slurry, granulating to obtain particles with the particle size of 20 meshes, and drying at 50 ℃ for later use;
step II, dispersing 250 parts of hydroxypropyl methylcellulose, 25 parts of magnesium stearate and 25 parts of titanium dioxide, dissolving in 6000 parts of 80% ethanol solution, and uniformly mixing to obtain an isolation layer coating solution; placing the particles obtained in the step I into a fluidized bed, spraying the obtained isolation layer coating liquid at room temperature, and drying for 3 hours to volatilize the water completely, so as to obtain particles with the isolation layer coating on the surfaces;
step III, adding 484 parts of acetone into 55 parts of HPMCP-50 and 11 parts of glycerol acetate, and stirring until the mixture is dissolved to obtain enteric coating liquid; and (3) placing the particles with the isolation layer coating on the surface obtained in the step (II) in a fluidized bed, spraying the obtained enteric coating liquid at room temperature, and drying for 3 hours to volatilize the water completely, so as to obtain the oral enteric particles with the enteric coating on the surface.
Example 5
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The pharmaceutical composition in the embodiment is oral enteric particles, and consists of the following components in parts by mass: 10 parts of tiopronin, 250 parts of drug-loaded liposome, 50 parts of whey protein polypeptide, 300 parts of starch, 200 parts of microcrystalline cellulose, 300 parts of isolation layer coating agent and 550 parts of enteric layer coating agent; wherein the isolating layer coating agent contains hydroxypropyl methylcellulose, magnesium stearate and titanium dioxide in a mass ratio of 10:1:1; the enteric coating agent contains HPMCP-50, acetin and acetone in the mass ratio of 10:2:88.
The preparation method of the drug-loaded liposome and the extraction method of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2, and the preparation method of the whey protein polypeptide is the same as that in example 3.
The preparation method of the oral enteric particles of the traditional Chinese medicine composition in the embodiment comprises the following steps:
step I, mixing tiopronin, drug-loaded liposome and whey protein polypeptide with starch and microcrystalline cellulose, bonding with a proper amount of 5% starch slurry, granulating to obtain particles with the particle size of 20 meshes, and drying at 50 ℃ for later use;
step II, dispersing 250 parts of hydroxypropyl methylcellulose, 25 parts of magnesium stearate and 25 parts of titanium dioxide, dissolving in 6000 parts of 80% ethanol solution, and uniformly mixing to obtain an isolation layer coating solution; placing the particles obtained in the step I into a fluidized bed, spraying the obtained coating liquid of the isolation layer at room temperature, and drying for 3 hours to volatilize the water completely, so as to obtain the particles with the isolation layer on the surface;
step III, adding 484 parts of acetone into 55 parts of HPMCP-50 and 11 parts of glycerol acetate, and stirring until the mixture is dissolved to obtain enteric coating liquid; and (3) placing the particles with the isolation layer on the surface obtained in the step (II) in a fluidized bed, spraying the obtained enteric coating liquid at room temperature, and drying for 3 hours to volatilize the water completely, so as to obtain the oral enteric particles.
In the embodiment 4 and the embodiment 5, the active ingredients of the medicine are prepared into oral enteric-coated particle preparations, and enteric-coated preparations are not disintegrated in the stomach, but release the medicine in intestinal tracts, so that the stability and bioavailability of tiopronin, medicine-carrying liposome and whey protein polypeptide can be improved, the irritation of the medicine to the stomach of a chemotherapy patient is reduced, and the medication compliance is increased.
Example 6
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The traditional Chinese medicine composition in the embodiment is an oral liquid preparation, and comprises the following components in parts by mass: 10 parts of tiopronin, 300 parts of drug-loaded liposome and 500 parts of prebiotic aqueous solution.
In the embodiment, the prebiotics are tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide with equal mass ratio, and the concentration of the prebiotics in the prebiotic water solution is 15wt%.
The preparation method of the drug-loaded liposome and the extraction method of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2.
The preparation method of the oral liquid preparation in the embodiment comprises the following steps: the tiopronin, the drug-loaded liposome and the prebiotic aqueous solution are uniformly mixed.
Example 7
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The traditional Chinese medicine composition in the embodiment is an oral liquid preparation, and comprises the following components in parts by mass: 10 parts of tiopronin, 250 parts of drug-loaded liposome, 50 parts of whey protein polypeptide and 500 parts of prebiotic water solution.
In the embodiment, the prebiotics are tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide with equal mass ratio, and the concentration of the prebiotics in the prebiotic water solution is 15wt%.
The preparation method of the drug-loaded liposome and the extraction method of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2, and the preparation method of the whey protein polypeptide is the same as that in example 3.
The preparation method of the oral liquid preparation in the embodiment comprises the following steps: the tiopronin, the drug-loaded liposome, the whey protein polypeptide and the prebiotic aqueous solution are uniformly mixed.
Example 8
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The traditional Chinese medicine composition in the embodiment is an oral liquid preparation, and comprises the following components in parts by mass: 300 parts of oral enteric particles and 500 parts of prebiotic water solution.
The oral enteric particles in this example contain the following components in parts by mass: 10 parts of tiopronin, 300 parts of drug-loaded liposome, 300 parts of starch, 200 parts of microcrystalline cellulose, 300 parts of isolation layer coating and 550 parts of enteric layer coating. .
In the embodiment, the prebiotics are tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide with equal mass ratio, and the concentration of the prebiotics in the prebiotic water solution is 15wt%.
The preparation method of the drug-loaded liposome and the extraction method of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2, and the preparation method of the oral gastrointestinal microparticles in this example is the same as that in example 4.
The preparation method of the oral liquid preparation in the embodiment comprises the following steps: and uniformly mixing the oral enteric particles and the prebiotic water solution to obtain a suspension, namely the oral liquid preparation.
Example 9
The embodiment provides a medicine composition containing sulfur and protamine for preventing and treating leucopenia caused by chemotherapy and a preparation method thereof.
The traditional Chinese medicine composition in the embodiment is an oral liquid preparation, and comprises the following components in parts by mass: 300 parts of oral enteric particles and 500 parts of prebiotic water solution.
The pharmaceutical composition in the embodiment is oral enteric particles, and consists of the following components in parts by mass: 10 parts of tiopronin, 250 parts of drug-loaded liposome, 50 parts of whey protein polypeptide, 300 parts of starch, 200 parts of microcrystalline cellulose, 300 parts of isolation layer coating agent and 550 parts of enteric layer coating agent
In the embodiment, the prebiotics are tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide with equal mass ratio, and the concentration of the prebiotics in the prebiotic water solution is 15wt%.
The preparation method of the drug-loaded liposome and the extraction methods of the astragalus extract, the American ginseng extract, the poria extract, the licorice extract and the fructus psoraleae extract in this example are the same as those in example 2, the preparation method of the whey protein polypeptide is the same as that in example 3, and the preparation method of the oral gastrointestinal microparticles in this example is the same as that in example 5.
The preparation method of the oral liquid preparation in the embodiment comprises the following steps: and uniformly mixing the oral enteric particles and the prebiotic water solution to obtain a suspension, namely the oral liquid preparation.
The oral liquid preparation prepared in example 6-example 9 is added with tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide as prebiotics, the tremella polysaccharide, ganoderma lucidum polysaccharide and medlar polysaccharide can stimulate the growth of beneficial flora in intestinal tracts, and the recovery of hematopoiesis function is promoted by improving intestinal microecology of patients after chemotherapy; meanwhile, the intestinal function is enhanced, and the absorption of the intestinal tract to the effective medicinal components is further promoted, so that the effect of the medicinal composition on preventing and treating leucopenia caused by chemotherapy as a whole is enhanced.
Efficacy test:
1. test materials:
kunming mice, weight 18-22g, male and female halves, collar 8 weeks;
2. test grouping:
180 mice were randomly divided into 12 groups of 15 mice each; including normal control, model, tiopronin, example 1-example 9;
3. test model:
other mice than the normal control group were continuously intraperitoneally injected with cyclophosphamide at a dose of 100. Mu.L/20 g (100 mg/kg) body weight daily, 1 time daily, 7 times daily. Cyclophosphamide cell cycle nonspecific chemotherapeutics can cause bone marrow suppression in animal models, and the main manifestation is obvious leucopenia.
4. Test treatment:
normal control and model groups: normal feeding, normal saline is infused according to the dosage, and no special treatment is carried out;
tiopronin group: the tiopronin tablet is infused with 20mg/kg body weight, 1 time a day for 10 days;
example 1 group-example 9 group: the pharmaceutical compositions prepared in examples 1-9 were administered by drenching each of them 1 time a day for 10 days, based on the weight of Luo Ningji mg/kg of tiopronin;
5. detecting the index: peripheral blood white blood cells were counted and the results are shown in table 1. 10 9
TABLE 1
As can be seen from the comparison of the data in Table 1, the pharmaceutical composition provided by the invention can prevent leucopenia caused by chemotherapy, and compared with the single tiopronin, the combined use of the pharmaceutical composition realizes better effect of whitening by using smaller amount of the tiopronin.
Clinical trial:
the oral liquid pharmaceutical composition prepared in example 9 is used as a test drug, and a clinical test is performed on a patient with bone marrow suppression after chemotherapy.
1. Basic data: the total 68 cases of patients with bone marrow suppression after tumor chemotherapy, of which 36 men and 32 women, aged 30-70 years, have clinical manifestations of decreased appetite and fatigue weakness.
2. Curative effect judgment criteria:
the effect is shown: the peripheral blood white blood cell count returns to normal or rises by more than 1 time before taking medicine;
the method is effective: the peripheral blood leukocyte count is increased by more than 0.5X10 than before administration 9 /L；
Invalidation: the peripheral blood leukocyte count is not increased or increased by 0.5X10 than that before administration 9 /L。
3. The medicine taking method comprises the following steps: the oral liquid dosage form pharmaceutical composition prepared in example 9 of the present invention was taken twice daily, each time at a dose of Luo Ningji mg/kg body weight of tiopronin, for two consecutive weeks.
3. And (3) result statistics: blood routine tests were performed on 68 patients taking the drug and the results are shown in Table 2 based on the statistics of peripheral blood white cell count.
| Group of | Total number of cases | Has obvious effect | Effective and effective | Invalidation of | The total effective rate is% |
| Example 9 | 68 cases | 21 | 44 | 3 | 95.58％ |
From the data in Table 2, it can be seen that the pharmaceutical composition provided by the invention can alleviate bone marrow suppression after chemotherapy and promote leucopoiesis.
Claims (8)
1. A pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which is characterized by comprising the following components in parts by mass: 1-5 parts of tiopronin, 20-30 parts of astragalus extract, 15-25 parts of American ginseng extract, 10-15 parts of poria extract, 10-15 parts of licorice extract and 20-25 parts of fructus psoraleae extract.
2. A pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which is characterized by comprising the following components in parts by mass: 1-10 parts of tiopronin and 1-300 parts of drug-loaded liposome; the medicine carried by the medicine-carrying liposome is astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract, and the mass ratio of the medicine carried by astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract is 20-30:15-25:10-15:10-15:20-25.
3. The pharmaceutical composition for preventing and treating leukopenia caused by chemotherapy according to claim 2, wherein the preparation method of the drug-loaded liposome is as follows:
accurately weighing astragalus extract, american ginseng extract, poria cocos extract, licorice root extract, fructus psoraleae extract, egg yolk lecithin and cholesterol;
dissolving astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract in purified water to obtain a traditional Chinese medicine extract aqueous solution, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained traditional Chinese medicine extract aqueous solution, removing a solvent by rotary evaporation, drying overnight in vacuum to obtain a lipid film, dissolving and hydrating the lipid film, carrying out ultrasonic treatment on the obtained hydration system to enable the liposome to be fully dispersed in the hydration system, and carrying out film treatment on the hydration system after ultrasonic treatment to obtain the drug-loaded liposome with the particle size of 100-150 nm.
4. The pharmaceutical composition for preventing and treating leucopenia caused by chemotherapy according to claim 2, further comprising the following components in parts by mass: 1-100 parts of whey protein polypeptide.
5. The pharmaceutical composition for preventing and treating chemotherapy-induced leukopenia according to claim 4, wherein the preparation method of the whey protein polypeptide comprises:
dissolving whey protein powder in water to obtain whey protein water solution, regulating pH value of the obtained whey protein water solution to 8, adding alkaline protease, performing enzymolysis at 50deg.C for 2h, inactivating at 95deg.C for 10min, centrifuging, collecting supernatant, dialyzing the supernatant, concentrating, purifying, lyophilizing, and pulverizing to obtain whey protein polypeptide with molecular weight of 2 kDa.
6. A pharmaceutical composition containing tiopronin for preventing and treating leucopenia caused by chemotherapy, which is characterized by being oral enteric microparticles, wherein the oral enteric microparticles comprise the following components in parts by mass: 1-10 parts of tiopronin, 1-300 parts of drug-loaded liposome, 200-300 parts of starch, 100-200 parts of microcrystalline cellulose, 200-300 parts of isolation layer coating and 450-550 parts of enteric layer coating;
or the oral enteric particles comprise the following components in parts by mass: 1-10 parts of tiopronin, 1-250 parts of drug-loaded liposome, 1-50 parts of whey protein polypeptide, 200-300 parts of starch, 100-200 parts of microcrystalline cellulose, 200-300 parts of isolation layer coating and 450-550 parts of enteric layer coating;
the medicine carried by the medicine-carrying liposome is astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract, and the mass ratio of the medicine carried by astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract is 20-30:15-25:10-15:10-15:20-25.
7. A method of preparing a pharmaceutical composition for the prevention and treatment of chemotherapy-induced leukopenia in accordance with claim 6, comprising the steps of:
step I, mixing tiopronin and drug-loaded liposome with starch and microcrystalline cellulose, bonding with a proper amount of 5% starch slurry, granulating to obtain particles with the particle size of 20 meshes, and drying at 50 ℃ for later use;
or mixing tiopronin, drug-loaded liposome and whey protein polypeptide with starch and microcrystalline cellulose, bonding with appropriate amount of 5% starch slurry, granulating to obtain particles with particle diameter of 20 mesh, and drying at 50deg.C;
step II, placing the particles obtained in the step I in a fluidized bed, spraying an isolating layer coating liquid at room temperature, and drying completely to obtain particles with isolating layer coating on the surfaces;
step III, placing the particles with the isolation layer coating on the surface obtained in the step II in a fluidized bed, spraying enteric coating liquid at room temperature, and drying completely to obtain oral enteric particles with the enteric coating on the surface;
the preparation method of the drug-loaded liposome comprises the following steps:
accurately weighing astragalus extract, american ginseng extract, poria cocos extract, licorice root extract, fructus psoraleae extract, egg yolk lecithin and cholesterol;
dissolving astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract in purified water to obtain a traditional Chinese medicine extract aqueous solution, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained traditional Chinese medicine extract aqueous solution, removing a solvent by rotary evaporation, drying overnight in vacuum to obtain a lipid film, dissolving and hydrating the lipid film, carrying out ultrasonic treatment on the obtained hydration system to enable the liposome to be fully dispersed in the hydration system, and carrying out film treatment on the hydration system after ultrasonic treatment to obtain the drug-loaded liposome with the particle size of 100-150 nm.
8. The medicine composition containing the sulfur-containing protamine for preventing and treating leucopenia caused by chemotherapy is characterized by being an oral liquid preparation, wherein the oral liquid preparation comprises the following components in parts by mass: 1-10 parts of tiopronin, 1-300 parts of drug-loaded liposome and 300-500 parts of prebiotic aqueous solution;
or the oral liquid preparation comprises the following components in parts by mass: 1-10 parts of tiopronin, 1-250 parts of drug-loaded liposome, 1-50 parts of whey protein polypeptide and 300-500 parts of prebiotic aqueous solution;
or the oral liquid preparation comprises the following components in parts by mass: 1-300 parts of oral enteric particles and 300-500 parts of prebiotic aqueous solution;
the oral enteric particles comprise the following components in parts by mass: 1-10 parts of tiopronin, 1-300 parts of drug-loaded liposome, 200-300 parts of starch, 100-200 parts of microcrystalline cellulose, 200-300 parts of isolation layer coating and 450-550 parts of enteric layer coating;
or the oral enteric particles comprise the following components in parts by mass: 1-10 parts of tiopronin, 1-250 parts of drug-loaded liposome, 1-50 parts of whey protein polypeptide, 200-300 parts of starch, 100-200 parts of microcrystalline cellulose, 200-300 parts of isolation layer coating and 450-550 parts of enteric layer coating;
the medicine carried by the medicine-carrying liposome is astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract, and the mass ratio of the medicine carried by astragalus extract, american ginseng extract, poria cocos extract, licorice root extract and fructus psoraleae extract is 20-30:15-25:10-15:10-15:20-25;
the prebiotics are one or more of tremella polysaccharide, ganoderma lucidum polysaccharide, wolfberry polysaccharide, agaric polysaccharide, lentinan or aloe polysaccharide; the concentration of the prebiotics in the prebiotic water solution is 1-20wt%.
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| CN102078511A (en) * | 2010-12-30 | 2011-06-01 | 山西振东制药股份有限公司 | Medicine for promoting leukopoiesis |
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|---|---|---|---|---|
| CN101062024A (en) * | 2006-04-25 | 2007-10-31 | 刘祥华 | Pronin medicinal composition and its preparing method |
| CN102078511A (en) * | 2010-12-30 | 2011-06-01 | 山西振东制药股份有限公司 | Medicine for promoting leukopoiesis |
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