CN117338748B - Capsule for treating atrial and ventricular premature beat and its preparing process - Google Patents

Capsule for treating atrial and ventricular premature beat and its preparing process Download PDF

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CN117338748B
CN117338748B CN202311535066.6A CN202311535066A CN117338748B CN 117338748 B CN117338748 B CN 117338748B CN 202311535066 A CN202311535066 A CN 202311535066A CN 117338748 B CN117338748 B CN 117338748B
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quartz sand
trifluoromethanesulfonyl
glucan
amide
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CN117338748A (en
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何德海
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Quanzhou Ryan Biochemical Co ltd
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Quanzhou Ryan Biochemical Co ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
    • A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4816—Wall or shell material
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P19/00—Preparation of compounds containing saccharide radicals
    • C12P19/04—Polysaccharides, i.e. compounds containing more than five saccharide radicals attached to each other by glycosidic bonds
    • C12P19/08—Dextran
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/645—Fungi ; Processes using fungi
    • C12R2001/85—Saccharomyces
    • C12R2001/865—Saccharomyces cerevisiae

Abstract

The invention discloses a capsule for treating premature beat of atrium and ventricle, which is characterized by comprising a hollow capsule and a medicine active ingredient in the capsule, wherein the medicine active ingredient consists of the following components: coenzyme Q10, IPE and beta-glucan, wherein the mass ratio of the coenzyme Q10 to the IPE is 1:18-1:22, and the mass ratio of the IPE to the beta-glucan is 1:0.2-1:0.3. The invention also provides a preparation method of the capsule for treating the premature beat of the atrium and the ventricle. The invention has the advantages of simple components and good treatment effect, and is convenient for industrialization.

Description

Capsule for treating atrial and ventricular premature beat and its preparing process
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a capsule for treating premature beat of an atrium and a ventricle and a preparation method thereof.
Background
The premature beat is also called extra-systole, and is called as premature beat for short, which means that 1 or 2 heart beats caused by the advanced activation of the ectopic pacing points below the sinus node are one of the most common clinical arrhythmias, and are mainly expressed by the level downshifts and T wave changes of the S-T section of an electrocardiogram. Premature beat is the most common and common ectopic heart rhythm. Premature beats can be classified into atrial, atrioventricular, and ventricular based on the location of the onset of the ectopic beat. Where ventricular premature beats are most common, they may be sporadic or sporadic, or they may occur frequently.
The short term goal of premature beat therapy is to improve the symptoms and stabilize hemodynamic status of the patient, with the goal of reducing hospitalization and mortality; common therapeutic agents include beta blockers, aldosterone receptor antagonists, angiotensin Converting Enzyme Inhibitors (ACEI), and the like. Wherein, mexiletine can increase heart blood discharge amount, strengthen myocardial contraction, directly relax vascular smooth muscle, and rapidly improve heart function.
These drugs are generally formulated into tablets, capsules, granules, injections, etc. Different pharmaceutical forms play an important role in the therapeutic effect and the release rate of the drug. Capsules are used in a variety of pharmaceutical preparations as a common pharmaceutical form. At present, the gelatin capsule is used as a main loading material of partial medicines and health food raw materials, and plays a positive role in protecting the medicines and food raw materials in the capsule, realizing in-vivo slow release, masking the odor or taste of the loaded objects and the like. At the same time, gelatin capsules also have certain limitations of use. There are also considerable technical disclosures concerning other capsule materials such as polylactic acid-glycolic acid copolymer microcapsules (CN 201310664637.6), modified soy protein hollow capsule materials (CN 201510496254.1), and the like. Based on the above, a capsule matching with the pharmaceutical composition of the present invention is expected to be effective in exerting the effect of a drug.
Disclosure of Invention
The invention aims to overcome the problems in the prior art and provides a capsule for treating premature beat of atria and ventricles and a preparation method thereof. The medicine capsule of the invention can effectively treat the premature beat of the heart and improve the heart function through the synergistic effect of the capsule and the active ingredients in the capsule.
The aim and the technical problems of the invention are realized by adopting the following technical proposal.
In one aspect, the invention provides a capsule for treating atrial and ventricular premature beat, comprising a hollow capsule and a pharmaceutically active ingredient within the capsule, the pharmaceutically active ingredient consisting of: coenzyme Q10, IPE and beta-glucan, wherein the mass ratio of the coenzyme Q10 to the IPE is 1:18-1:22, and the mass ratio of the IPE to the beta-glucan is 1:0.2-1:0.3.
Preferably, the mass ratio of the coenzyme Q10 to the IPE is 1:20, and the mass ratio of the IPE to the beta-glucan is 1:1.
Preferably, the method comprises the steps of preparing microparticles and empty capsules of the pharmaceutically active ingredient; the preparation method of the medicine active ingredient comprises the following steps:
dissolving coenzyme Q10 in IPE to form mixed solution, adding beta-glucan particles with the particle size of 0.5-1.5 μm, stirring uniformly, emulsifying the obtained mixed solution at 45-60 ℃ for 30-50min under the anaerobic state, homogenizing for five times under the high pressure of 40Mpa to obtain emulsion oil drops with the particle size of 0.8-1.3 μm, adjusting the air inlet temperature of a spray dryer to 200-240 ℃ and the air outlet temperature to 90-130 ℃ to obtain the pharmaceutically active ingredient particles with the particle size of 0.8-1.3 μm.
Preferably, the beta-glucan is prepared by the following steps: washing Saccharomyces cerevisiae with deionized water, preparing into bacterial suspension, filtering, removing impurities, and sequentially adding glucose, yeast extract, potassium dihydrogen phosphate, magnesium sulfate, water and fungus schizophyllum commune with concentration of 2 g/L; adding 50wt% nitric acid to adjust pH, controlling pH to 2.0-4.0, and fermenting at 25-30deg.C; in the process, 0.1-10 mu m particles are removed by filtration, so that the biomass concentration of the fermentation broth is increased, after enzymolysis is finished, the fermentation broth is centrifugally washed by deionized water until supernatant is clear and transparent, and wet beta 1,3-1,6 glucan is obtained by centrifugal precipitation, and beta-glucan powder is obtained after drying.
Coenzyme Q10 is the only coenzyme Q substance naturally existing in cells in human body, also called ubiquinone, and is a fat-soluble polyene quinone compound; mainly exists on the inner membrane of the mitochondria of cells of the heart, the liver and the kidney, and is an important hydrogen-transmitting body in the respiratory chain of biological cells. Coenzyme Q10 is a natural antioxidant and cell metabolism activator synthesized by cells themselves. Coenzyme Q10 also directly affects the immune system and aging processes of the body, and if coenzyme Q10 is absent in the body, many health problems such as arrhythmia, heart failure, arteriosclerosis, heart attack, hypertension or muscle atrophy and the like occur in the body. Coenzyme Q10 is the highest in heart content and, as an important cofactor, plays a key role in the oxidative phosphorylation of mitochondria to form ATP. It helps in the biological energy conversion in the body, and energy ATP is produced by the electron transfer chain in the tricarboxylic acid cycle, so that cardiac myocytes can repeatedly obtain ATP continuously, and the heart can continuously keep beating.
The essential components of IPE are Omega-3 series unsaturated fat EPA and small amount of DHA, which are derived from tuna oil. EPA has effects of lowering blood viscosity, dissolving superfluous fat in blood vessel wall, lowering triglyceride and cholesterol (LDL) concentration, cleaning thrombi, reducing blood lipid, and preventing and improving cardiovascular and cerebrovascular diseases; DHA is the material basis for brain cell production, and the lack of DHA causes brain development disorder, hypomnesis and senile dementia.
The purified yeast beta-glucan obtained by the method of the invention has a very stable three-dimensional structure similar to that of natural yeast cells. This three-dimensional structure is very important for the activity of beta-glucan. Purified yeast beta-glucan is site-specifically recognized by Dectin-1 of M cells and allowed to enter lymph nodes because of its natural three-dimensional structure. Therefore, it is important to maintain the three-dimensional structure of yeast glucan during purification, and the three-dimensional structure is important for the activity of beta-glucan.
The beta-glucan adopts a special gentle purification process, has high product purity (the content is at least over 95 percent), maintains the natural three-dimensional structure and the pure anaerobic growth environment of the yeast, and is very important for activity (similar to the three-dimensional structure in natural yeast cells). The beta-glucan can be specifically identified by Dectin-1 site of M cells of intestinal immune tissues because of the natural three-dimensional structure, and can enter lymph nodes, the beta-glucan can activate lymphocytes to generate antibodies, combine with antibody antigens and then combine with complement to activate and kill pathogens, and the beta-glucan can also activate stem cells and macrophages to secrete various cytokines (interleukins), promote proliferation and differentiation of target cells and participate in regulating immune responses of organisms and inhibiting inflammatory responses.
Coenzyme Q10 provides sufficient energy and oxygen to the heart, protecting the cardiovascular system and enhancing cardiac function; IPE can reduce blood viscosity, dissolve redundant fat in blood vessel wall, reduce triglyceride and cholesterol (LDL) concentration, and achieve effects of cleaning thrombi, reducing blood lipid, and softening blood vessel; beta-glucan can activate lymphocytes, generate antibodies to improve the immunity of the organism, and has the functions of scavenging free radicals and assisting damaged tissues to accelerate recovery and produce cytokines.
Preferably, the preparation method of the hollow capsule comprises the following steps:
dissolving sodium or potassium carboxymethylcellulose in water to obtain solution with concentration of 0.1-0.3g/mL, and continuously introducing O into the solution at an amount of 10mL/min under sealed environment 3 After the introduction, adding a functional monomer and ammonium persulfate into the solution to react for 20-45min at the temperature of 30-50 ℃ to obtain solution A after the reaction is finished; the addition amount of the functional monomer in the process is 50-70% of the mass of sodium or potassium carboxymethylcellulose, and the addition amount of the ammonium persulfate is 5-10% of the mass of sodium or potassium carboxymethylcellulose;
washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 Stirring in HCl solution for 3-5 min for sensitization, then taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into 80-90wt% ionic liquid aqueous solution, performing ultrasonic treatment for 1-5h for activation, taking out the quartz sand, washing and drying to obtain activated quartz sand;
mixing lactic acid and glycerin according to the volume ratio of 1:5-10 to obtain a mixed solution, and then mixing the lactic acid and the glycerin according to the mass volume ratio of 3-5g: adding 100mL of activated quartz sand, shearing in a high-speed shearing machine at a rotating speed of 2000-3000rpm for 1-3min, and filtering the quartz sand to obtain a solution B;
the solution A and the solution B obtained above are mixed according to the volume ratio of 10:3-5 adding the mixture into a sol tank for mixing, heating the system to 80-90 ℃, sequentially adding a gel agent and a coagulant aid into the AB mixed solution, uniformly mixing, and continuously stirring to prepare a glue solution; and preparing the obtained glue solution into the hollow capsule according to a conventional process.
Preferably, the functional monomer is selected from one or more of 2-aminoethyl methacrylate, methacrylic hydrazide, acrylic hydrazide, 2-methylallylamine, 3-butene-1-amine, pent-4-ene-1-amine and double bonded polylysine.
Preferably, the ionic liquid is selected from one or more of 1-methyl-3-ethoxyethylimidazole bistrifluoromethylsulfonylimine salt, N-butyl-N-methylpyrrolidine bistrifluoromethylsulfonylimine salt, 1, 2-dimethyl-3-ethoxyethylimidazole bistrifluoromethylsulfonylimine salt, 1-methyl-3-butylimidazole bistrifluoromethylsulfonylimine salt, N-ethoxyethyl-N-methylpyrrolidine bistrifluoromethylsulfonylimine salt, 1-methyl-3-ethoxymethylimidazole bistrifluoromethylsulfonylimine salt, N-ethoxymethyl-N-methylpyrrolidine bistrifluoromethylsulfonylimine salt and N, N-diethyl-2-methoxyethyl-N-methylamine bistrifluoromethylsulfonylimine salt.
Preferably, the adding amount of the gel is 1-5g of the gel per 100mL of AB mixed solution, and the gel is one or more selected from carrageenan, gellan gum, acacia gum, dragon whisker gum, tamarind gum, chitosan oligosaccharide, trehalose and mannan.
Preferably, the coagulant aid is added in an amount of 0.1-0.3g per 100mL of AB mixed solution, and the gel is one or more selected from potassium citrate, sodium acetate, potassium chloride and magnesium chloride.
Preferably, the SnCl 2 The HCl solution is prepared by mixing 1-5g SnCl 2 Is dissolved in 25-28wt% hydrochloric acid solution.
By means of the technical scheme, the invention has at least the following advantages: the pharmaceutical active ingredients of the invention include coenzyme Q10, IPE and beta-glucan. The invention has the innovation point that the preparation process of the beta-glucan adopts Saccharomyces cerevisiae as bacterial suspension, glucose, yeast extract, monopotassium phosphate, magnesium sulfate and water are added as nutrition sources, then fungus schizophyllum and saccharomycetes are added for co-fermentation, an asymmetric filter membrane is used in the fermentation process, and particles with the particle size of 0.1-10 mu m are removed by cross flow micro filtration, so that the fermentation is realized The biomass concentration of the fermentation broth is increased. After fermentation broth is produced, enzymolysis, washing and centrifugation are carried out, and the combined actions of the processes ensure that the original three-dimensional structure of the beta-glucan cannot be changed. The preparation process of the beta-glucan can ensure the original three-dimensional structure of the beta-glucan to the maximum extent, thereby exerting the function of the beta-glucan to the maximum extent. The second innovation point of the invention is that in one aspect, sodium or potassium carboxymethylcellulose is used for carrying out electronic exchange with sodium or potassium carboxymethylcellulose by continuously introducing ozone with strong oxidability, so that the surface charge quantity of the sodium or potassium carboxymethylcellulose is increased, the reactivity of the sodium or potassium carboxymethylcellulose is enhanced, the sodium or potassium carboxymethylcellulose and a functional monomer after the strong oxidation of ozone initiate free radical polymerization under the action of an initiator, and the functional monomer is grafted to a carboxymethyl cellulose molecular chain through polymerization, so as to obtain a solution A taking a carboxymethyl cellulose grafted copolymer as a main component; in another aspect, the invention uses quartz sand as the base material, and is made by SnCl 2 The method has the advantages that the quartz sand which is insensitive to micromolecular organic matters originally is subjected to activation treatment under the actions of HCl sensitization and ionic liquid activation, the treatment process can ensure that the edge angle in the original quartz sand structure is unchanged, the surface of the quartz sand is negatively charged, and the quartz sand can be mixed with H contained in a mixture of lactic acid and glycerin under the action of high-speed shearing + And (3) carrying out a neutralization reaction to increase the content of organic anions in the solution, thereby obtaining a solution B containing lactate ions. In the last aspect, the solution A and the solution B are heated after being mixed, the solution B can keep the uniformity of the whole solution system, finally, the gel and the coagulant aid are added, and are mixed uniformly and then are continuously stirred to prepare a glue solution, and the glue solution is prepared into capsules according to the conventional process. The capsule has good toughness, low friability, good stability, and rapid disintegration. The synergistic effect of the active ingredients of the medicine and the capsules can fully exert the activity of the medicine and effectively improve the treatment effect on the premature beat of the heart.
The foregoing description is only an overview of the present invention, and is intended to provide a more thorough understanding of the present invention, and is to be accorded the full scope of the present invention.
Drawings
FIG. 1 is a block diagram of native yeast beta-glucan in the cell wall of a dry yeast;
FIG. 2 is a block diagram of purified yeast beta-glucan obtained according to the method of example 1 of the present invention;
FIG. 3 is a comparison of superoxide and oxygen radicals produced by different yeast beta-glucans stimulated monocytes.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purposes and the effects of the present invention easy to understand, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention, and it is obvious that the described embodiments are only some embodiments of the present invention, not all embodiments. All other embodiments, which can be made by those skilled in the art based on the embodiments of the invention without making any inventive effort, are intended to be within the scope of the invention.
Example 1: preparation of beta-glucan
Washing 3kg of Saccharomyces cerevisiae with deionized water, preparing a bacterial suspension with mass fraction of 22% with deionized water (filtering, removing impurities), and adding glucose 2g/L, yeast extract (CAS: 8013-01-2, sigma) 5g/L, potassium dihydrogen phosphate 35mg/L, magnesium sulfate 35mg/L, and water 1L; adding Schizophyllum commune (Schizosaccharomyces cerevisiae modified chemically, enzymatically or physically) with a content of 50% of Saccharomyces cerevisiae, and counting 2.8-3.2X10 9 Hundred million cfu/g; adding 50wt% nitric acid to adjust the pH to 2.0-4.0, and controlling the temperature to be: fermenting at 25-30deg.C for 12-24 hr; in the process, an asymmetric filter membrane is used, particles with the size of 0.1-10 mu m are removed through cross flow microfiltration, so that the biomass concentration of fermentation liquor is improved, 10mg of compound enzyme consisting of mannanase, yeast extraction enzyme and neutral protease (the mass ratio of the mannanase to the yeast extraction enzyme is 1:1.5:1.5) is added after fermentation, enzymolysis treatment is carried out for 60min, deionized water is used for centrifugal washing until supernatant is clear and transparent after the enzymolysis is finished, and wet beta 1,3-1,6 glucan is obtained through centrifugal precipitation; finally, the granules are obtained after drying, and the granules are uniform, have good free mobility and are pure Beta-glucan powder having a degree of concentration of 98% or more.
FIG. 1 is a block diagram of native yeast beta-glucan in the cell wall of a dry yeast; FIG. 2 is a block diagram of purified yeast beta-glucan obtained according to the method of example 1 of the present invention. As can be seen from fig. 1 and 2, the yeast β -glucan purified by the above method has a very stable three-dimensional structure similar to that of natural yeast cells. This three-dimensional structure is very important for the activity of beta-glucan. Purified yeast beta-glucan is site-specifically recognized by Dectin-1 of M cells and allowed to enter lymph nodes because of its natural three-dimensional structure. Therefore, it is important to maintain the three-dimensional structure of yeast glucan during purification, and the three-dimensional structure is important for the activity of beta-glucan.
In addition, by comparing the superoxide and oxygen radical content of the different beta-glucans stimulated monocytes produced by in vitro experiments, it was found that the higher the purity, the higher the superoxide and oxygen radical content of the beta-glucan produced (FIG. 3). Stimulation and promotion of the innate immune system is very strongly dependent on the purity of yeast beta-glucan, and partial purification is much worse than the effect of high purity yeast beta-glucan in example 1. Furthermore, the so-called "natural" yeast cell wall, although itself containing natural yeast β -glucan, as can be seen from the study data in the above figures, the "lazy" simple eating yeast cell wall does not have an enhancing effect on the immune system.
Example 2:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:20, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.25; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 0.8 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: dissolving sodium carboxymethylcellulose in water to obtain 0.2g/mL solution, and continuously introducing O into the solution at a concentration of 10mL/min under sealed environment 3 After the introduction, adding 2-amino ethyl methacrylate and ammonium persulfate into the solution to react for 33min at 40 ℃ to obtain solution A after the reaction is finished; the adding amount of the 2-amino ethyl methacrylate in the process is 60% of the mass of sodium or potassium carboxymethyl cellulose, and the adding amount of the ammonium persulfate is 7.5% of the mass of sodium or potassium carboxymethyl cellulose. Washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 HCl solution (3 g SnCl) 2 Dissolving in 26wt% hydrochloric acid solution) for 4min to sensitize, taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into 85wt% N-ethoxyethyl-N-methyl pyrrolidine bis (trifluoromethanesulfonyl imide) salt aqueous solution, performing ultrasonic treatment for 3h to activate, taking out the quartz sand, washing and drying to obtain activated quartz sand. Mixing lactic acid and glycerin according to a volume ratio of 1:7.5 to obtain a mixed solution, and then mixing the mixed solution with 4g: the activated silica sand was added in an amount of 100mL and sheared in a high speed shearing machine at 2500rpm for 2min, after which the silica sand was filtered off to obtain solution B. The solution A and the solution B obtained above are mixed according to the volume ratio of 10:4 adding the solution into a sol tank for mixing, heating the system to 85 ℃, then sequentially adding carrageenan (the adding amount is 3g in each 100mL of AB mixed solution) and potassium citrate (the adding amount is 0.2g in each 100mL of AB mixed solution) into the AB mixed solution, uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and sequentially carrying out color matching, standing, sealing and self-cleaning on the glue solution in the glue barrel Defoaming; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Example 3:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, opening the feed inlet, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:18, closing the feed inlet, vacuumizing and filling the vacuum once with nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.3; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, starting a high-shear emulsifying machine under an anaerobic state, and emulsifying for 40 minutes at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 1.0 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: dissolving sodium carboxymethylcellulose in water to obtain 0.1g/mL solution, and continuously introducing O into the solution at a concentration of 10mL/min under sealed environment 3 After the introduction, adding methyl acrylic hydrazide and ammonium persulfate into the solution to react for 45min at 30 ℃ to obtain solution A after the reaction is finished; the adding amount of the methyl acrylic hydrazide in the process is 50% of the mass of sodium or potassium salt of the carboxymethyl cellulose, and the adding amount of the ammonium persulfate is 10% of the mass of the sodium or potassium salt of the carboxymethyl cellulose. Washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 HCl solution (3 g SnCl) 2 Dissolving in 26wt% hydrochloric acid solution) for 3min to sensitize, taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into 80wt%1, 2-dimethyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) imide aqueous solution, performing ultrasonic treatment for 5h to activate, taking out the quartz sand, washing and drying to obtain activated quartz sand. Mixing lactic acid and glycerin according to a volume ratio of 1:10 to obtain a mixed solution, and then mixing the mixed solution according to a mass-volume ratio of 3g: the activated silica sand was added in an amount of 100mL, sheared in a high speed shearing machine at a rotation speed of 3000rpm for 1min, and then the silica sand was filtered off to obtain solution B. The solution A and the solution B obtained above are mixed according to the volume ratio of 10:3 adding the solution into a sol tank for mixing, heating the system to 80 ℃, then sequentially adding carrageenan (the adding amount is 3g in each 100mL of AB mixed solution) and potassium citrate (the adding amount is 0.2g in each 100mL of AB mixed solution) into the AB mixed solution, uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and sequentially carrying out color matching, standing, sealing and natural defoaming on the glue solution in the glue barrel; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Example 4:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:22, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.2; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 1.3 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: dissolving sodium carboxymethylcellulose in water to obtain 0.3g/mL solution, and continuously introducing O into the solution at a concentration of 10mL/min under sealed environment 3 After the introduction, adding 2-methylallylamine and ammonium persulfate into the solution, and reacting at 50 ℃ for 20min to obtain solution A after the reaction is finished; the addition amount of the 2-methylallylamine in the process is 70% of the mass of sodium or potassium carboxymethylcellulose, and the addition amount of the ammonium persulfate is 5% of the mass of sodium or potassium carboxymethylcellulose. Washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 HCl solution (3 g SnCl) 2 Dissolving in 26wt% hydrochloric acid solution) for 5min, stirring for sensitization, taking out quartz sand, washing, drying to obtain sensitized quartz sand, adding the sensitized quartz sand into 90wt% 1-methyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) imide aqueous solution, performing ultrasonic treatment for 1h for activation, taking out the quartz sand, washing, and drying to obtain activated quartz sand. Mixing lactic acid and glycerin according to a volume ratio of 1:5 to obtain a mixed solution, and then mixing the mixed solution according to a mass volume ratio of 5g: the activated silica sand was added in an amount of 100mL, sheared in a high speed shearing machine at a rotation speed of 2000rpm for 3min, and then the silica sand was filtered to obtain solution B. The solution A and the solution B obtained above are mixed according to the volume ratio of 10:5 adding the mixture into a sol tank for mixing, heating the system to 90 ℃, then sequentially adding carrageenan (the addition amount is 3g in each 100mL of AB mixed solution) and potassium citrate (the addition amount is 0.2g in each 100mL of AB mixed solution) into the AB mixed solution, uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and the glue barrel The glue solution in the glass fiber reinforced plastic composite material is subjected to color matching, standing, sealing and natural defoaming in sequence; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Comparative example 1:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:20, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.25; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 0.8 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: dissolving sodium carboxymethylcellulose in water to obtain 0.2g/mL solution, and continuously introducing O into the solution at a concentration of 10mL/min under sealed environment 3 After the introduction, adding 2-amino ethyl methacrylate and ammonium persulfate into the solution to react for 33min at 40 ℃ to obtain solution A after the reaction is finished; the adding amount of the 2-amino ethyl methacrylate in the process is 60% of the mass of sodium or potassium carboxymethyl cellulose, and the adding amount of the ammonium persulfate is 7.5% of the mass of sodium or potassium carboxymethyl cellulose.Mixing lactic acid and glycerin according to a volume ratio of 1:7.5 to obtain a mixed solution, and shearing the mixed solution in a high-speed shearing machine at a rotating speed of 2500rpm for 2min to obtain a solution B. The solution A and the solution B obtained above are mixed according to the volume ratio of 10:4 adding the solution into a sol tank for mixing, heating the system to 85 ℃, then sequentially adding carrageenan (the adding amount is 3g in each 100mL of AB mixed solution) and potassium citrate (the adding amount is 0.2g in each 100mL of AB mixed solution) into the AB mixed solution, uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and sequentially carrying out color matching, standing, sealing and natural defoaming on the glue solution in the glue barrel; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Comparative example 2:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:20, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.25; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 0.8 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
PreparationHollow capsule: dissolving sodium carboxymethylcellulose in water to obtain 0.2g/mL solution, and continuously introducing O into the solution at a concentration of 10mL/min under sealed environment 3 After the introduction, adding 2-amino ethyl methacrylate and ammonium persulfate into the solution to react for 33min at 40 ℃ to obtain solution A after the reaction is finished; the adding amount of the 2-amino ethyl methacrylate in the process is 60% of the mass of sodium or potassium carboxymethyl cellulose, and the adding amount of the ammonium persulfate is 7.5% of the mass of sodium or potassium carboxymethyl cellulose. Adding the solution A obtained above into a sol tank for mixing, heating the system to 85 ℃, sequentially adding carrageenan (the addition amount is 3g in every 100mL of the solution A) and potassium citrate (the addition amount is 0.2g in every 100mL of the solution A), uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and sequentially carrying out color matching, standing, sealing and natural defoaming on the glue solution in the glue barrel; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Comparative example 3:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:20, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.25; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 0.8 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: sodium carboxymethyl cellulose is dissolved in water to form a solution with the concentration of 0.2g/mL, and a solution A is obtained. Washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 HCl solution (3 g SnCl) 2 Dissolving in 26wt% hydrochloric acid solution) for 4min to sensitize, taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into 85wt% N-ethoxyethyl-N-methyl pyrrolidine bis (trifluoromethanesulfonyl imide) salt aqueous solution, performing ultrasonic treatment for 3h to activate, taking out the quartz sand, washing and drying to obtain activated quartz sand. Mixing lactic acid and glycerin according to a volume ratio of 1:7.5 to obtain a mixed solution, and then mixing the mixed solution with 4g: the activated silica sand was added in an amount of 100mL and sheared in a high speed shearing machine at 2500rpm for 2min, after which the silica sand was filtered off to obtain solution B. The solution A and the solution B obtained above are mixed according to the volume ratio of 10:4 adding the solution into a sol tank for mixing, heating the system to 85 ℃, then sequentially adding carrageenan (the adding amount is 3g in each 100mL of AB mixed solution) and potassium citrate (the adding amount is 0.2g in each 100mL of AB mixed solution) into the AB mixed solution, uniformly mixing, and continuously stirring to prepare the glue solution. Filtering the obtained glue solution into a glue barrel through a filter bag, and sequentially carrying out color matching, standing, sealing and natural defoaming on the glue solution in the glue barrel; injecting the glue solution after natural deaeration into a glue tray, dipping the glue in the glue tray by using a die to prepare a sample, and then sending the sample into a drying system for drying; and demolding, cutting, sleeving, inspecting and packaging the dried sample to obtain the hollow capsule.
Comparative example 4:
preparation of pharmaceutically active ingredients: and (3) performing anaerobic operation on the oil melting pot in advance, namely vacuumizing, wherein the vacuum degree reaches more than-0.9 Mpa, closing a vacuum valve, and supplementing nitrogen to normal pressure. Repeating the above operation for three times, then opening the charging port, slightly opening nitrogen, adding coenzyme Q10 and IPE according to the mass ratio of 1:20, closing the charging port, vacuumizing and filling the vacuum once by nitrogen. Stirring was started and heated to an internal temperature of 55 ℃. Deoxidizing the purified water by thermal spraying, adding the deoxidized water into an emulsifying pot, and then adding beta-glucan with the mass ratio of IPE to beta-glucan of 1:0.25; and heating and dissolving the emulsified kettle after deoxidizing again. The dissolution temperature was 55℃and stirring was carried out for 20 minutes. And (3) feeding the dissolved coenzyme Q10 and IPE mixed solution into an emulsifying pot, and starting a high-shear emulsifying machine to emulsify for 40 minutes in an anaerobic state at the emulsifying temperature of 50 ℃. Homogenizing the emulsified liquid under high pressure for five times under homogenizing pressure of 40Mpa, observing with electron microscope to obtain emulsion oil drop with particle diameter of 0.8 μm, adjusting air inlet temperature of spray dryer to 220 deg.C and air outlet temperature to 110 deg.C, and obtaining powder of medicinal active ingredient.
Preparing a hollow capsule: commercially available plant starch capsules (available from Shanghai Red Star Capsule Co., ltd.).
And finally, assembling the active ingredients into the hollow capsule to obtain a finished product of the medicine capsule.
Test example 1: empty capsule performance comparison in different examples
The experimental object: examples 2 to 4 and comparative examples 1 to 4 were prepared as empty capsules
The experimental method comprises the following steps:
1. friability test: taking 100 grains of a test sample, placing the test sample into a surface dish, moving the test sample into a dryer containing a saturated solution of magnesium nitrate, keeping the temperature at 25+/-1 ℃ for 24 hours, taking out the test sample, immediately placing the test sample into glass tubes (with the inner diameter of 24mm and the length of 200 mm) erected on a wood plate (with the thickness of 2 cm) one by one respectively, freely falling cylindrical weights (made of polytetrafluoroethylene, with the diameter of 22mm and the weight of 20 g+/-0.1 g) from the mouth of the glass tube, and if the capsule is broken, not exceeding 1 grain.
2. And (3) testing disintegration time limit: taking 10 test samples, filling talcum powder, and detecting by adding a baffle plate according to the method under the capsule item of four parts (general rule 0921) of the 2020 edition of Chinese pharmacopoeia of disintegration time limit inspection method.
3. Capsule dissolutionDegree: the content is 800mg potassium nitrate, the dissolution medium is 800mL 0.1mOL/L HCl, a spin basket method is adopted, the rotation speed is 100r/min, and the temperature is 37 ℃. Diluting 10ml of dissolution medium for 5 times at 15min, and testing absorbance A at 236 nm; setting a reference: 800mg of potassium nitrate was dissolved in 800mL of 0.1mOl/L hydrochloric acid, 10mL was diluted 5-fold, and absorbance A was measured at 236nm 0 The method comprises the steps of carrying out a first treatment on the surface of the Dissolution = a/a 0 ×100％。
Experimental results: see table 1.
Table 1 results of empty capsule performance measurements in different examples
Friability (granule) Disintegration time (min) Dissolution of capsules (%)
Example 2 0 4.5 94
Example 3 0 5.0 89
Example 4 0 4.8 92
Comparative example 1 5 5.5 85
Comparative example 2 26 11.4 82
Comparative example 3 43 13.3 68
Comparative example 4 1 5.1 88
As can be seen from the results in Table 1, the empty capsules of examples 2 to 4 of the present invention had slightly higher friability and dissolution rate than the commercially available products, but were significantly more excellent in various properties than those of comparative examples 1 to 3, as compared with the commercially available plant capsules (comparative example 4).
Test example 2: drug capsule finished product stability detection in different embodiments
The experimental object: finished pharmaceutical capsules prepared in example 2 and comparative examples 1 to 4
The experimental method comprises the following steps: the finished products of the medicine capsules are placed in a constant temperature and humidity test box, and disintegration time limit measurement is carried out at 0 month, 6 months, 12 months, 24 months, 30 months and 36 months respectively, and the results are shown in Table 2.
Table 2 different drug capsule stability assays
0 month 6 months of For 12 months 24 months of For 30 months For 36 months
Example 2 4.5 4.5 4.5 4.5 4.5 4.6
Comparative example 1 5.5 5.5 5.6 5.8 6.0 6.9
Comparative example 2 11.4 11.4 11.5 11.9 12.1 12.9
Comparative example 3 13.3 13.3 13.3 13.8 14.4 15.2
Comparative example 4 5.1 5.1 5.1 5.2 5.3 6.1
As can be seen from the results of Table 2, the pharmaceutical capsule of example 2 of the present invention has good stability and can be stored for a long period of time as compared with comparative examples 1 to 4.
Test example 3: clinical trial
Symptoms appearance: dizziness, palpitation, hypodynamia, chest distress, chest pain and other symptoms, ventricular premature beat more than 6 times per minute or more than 30 times per hour. Eliminating ventricular premature beat caused by ischemia, anoxia, electrolyte disturbance, acid-base balance disturbance, myocarditis, coronary heart disease, and high heart disease.
144 cases are selected, wherein the cases comprise 4 cases of simple hypertension patients and 7 cases of diabetes; hypertension combined with diabetes 2 cases; the patients all conduct chest radiography, heart color Doppler ultrasound, thyroid function detection, blood biochemistry and other examination to remove organic heart diseases. Randomization into treatment and control groups; the treatment groups were 72, and the differences were statistically significant in clinical settings (gender, age, blood lipid, weight) such as age, gender, heart function, etc. among the groups.
The control group was orally taken trimetazidine 40 mg/time, mexiletine 200mg 3 times daily. The observation group took the capsule of example 2 of the present invention for 3 months as a treatment course, and the dosage of the capsule was: one granule/time, once/day; the net content of one capsule is 1g. The treatment process records data of electrocardio and dynamic electrocardio respectively, and detects systolic pressure/diastolic pressure, liver and kidney functions, uric acid and the like.
Evaluation criteria:
the effect is shown: no ventricular premature beat or more than 90% reduction;
the method is effective: the reduction of 50% -90%;
invalidation: reduced by less than 50%
The statistical results are shown in Table 3.
Table 3 comparison of clinical symptoms
Group of Display effect/example Effectiveness/example Invalidation/instance Total effective rate (%)
Observation group 70 2 0 100
Control group 28 26 18 75
As can be seen from the results of table 3, ventricular premature beat was significantly reduced (P < 0.05) after treatment in the observation group, and the extent of the reduction was significantly greater than in the control treatment group; uric acid and liver and kidney functions are not significantly changed (P < 0.05).
While the invention has been described with respect to preferred embodiments, it will be understood by those skilled in the art that various changes and modifications may be made without departing from the spirit and scope of the invention, and that any such changes and modifications as described in the above embodiments are intended to be within the scope of the invention.

Claims (7)

1. A capsule for treating atrial and ventricular premature beat comprising a hollow capsule and a pharmaceutically active ingredient within the capsule, the pharmaceutically active ingredient consisting of: coenzyme Q10, tuna oil and beta-glucan, wherein the mass ratio of the coenzyme Q10 to the tuna oil is 1:18-1:22, and the mass ratio of the tuna oil to the beta-glucan is 1:0.2-1:0.3;
The preparation method of the hollow capsule comprises the following steps:
dissolving sodium or potassium carboxymethylcellulose in water to obtain solution with concentration of 0.1-0.3g/mL, and continuously introducing O into the solution at an amount of 10mL/min under sealed environment 3 After the introduction, adding a functional monomer and ammonium persulfate into the solution to react for 20-45min at the temperature of 30-50 ℃ to obtain solution A after the reaction is finished; the addition amount of the functional monomer in the process is 50-70% of the mass of sodium or potassium carboxymethylcellulose salt, and the addition amount of the ammonium persulfate is carboxyl5-10% of the mass of sodium or potassium methylcellulose;
washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 Stirring for 3-5 min in an HCl solution for sensitization, then taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into an 80-90wt% ionic liquid aqueous solution for ultrasonic treatment for 1-5h for activation, taking out the quartz sand, washing and drying to obtain activated quartz sand;
mixing lactic acid and glycerin according to the volume ratio of 1:5-10 to obtain a mixed solution, and then mixing the lactic acid and the glycerin according to the mass volume ratio of 3-5g: adding 100mL of activated quartz sand, shearing in a high-speed shearing machine at a rotating speed of 2000-3000rpm for 1-3min, and filtering the quartz sand to obtain a solution B;
The solution A and the solution B obtained above are mixed according to the volume ratio of 10:3-5 adding the mixture into a sol tank for mixing, heating the system to 80-90 ℃, obtaining a mixed solution which is an AB mixed solution, sequentially adding a gel agent and a coagulant aid into the AB mixed solution, uniformly mixing, and continuously stirring to prepare a glue solution; preparing the obtained glue solution into a hollow capsule according to a conventional process;
the functional monomer is selected from one or more of methacrylic acid 2-aminoethyl ester, methacrylic hydrazide, acrylic hydrazide, 2-methylallylamine, 3-butene-1-amine and pent-4-ene-1-amine;
the ionic liquid is selected from one or more of 1-methyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) amide, N-butyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide, 1, 2-dimethyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) amide, 1-methyl-3-butylimidazole bis (trifluoromethanesulfonyl) amide, N-ethoxyethyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide, 1-methyl-3-ethoxymethylimidazole bis (trifluoromethanesulfonyl) amide, N-ethoxymethyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide and N, N-diethyl-2-methoxyethyl-N-methylamine bis (trifluoromethanesulfonyl) amide.
2. The capsule for treating atrial and ventricular premature beat of claim 1, wherein the mass ratio of coenzyme Q10 to tuna oil is 1:20 and the mass ratio of tuna oil to β -glucan is 1:0.25.
3. A method for preparing a capsule for treating premature beat of atrium and ventricle, comprising the steps of preparing microparticles of pharmaceutically active ingredient and hollow capsules; the preparation method of the medicine active ingredient particles comprises the following steps:
dissolving coenzyme Q10 in tuna oil to form a mixed solution, adding beta-glucan particles with the particle size of 0.5-1.5 mu m, stirring uniformly, emulsifying the obtained mixed solution for 30-50min at 45-60 ℃ under the anaerobic state, homogenizing for five times under the high pressure of 40Mpa to obtain emulsion oil drops with the particle size of 0.8-1.3 mu m, adjusting the air inlet temperature of a spray dryer to 200-240 ℃ and the air outlet temperature to 90-130 ℃ to obtain the medicinal active ingredient particles with the particle size of 0.8-1.3 mu m; the medicine active ingredient particles consist of the following components: coenzyme Q10, tuna oil and beta-glucan, wherein the mass ratio of the coenzyme Q10 to the tuna oil is 1:18-1:22, and the mass ratio of the tuna oil to the beta-glucan is 1:0.2-1:0.3;
The preparation method of the hollow capsule comprises the following steps:
dissolving sodium or potassium carboxymethylcellulose in water to obtain solution with concentration of 0.1-0.3g/mL, and continuously introducing O into the solution at an amount of 10mL/min under sealed environment 3 After the introduction, adding a functional monomer and ammonium persulfate into the solution to react for 20-45min at the temperature of 30-50 ℃ to obtain solution A after the reaction is finished; the addition amount of the functional monomer in the process is 50-70% of the mass of sodium or potassium carboxymethylcellulose, and the addition amount of the ammonium persulfate is 5-10% of the mass of sodium or potassium carboxymethylcellulose;
washing 100-200 mesh quartz sand with deionized water, drying, and adding into SnCl 2 Stirring for 3-5 min in an HCl solution for sensitization, then taking out quartz sand, washing and drying to obtain sensitized quartz sand, adding the sensitized quartz sand into an 80-90wt% ionic liquid aqueous solution for ultrasonic treatment for 1-5h for activation, taking out the quartz sand, washing and drying to obtain activated quartzSand;
mixing lactic acid and glycerin according to the volume ratio of 1:5-10 to obtain a mixed solution, and then mixing the lactic acid and the glycerin according to the mass volume ratio of 3-5g: adding 100mL of activated quartz sand, shearing in a high-speed shearing machine at a rotating speed of 2000-3000rpm for 1-3min, and filtering the quartz sand to obtain a solution B;
The solution A and the solution B obtained above are mixed according to the volume ratio of 10:3-5 adding the mixture into a sol tank for mixing, heating the system to 80-90 ℃, obtaining a mixed solution which is an AB mixed solution, sequentially adding a gel agent and a coagulant aid into the AB mixed solution, uniformly mixing, and continuously stirring to prepare a glue solution; preparing the obtained glue solution into a hollow capsule according to a conventional process;
the functional monomer is selected from one or more of methacrylic acid 2-aminoethyl ester, methacrylic hydrazide, acrylic hydrazide, 2-methylallylamine, 3-butene-1-amine and pent-4-ene-1-amine;
the ionic liquid is selected from one or more of 1-methyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) amide, N-butyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide, 1, 2-dimethyl-3-ethoxyethylimidazole bis (trifluoromethanesulfonyl) amide, 1-methyl-3-butylimidazole bis (trifluoromethanesulfonyl) amide, N-ethoxyethyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide, 1-methyl-3-ethoxymethylimidazole bis (trifluoromethanesulfonyl) amide, N-ethoxymethyl-N-methylpyrrolidine bis (trifluoromethanesulfonyl) amide and N, N-diethyl-2-methoxyethyl-N-methylamine bis (trifluoromethanesulfonyl) amide.
4. A method according to claim 3, wherein the β -glucan is prepared by: washing Saccharomyces cerevisiae with deionized water, preparing into bacterial suspension, filtering, removing impurities, and sequentially adding glucose, yeast extract, potassium dihydrogen phosphate, magnesium sulfate, water and fungus schizophyllum commune with concentration of 2 g/L; adding 50wt% nitric acid to adjust pH, controlling pH to 2.0-4.0, and fermenting at 25-30deg.C; in the process, 0.1-10 mu m particles are removed by filtration, so that the biomass concentration of the fermentation broth is increased, after enzymolysis is finished, the fermentation broth is centrifugally washed by deionized water until supernatant is clear and transparent, and wet beta 1,3-1,6 glucan is obtained by centrifugal precipitation, and beta-glucan powder is obtained after drying.
5. The preparation method according to claim 3, wherein the addition amount of the gelling agent is 1-5g of the gelling agent per 100mL of the AB mixed solution, and the gelling agent is one or more selected from carrageenan, gellan gum, acacia gum, dragon's gum, tamarind gum, chitosan oligosaccharide, trehalose and mannan.
6. The method according to claim 3, wherein the coagulant aid is added in an amount of 0.1 to 0.3g per 100mL of the AB mixed solution, and the coagulant aid is one or more selected from the group consisting of potassium citrate, sodium acetate, potassium chloride and magnesium chloride.
7. The preparation method according to claim 3, wherein the SnCl 2 The HCl solution is prepared by mixing 1-5g SnCl 2 Is dissolved in 25-28wt% hydrochloric acid solution.
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