CN117243968A - Celecoxib compound preparation and preparation method thereof - Google Patents

Celecoxib compound preparation and preparation method thereof Download PDF

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Publication number
CN117243968A
CN117243968A CN202311500436.2A CN202311500436A CN117243968A CN 117243968 A CN117243968 A CN 117243968A CN 202311500436 A CN202311500436 A CN 202311500436A CN 117243968 A CN117243968 A CN 117243968A
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celecoxib
parts
polysaccharide
compound preparation
weight
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CN117243968B (en
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邵建树
赵晗柯
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Changzhou Wujin People's Hospital Changzhou Eighth People's Hospital
Jinan Shunjing Pharmaceutical Technology Co ltd
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Changzhou Wujin People's Hospital Changzhou Eighth People's Hospital
Jinan Shunjing Pharmaceutical Technology 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
    • A61K31/70—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
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • 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
    • 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
    • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
    • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
    • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
    • C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
    • C08B37/0003—General processes for their isolation or fractionation, e.g. purification or extraction from biomass

Abstract

The invention relates to a celecoxib compound preparation and a preparation method thereof, belonging to the field of pharmaceutical preparations. The celecoxib compound preparation provided by the invention comprises the following components: 1-3 parts of celecoxib, 3-6 parts of Chinese yam polysaccharide, 5-15 parts of cyclodextrin, 2-5 parts of carrier material I, 2-5 parts of carrier material II, 3-6 parts of solubilizer, 1-5 parts of disintegrating agent, 1-5 parts of filler, 0.5-2 parts of adhesive and 0.2-1 part of lubricant. The celecoxib compound preparation provided by the invention has a significantly better treatment effect on arthritis than celecoxib alone, can significantly improve the knee joint inflammation model rat joint symptoms, regulate inflammatory factors, improve the pathological cooling of articular cartilage tissues, and has a remarkable effect.

Description

Celecoxib compound preparation and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a celecoxib compound preparation and a preparation method thereof.
Background
Celecoxib is a non-steroidal anti-inflammatory drug which is commonly developed by French and the company of pyroxene in the United states, and can specifically inhibit the II type enzyme protein (COX-2) in cyclooxygenase to block the prostaglandin biosynthesis process and the generation of tissue prostaglandin inflammatory substances, so that the effects of anti-inflammation, pain relieving and antipyretic are achieved. Celecoxib is mainly used for clinically relieving symptoms and signs of osteoarthritis, relieving symptoms and signs of adult rheumatoid arthritis, treating adult acute pain, relieving symptoms and signs of ankylosing spondylitis and assisting treatment of familial adenomatous polyposis, and is the only oral selective COX-2 inhibitor in China. At present, celecoxib preparations marketed at home and abroad are only one dosage form of capsule.
Celecoxib is almost insoluble in water due to the crystal structure, belongs to insoluble drugs, and has extremely poor physicochemical properties in preparation performance. Firstly, celecoxib is almost insoluble in water, the solubility in water at 25 ℃ is only 0.007mg/ml, the dissolution in a common dissolution medium is slow, if the capsule is directly filled with an uncrushed drug, the uncrushed celecoxib is not easily dissolved and dispersed, and therefore, the celecoxib cannot be rapidly absorbed in the gastrointestinal tract; secondly, the preparation has light texture, low bulk density, easy agglomeration and uniform mixing with auxiliary materials, and not only can make the content uniformity of the preparation medicine unqualified, but also can influence the absorption.
In addition, there are many adverse reactions of celecoxib administration, and according to foreign literature reports, adverse reactions include cardiovascular thrombosis, gastrointestinal bleeding, ulcers and perforations, hypertension, heart failure, edema, allergic reactions and the like.
The yam is a yam, is an underground fleshy tuber of the plant yam, is an important traditional Chinese medicine, and is a common vegetable. History has been reported that, 700 years before the official, each of the candidates treated it as a tribute, and paid Zhou Wangshi. The Chinese yam is firstly carried in Shennong Ben Cao Jing (Shennong's herbal), and is named as superior product, which is sweet in taste, warm in temperature, deficiency-tonifying, deficiency-eliminating, pathogenic qi-cold-heat-eliminating, middle-jiao-tonifying, qi-tonifying, muscle-growing, and hearing-improving after long-term taking. Furthermore, ancient books have been described for their effects on the smooth complement of yam. Modern researches show that the Chinese yam not only has a plurality of nutritional ingredients, but also has very high medicinal value, and is one of the medical and edible plants published by the Ministry of health. The Chinese yam polysaccharide is a polysaccharide compound extracted and purified from Chinese yam, is one of main active ingredients of Chinese yam, and is widely applied to medicines, foods, beverages and health care products. Researches show that the Chinese yam polysaccharide has various functional activities of resisting fatigue, regulating immunity, resisting aging, improving sexual function, reducing blood sugar and blood fat, resisting oxidation, protecting liver, resisting cancer, protecting nerves, preventing senile dementia, resisting bacteria, regulating intestinal flora, resisting stress and the like. The composition and structure of the Chinese yam polysaccharide are complex, the Chinese yam polysaccharide comprises homopolysaccharide, heteropolysaccharide and glycoprotein, the glycosyl composition and content of the Chinese yam polysaccharide are different, and the glycosyl composition mainly comprises glucose, galactose, rhamnose, arabinose, xylose, mannose and glucuronic acid.
At present, no related study shows that the Chinese yam polysaccharide has an improvement or treatment effect on arthritis.
Disclosure of Invention
The invention mainly aims to provide a celecoxib compound preparation and a preparation method thereof, wherein the celecoxib compound preparation is combined drug of celecoxib and Chinese yam polysaccharide, the treatment effect of the celecoxib compound preparation on arthritis is obviously better than that of celecoxib alone, the dosage of celecoxib can be reduced, and the side effect of celecoxib can be reduced.
The invention adopts the following technical scheme to realize the purposes:
a celecoxib compound preparation comprises the following raw materials:
celecoxib 1-3 weight portions
3-6 parts by weight of Chinese yam polysaccharide
5-15 parts by weight of cyclodextrin
2-5 parts by weight of a carrier material I
2-5 parts by weight of carrier material II
3-6 parts by weight of solubilizer
1-5 parts by weight of disintegrating agent
1-5 parts by weight of filler
0.5-2 parts by weight of adhesive
0.2-1 parts by weight of a lubricant;
further preferably, the cyclodextrin is hydroxypropyl-beta-cyclodextrin.
Further preferably, the carrier material I is cellulose acetate peptide.
Further preferably, the carrier material II is a mixture of hypromellose and sodium alginate; the mass ratio of the hypromellose to the sodium alginate is 3:2.
Further preferably, the solubilizer is a mixture of polyvinylpyrrolidone and sorbitol; the mass ratio of the polyvinylpyrrolidone to the sorbitol is 1:2.
Further preferred, the disintegrant is one or more of dry starch, sodium carboxymethyl starch, low substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
Further preferably, the filler is one or more of starch, lactose, microcrystalline cellulose, pharmaceutical calcium carbonate, mannitol, and pregelatinized starch.
Further preferably, the binder is one or more of starch slurry, sodium carboxymethyl cellulose, methyl cellulose and ethyl cellulose.
Further preferably, the lubricant is one or more of magnesium stearate, micro silica gel, talcum powder, hydrogenated vegetable oil and polyethylene glycol.
The invention provides a preparation method of the Chinese yam polysaccharide, which comprises the following steps:
extracting rhizoma Dioscoreae, pulverizing, adding water according to a feed liquid ratio of 1 (10-30), heating or ultrasonic-assisted extraction, filtering the extractive solution, adding 95% ethanol 1-3 times of the volume of the filtrate, standing, and filtering to obtain residue as rhizoma Dioscoreae crude polysaccharide.
Purifying: dissolving rhizoma Dioscoreae crude polysaccharide in water, adsorbing with macroporous resin, eluting with ethanol solution, collecting 65% ethanol eluate, and drying to obtain target rhizoma Dioscoreae polysaccharide.
The invention provides a preparation method of the celecoxib compound preparation, which comprises the following steps:
and step A, adding the yam polysaccharide into a saturated aqueous solution of cyclodextrin, and drying to obtain the yam polysaccharide clathrate.
And B, uniformly mixing celecoxib, a solubilizer and a carrier material I, and granulating to obtain drug-containing particles.
And C, dissolving the Chinese yam polysaccharide inclusion compound and the carrier material II obtained in the step A, spraying the solution onto the surfaces of the medicine-containing particles obtained in the step B, drying, adding a disintegrating agent, a filling agent, an adhesive and a lubricant, and preparing the clinically common oral solid preparation according to a conventional process.
Compared with the prior art, the invention has the following beneficial effects:
1) The celecoxib compound preparation provided by the invention is a combined drug of celecoxib and Chinese yam polysaccharide, and the two active ingredients form a synergistic effect, so that the celecoxib compound preparation has a good therapeutic effect on arthritis. The Chinese yam polysaccharide has the functions of regulating immunity and resisting oxidation, and the applicant considers that the Chinese yam polysaccharide and celecoxib in the compound preparation form a synergistic effect, and the action mechanism of the Chinese yam polysaccharide is likely to be that the Chinese yam polysaccharide regulates the immunity, improves the body function and is convenient for the celecoxib to act on focus positions.
2) According to the invention, the yam polysaccharide is further screened, and the yam polysaccharide eluted by 65% ethanol solution is finally obtained to have a synergistic effect with celecoxib. Pharmacological experiments prove that the compound preparation has a treatment effect on arthritis which is obviously better than that of celecoxib alone, and the treatment effect of 1+1 & gt2 is obtained; in addition, the compound preparation provides a new treatment idea for clinic, can reduce the usage amount of celecoxib under the condition of achieving the same treatment effect, and can effectively avoid adverse reactions caused by celecoxib.
3) Aiming at the celecoxib compound preparation, the inventor optimizes the preparation process, and the Chinese yam polysaccharide has viscosity, so that the celecoxib has the property of indissolvable property and poor dispersibility, and the dissolution of celecoxib is affected to a certain extent by the Chinese yam polysaccharide, so that the inventor adopts a mode of clathrating the Chinese yam polysaccharide, reduces the viscosity of the Chinese yam polysaccharide, and adopts a spraying mode to uniformly distribute the Chinese yam polysaccharide on the surfaces of drug-containing particles, so that the influence of the Chinese yam polysaccharide on the dissolution of celecoxib is reduced; simultaneously, the solubilizer and the carrier material are screened, so that the solubility of the celecoxib is increased, the celecoxib is more soluble, the dissolution of the celecoxib in 60min can reach more than 95%, and the dissolution effect is good.
Drawings
Fig. 1: the knee diameter of each group of rats, where # represents P < 0.05 compared to the model group.
Fig. 2: IL-1β levels in each group, wherein # represents P < 0.05 compared to the model group; * P < 0.05 compared to the control group is shown.
Fig. 3: IL-6 levels in each group of rats, wherein # represents P < 0.05 compared to the model group; * P < 0.05 compared to the control group is shown.
Fig. 4: each group of rats had TNF- α levels, wherein # represents P < 0.05 compared to the model group; * P < 0.05 compared to the control group is shown.
Fig. 5: the pathological condition of cartilage tissue of the knee joint of the rat, wherein A is a false operation group, B is a model group, C is a control group, D is a test 1 group, E is a test 2 group, and F is a test 5 group.
Fig. 6: dissolution profile for each celecoxib compound formulation.
Detailed Description
The present invention is further illustrated below with reference to specific examples, which are to be construed as merely illustrative of the invention and not limiting of its scope, as various equivalent modifications to the invention will fall within the scope of the claims of the application after reading the invention.
EXAMPLE 1 preparation of Dioscorea polysaccharide
Extracting, namely crushing 50kg of Chinese yam, adding water according to a feed-liquid ratio of 1:10, heating and extracting for 2 times, mixing the extracting solutions, filtering, adding 95% ethanol with 3 times of volume into the filtrate, standing overnight, and filtering to obtain filter residues, namely crude polysaccharide of the Chinese yam;
purifying: dissolving rhizoma Dioscoreae crude polysaccharide in appropriate amount of water, adsorbing with D101 macroporous resin, eluting with 95% ethanol solution, 75% ethanol solution, and 65% ethanol solution sequentially, collecting 65% ethanol eluate, recovering ethanol under reduced pressure, and drying to obtain target rhizoma Dioscoreae polysaccharide.
EXAMPLE 2 preparation of Dioscorea polysaccharide
Extracting, namely crushing 50kg of Chinese yam, adding water according to a feed-liquid ratio of 1:30, carrying out ultrasonic-assisted extraction for 2 times, merging the extracting solutions, filtering, adding 95% ethanol with the volume being 1 time of that of the filtrate, standing overnight, and filtering to obtain filter residues, namely crude polysaccharide of the Chinese yam;
purifying: dissolving rhizoma Dioscoreae crude polysaccharide in appropriate amount of water, adsorbing with D101 macroporous resin, eluting with 95% ethanol solution, 75% ethanol solution, and 65% ethanol solution sequentially, collecting 65% ethanol eluate, recovering ethanol under reduced pressure, and drying to obtain target rhizoma Dioscoreae polysaccharide.
EXAMPLE 3 preparation of Dioscorea opposita polysaccharide
Extracting, namely crushing 50kg of Chinese yam, adding water according to a feed-liquid ratio of 1:20, heating and extracting for 2 times, mixing the extracting solutions, filtering, adding 95% ethanol with the volume being 2 times of that of the filtrate, standing overnight, and filtering to obtain filter residues, namely crude polysaccharide of the Chinese yam;
purifying: dissolving rhizoma Dioscoreae crude polysaccharide in appropriate amount of water, adsorbing with D101 macroporous resin, eluting with 95% ethanol solution, 75% ethanol solution, and 65% ethanol solution sequentially, collecting 65% ethanol eluate, recovering ethanol under reduced pressure, and drying to obtain target rhizoma Dioscoreae polysaccharide.
Example 4 preparation of celecoxib Compound preparation
Step A, adding 300g of the yam polysaccharide prepared in the embodiment 3 into 100g of saturated aqueous solution containing hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at the constant temperature of 50 ℃, and spray drying to obtain a yam polysaccharide inclusion compound;
step B, 100g of celecoxib, 100g of polyvinylpyrrolidone, 200g of sorbitol and 200g of cellulose acetate peptide acid ester are uniformly mixed and granulated to obtain drug-containing particles;
and C, adding a proper amount of water into 120g of the yam polysaccharide inclusion compound obtained in the step A, 80g of the sodium alginate and a proper amount of water for dissolution, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step B, drying, adding 100g of carboxymethyl starch sodium and 100g of mannitol, uniformly mixing, adding 50g of starch slurry, preparing into a soft material, sieving, preparing into particles, drying, adding 20g of magnesium stearate, uniformly mixing, and pressing into 1000 tablets to obtain the tablet.
Example 5 preparation of celecoxib Compound preparation
Step A, adding 400g of the yam polysaccharide prepared in the embodiment 3 into a saturated aqueous solution containing 400g of hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at the constant temperature of 50 ℃, and spray drying to obtain a yam polysaccharide inclusion compound;
step B, mixing 500g of celecoxib, 20000g of polyvinylpyrrolidone, 400g of sorbitol and 500g of cellulose acetate peptide acid ester uniformly, and granulating to obtain drug-containing particles;
and C, adding an appropriate amount of water into 240g of the yam polysaccharide inclusion compound obtained in the step A, 160g of sodium alginate and dissolving, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step B, drying, adding 300g of dry starch, 200g of starch, 300g of microcrystalline cellulose and 100g of sodium carboxymethyl cellulose, uniformly mixing, granulating by a wet method, drying, adding 50g of micro-powder silica gel and 50g of talcum powder, uniformly mixing, and pressing into 2000 tablets to obtain the tablets.
Example 6 preparation of celecoxib Compound preparation
Step A, adding 600g of the yam polysaccharide prepared in the example 3 into a saturated aqueous solution containing 600g of hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at a constant temperature of 50 ℃, and spray drying to obtain a yam polysaccharide inclusion compound;
step B, evenly mixing 300g of celecoxib, 200g of polyvinylpyrrolidone, 400g of sorbitol and 300g of cellulose acetate peptide acid ester, and granulating to obtain drug-containing particles;
and C, adding a proper amount of water into 300g of the yam polysaccharide inclusion compound obtained in the step A, 200g of sodium alginate, dissolving, spraying to the surfaces of the drug-containing particles obtained in the step B, drying, adding 500g of crosslinked povidone, 500g of lactose and 60g of ethylcellulose, uniformly mixing, granulating by a wet method, drying, adding 20g of hydrogenated vegetable oil, uniformly mixing, drying, and pressing into 3000 tablets to obtain the tablets.
Example 7 preparation of celecoxib Compound preparation
Step A, adding 500g of the yam polysaccharide prepared in the embodiment 3 into 400g of saturated aqueous solution containing hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at the constant temperature of 50 ℃, and spray drying to obtain a yam polysaccharide inclusion compound;
step B, uniformly mixing 200g of celecoxib, 100g of polyvinylpyrrolidone, 200g of sorbitol and 200g of cellulose acetate peptide acid ester, and granulating to obtain drug-containing particles;
and C, adding a proper amount of water into 120g of the yam polysaccharide inclusion compound obtained in the step A and 80g of sodium alginate for dissolution, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step B, drying, adding 200g of crosslinked sodium carboxymethyl cellulose, 200g of low-substituted hydroxypropyl cellulose, 300g of pregelatinized starch and 100g of medicinal calcium carbonate, uniformly mixing, adding 30g of sodium carboxymethyl cellulose and 30g of methyl cellulose for wet granulation, drying, adding 30g of micro silica gel and 30g of polyethylene glycol for uniform mixing, drying, and pressing into 2000 tablets to obtain tablets.
Comparative example 1 preparation of Dioscorea polysaccharide
Extracting, namely crushing 50kg of Chinese yam, adding water according to a feed-liquid ratio of 1:20, heating and extracting for 2 times, mixing the extracting solutions, filtering, adding 95% ethanol with the volume being 2 times of that of the filtrate, standing overnight, and filtering to obtain filter residues, namely crude polysaccharide of the Chinese yam;
purifying: dissolving rhizoma Dioscoreae crude polysaccharide in appropriate amount of water, adsorbing with D101 macroporous resin, eluting with 95% ethanol solution, collecting eluate, recovering ethanol under reduced pressure, and drying to obtain rhizoma Dioscoreae polysaccharide.
Comparative example 2 celecoxib Compound preparation
Step A, adding 300g of the Chinese yam polysaccharide prepared in the comparative example 1 into 100g of saturated aqueous solution containing hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at the constant temperature of 50 ℃, and spray drying to obtain a Chinese yam polysaccharide inclusion compound;
step B, 100g of celecoxib, 100g of polyvinylpyrrolidone, 200g of sorbitol and 200g of cellulose acetate peptide acid ester are uniformly mixed and granulated to obtain drug-containing particles;
and C, adding a proper amount of water into 120g of the yam polysaccharide inclusion compound obtained in the step A, 80g of the sodium alginate and a proper amount of water for dissolution, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step B, drying, adding 100g of carboxymethyl starch sodium and 100g of mannitol, uniformly mixing, adding 50g of starch slurry, preparing into a soft material, sieving, preparing into particles, drying, adding 20g of magnesium stearate, uniformly mixing, and pressing into 1000 tablets to obtain the tablet.
Comparative example 3 celecoxib Compound preparation
Mixing the yam polysaccharide prepared in example 3 in 300g, celecoxib in 100g, polyvinylpyrrolidone in 100g, sorbitol in 200g and cellulose acetate peptide in 200g uniformly, granulating to obtain medicine-containing granules; adding 100g of sodium carboxymethyl starch and 100g of mannitol, mixing uniformly, adding 50g of starch slurry, preparing into soft materials, sieving, granulating, drying, adding 20g of magnesium stearate, mixing uniformly, and pressing into 1000 tablets to obtain the tablets.
Comparative example 4 celecoxib Compound preparation
Step A, 100g of celecoxib, 100g of polyvinylpyrrolidone, 200g of sorbitol and 200g of cellulose acetate peptide acid ester are uniformly mixed and granulated to obtain drug-containing particles;
and B, adding 120g of the yam polysaccharide, 120g of hydroxypropyl methylcellulose and 80g of sodium alginate prepared in the example 3 into a proper amount of water for dissolution, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step A, drying, adding 100g of carboxymethyl starch sodium and 100g of mannitol, uniformly mixing, adding 50g of starch slurry, preparing into a soft material, sieving, granulating, drying, adding 20g of magnesium stearate, uniformly mixing, and pressing into 1000 tablets to obtain the tablet.
Comparative example 5 celecoxib Compound preparation
Step A, adding 300g of the Chinese yam polysaccharide prepared in the comparative example 1 into 100g of saturated aqueous solution containing hydroxypropyl-beta-cyclodextrin at 50 ℃, stirring for 1 hour at the constant temperature of 50 ℃, and spray drying to obtain a Chinese yam polysaccharide inclusion compound;
step B, 100g of celecoxib and 200g of cellulose acetate peptide acid ester are uniformly mixed and granulated to obtain drug-containing particles;
and C, adding 120g of the yam polysaccharide inclusion compound and 120g of hydroxypropyl methylcellulose obtained in the step A into a proper amount of water for dissolution, spraying the mixture onto the surfaces of the drug-containing particles obtained in the step B, drying, adding 100g of carboxymethyl starch sodium and 100g of mannitol, uniformly mixing, adding 50g of starch slurry, preparing into a soft material, sieving, preparing into particles, drying, adding 20g of magnesium stearate, uniformly mixing, and pressing into 1000 tablets to obtain the tablet.
1. Therapeutic effect of celecoxib compound preparation on osteoarthritis model rats
In order to verify the efficacy of the celecoxib compound preparation in treating osteoarthritis, the applicant carries out related pharmacodynamic test researches preliminarily, and the following test researches are completed by a cooperative unit or a delegated third-party detection mechanism.
The medicine selected by the following pharmacodynamic tests is a representative formula and a medicine obtained by the preparation method of the invention; the inventor also performs pharmacodynamic experiments on other medicines obtained by other formulas and preparation methods, and experimental results show that the medicines obtained by other formulas and preparation methods have the same or similar effects, but are not exhaustive due to space limitations.
The applicant has shown that the following experimental studies are carried out on the basis of the safety of the medicines proved by acute toxicity test and long-term toxicity test, and the administration dosage in the experimental studies is within the safe dosage range. The following test models were completed in a model construction manner already established in the literature.
1. Material
1.1 animals
Wistar rats, 180-220g, were adapted for one week prior to the experiment.
1.2 Medicine and dosage
1.2.1 Medicament
The rhizoma Dioscoreae polysaccharide obtained in example 3
Celecoxib compound preparation obtained in example 4
Celecoxib compound preparation obtained in example 5
Chinese yam polysaccharide obtained in comparative example 1
Celecoxib compound preparation obtained in comparative example 2
Commercially available celecoxib capsule
1.2.2 Dosage of medication
The equivalent dose of the rat is calculated according to the body surface area between rats and human beings in the pharmacological experiment methodology.
The yam polysaccharide obtained in example 3: 18mg/kg
Celecoxib compound preparation obtained in example 4: 9mg/kg calculated by celecoxib
Celecoxib compound preparation obtained in example 5: 9mg/kg calculated by celecoxib
The yam polysaccharide obtained in comparative example 1: 18mg/kg
Celecoxib compound preparation obtained in comparative example 2: 9mg/kg calculated by celecoxib
Commercially available celecoxib capsules: 9mg/kg calculated by celecoxib
2. Test procedure
2.1 moulding
The model of osteoarthritis is established by reference to the papain method in the prior literature. Taking 96 rats, randomly dividing the rats into 8 groups, wherein each group comprises 12 rats, namely a prosthetic operation group, a model group, a control group and test 1-5 groups, and constructing knee osteoarthritis modeling by the rest groups except the prosthetic operation group, wherein the specific operation comprises the following steps: rats were anesthetized, the right knee joint was shaved, 0.5mL of 4% papain solution was injected into the joint cavity on days 1, 4, and 7, 2 rats were randomly selected from each group on day 10 for dissection, their articular cartilage and synovium were observed, model rats developed roughness of articular cartilage surface, disorder of tissue structure, diffuse increase of chondrocyte, makin's score > 7 minutes, and successful establishment of osteoarthritis model for each model rat was determined. The sham rats were injected with 0.5mL of physiological saline only at the right knee joint, and no significant changes were seen in the anatomically observed sham rats.
2.2 Pharmaceutical intervention
The rats in the sham operation group and the model group are respectively infused with 5ml/kg physiological saline;
the control group was given commercially available celecoxib capsules for intragastric administration;
group 1 was administered with the yam polysaccharide obtained in example 3 for gastric lavage;
group 2 administration of the celecoxib compound formulation obtained in example 4 was intragastric;
group 3 was administered with the celecoxib compound formulation obtained in example 5 for intragastric administration;
the group 4 was subjected to gastric lavage with the yam polysaccharide obtained in comparative example 1;
the celecoxib compound preparation obtained in comparative example 2 was administered to a test 5 group for gastric lavage;
the control group and the test 1-5 groups were administered by intragastric administration according to the dosage of "1.2.2".
All interventions were 1 time daily for a total of 30 days.
3. Index detection
3.1 Rat joint swelling condition
The diameter of the right knee joint of the rat is measured after the last administration, and the joint swelling condition of the rat is judged.
3.2 Inflammatory factor detection
After 24h from the last dose, the rats were sacrificed, the abdominal aorta was bled, centrifuged, serum was removed, and levels of interleukin-1 beta (IL-1 beta), interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha) were detected in the serum.
3.3 Cartilage histopathological changes
After the rat blood is taken, cartilage tissue at the joint is stripped, cartilage is taken out, a cartilage tissue section is made, and the pathological change of the cartilage is observed after staining.
3.4 Statistical analysis
Statistical analysis is carried out on the obtained data by adopting SPSS22.0 software, and the metering data is usedThe comparison between the groups adopts single-factor analysis of variance, and the analysis between the two groups adopts independent sample T test mode. With P<0.05 The difference is statistically significant.
4. Results and analysis
4.1 Rat joint swelling condition
As can be seen from fig. 1, the knee osteoarthritis model rats after drug intervention have a reduced joint diameter and a reduced swelling, wherein the celecoxib compound preparation prepared by the invention is used for intervention treatment in test group 2 and test group 3, and the effect of the celecoxib compound preparation is better than that of the control group. The joint swelling of the rats in the test group 1 and the test group 4 is not improved; the improvement effect of the rat joint swelling in the test 5 group was not obvious from that in the control group, but was superior to that in the model group.
4.2 Rat inflammatory factor levels
As can be seen from fig. 2, 3 and 4, the IL-1 beta, IL-6 and TNF-alpha levels in the test 2 group and the test 3 group are obviously lower than those in the model group, and the effect is better than that in the control group; the IL-1 beta, IL-6 and TNF-alpha levels of rats in the test 1 group and the test 4 group were not significantly different from those in the model group; the levels of IL-1β, IL-6, TNF- α were not significantly different in the rats in the test group 5 compared to the control group.
4.3 Pathological changes of rat cartilage tissue
As can be seen from fig. 5, the cartilage tissue of the sham operated rats has a smooth surface, no obvious protrusions, the tissue can be fully stained, and no fissures exist between the tissues; a large number of gaps appear among the tissues of the model group rat, most of the tissues are not stained, and the surface of the model group rat is provided with a part of bulges; rats of test 1 group and test 4 group showed substantially no change in cartilage tissue as compared with rats of model group; the surfaces of the cartilage tissues of the rats in the control group, the test 2 group, the test 3 group and the test 5 group are basically restored to be smooth, the dyeing losing part is obviously reduced, the tissues have no gaps or a small number of gaps, and the changes of the test 2 group and the test 3 group are most obvious and are basically the same as those of the sham operation group.
According to the analysis of the test results, the joint swelling condition, inflammatory factor level change and cartilage tissue pathological condition of a knee osteoarthritis model rat subjected to the dry prognosis of the celecoxib compound preparation medicine are obviously improved, wherein the improvement of the test group 2 and the test group 3 is most obvious, and the effect is obviously better than that of a control group, namely, the celecoxib alone is used for treatment. The different Chinese yam polysaccharides are respectively given to the test 1 group and the test 4 group, the model rat joint swelling condition, the inflammatory factor level and the joint tissue pathological condition are not improved, and the Chinese yam polysaccharide has no therapeutic effect on arthritis, forms a synergistic effect with celecoxib or assists celecoxib to a certain extent, realizes the therapeutic effect on arthritis, and has a therapeutic effect obviously superior to that of celecoxib alone. The compound preparation of celecoxib is administrated by stomach irrigation in a test 5 group, but the Chinese yam polysaccharide is eluted by 95% ethanol, and has the effect of improving the arthritis symptoms of model rats, and as compared with a control group, not all Chinese yam polysaccharide can form a synergistic effect with celecoxib to treat arthritis.
2. Dissolution investigation of celecoxib compound preparation
Dissolution test: taking celecoxib compound preparations prepared in example 4, example 5, comparative example 3, comparative example 4 and comparative example 5, referring to dissolution rate determination method "Chinese pharmacopoeia (2020 edition)", taking 1000mL of hydrochloric acid solution with pH of 1.0 as dissolution medium, sampling at the rotation speed of 50 rpm at 5, 15, 30, 45 and 60 minutes respectively, filtering, preparing test sample solution, and determining by high performance liquid chromatography.
Results and analysis:
the tablets prepared in example 4 and example 5 have dissolution rate of more than 95% in 60min, good dissolution effect, stable dissolution and no burst release phenomenon. In the comparative example 3, the conventional tablet process is adopted, the dissolution of celecoxib is affected to a certain extent by the Chinese yam polysaccharide, and the dissolution in 60 minutes is 93 percent, but the dissolution curve is not stable, and the burst release phenomenon occurs; the mountain polysaccharide in the comparative example 4 is not included, and has a certain influence on the dissolution of celecoxib, but the dissolution effect is better than that of the comparative example 3, the dissolution can reach 90% in 60min, and the burst release phenomenon occurs at individual points; celecoxib in comparative example 5 was dissolved more smoothly, but celecoxib was not dissolved more highly, only 75%. The specific dissolution curve is shown in FIG. 6.

Claims (7)

1. The celecoxib compound preparation is characterized by being prepared from the following raw materials:
celecoxib 1-3 weight portions
3-6 parts by weight of Chinese yam polysaccharide
5-15 parts by weight of cyclodextrin
2-5 parts by weight of a carrier material I
2-5 parts by weight of carrier material II
3-6 parts by weight of solubilizer
1-5 parts by weight of disintegrating agent
1-5 parts by weight of filler
0.5-2 parts by weight of adhesive
0.2-1 parts by weight of a lubricant;
the cyclodextrin is hydroxypropyl-beta-cyclodextrin, and the carrier material I is cellulose acetate peptide acid ester;
the carrier material II is a mixture of hypromellose and sodium alginate, and the mass ratio of the hypromellose to the sodium alginate is 3:2;
the solubilizer is a mixture of polyvinylpyrrolidone and sorbitol, and the mass ratio of the polyvinylpyrrolidone to the sorbitol is 1:2.
2. A method for preparing the celecoxib compound preparation as defined in claim 1, which comprises the following steps:
step A, adding yam polysaccharide into a saturated aqueous solution of hydroxypropyl-beta-cyclodextrin, and drying to obtain yam polysaccharide inclusion compound;
step B, uniformly mixing celecoxib, polyvinylpyrrolidone, sorbitol and cellulose acetate peptide acid ester, and granulating to obtain drug-containing particles;
and C, dissolving the Chinese yam polysaccharide inclusion compound, hydroxypropyl methylcellulose and sodium alginate obtained in the step A, spraying the solution onto the surfaces of the drug-containing particles obtained in the step B, drying, adding a disintegrating agent, a filling agent, an adhesive and a lubricant, and preparing the clinically common oral solid preparation according to a conventional process.
3. The celecoxib compound preparation according to claim 1, wherein the disintegrating agent is one or more of dry starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium and crospovidone.
4. The celecoxib compound preparation according to claim 1, wherein the filler is one or more of starch, lactose, microcrystalline cellulose, medicinal calcium carbonate, mannitol and pregelatinized starch.
5. The celecoxib compound preparation according to claim 1, wherein the adhesive is one or more of starch slurry, sodium carboxymethyl cellulose, methyl cellulose and ethyl cellulose.
6. The celecoxib compound preparation according to claim 1, wherein the lubricant is one or more of magnesium stearate, micro silica gel, talcum powder, hydrogenated vegetable oil and polyethylene glycol.
7. The preparation method of the celecoxib compound preparation according to claim 2, wherein the preparation method of the yam polysaccharide comprises the following steps:
extracting: pulverizing rhizoma Dioscoreae, adding water according to a feed liquid ratio of 1 (10-30), heating or ultrasonic-assisted extraction, filtering the extractive solution, adding 95% ethanol 1-3 times of the volume of the filtrate, standing, and filtering to obtain residue as rhizoma Dioscoreae crude polysaccharide;
purifying: dissolving rhizoma Dioscoreae crude polysaccharide in water, adsorbing with macroporous resin, eluting with ethanol solution, collecting 65% ethanol eluate, and drying to obtain target rhizoma Dioscoreae polysaccharide.
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