CN116966161A - Diacerein capsule composition and preparation method thereof - Google Patents
Diacerein capsule composition and preparation method thereof Download PDFInfo
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- CN116966161A CN116966161A CN202311156778.7A CN202311156778A CN116966161A CN 116966161 A CN116966161 A CN 116966161A CN 202311156778 A CN202311156778 A CN 202311156778A CN 116966161 A CN116966161 A CN 116966161A
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- diacerein
- mixing
- pregelatinized starch
- capsule
- preparation
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- TYNLGDBUJLVSMA-UHFFFAOYSA-N 4,5-diacetyloxy-9,10-dioxo-2-anthracenecarboxylic acid Chemical compound O=C1C2=CC(C(O)=O)=CC(OC(C)=O)=C2C(=O)C2=C1C=CC=C2OC(=O)C TYNLGDBUJLVSMA-UHFFFAOYSA-N 0.000 title claims abstract description 71
- 229960004590 diacerein Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 43
- 239000007963 capsule composition Substances 0.000 title claims abstract description 24
- 239000002775 capsule Substances 0.000 claims abstract description 36
- 229920000881 Modified starch Polymers 0.000 claims abstract description 35
- 238000002156 mixing Methods 0.000 claims abstract description 35
- 239000003814 drug Substances 0.000 claims abstract description 30
- 239000008187 granular material Substances 0.000 claims abstract description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 26
- 238000009826 distribution Methods 0.000 claims abstract description 17
- 239000002994 raw material Substances 0.000 claims abstract description 16
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 14
- 239000000853 adhesive Substances 0.000 claims abstract description 14
- 230000001070 adhesive effect Effects 0.000 claims abstract description 14
- 239000008101 lactose Substances 0.000 claims abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 13
- 238000010298 pulverizing process Methods 0.000 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 11
- 239000000843 powder Substances 0.000 claims abstract description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 9
- 239000008213 purified water Substances 0.000 claims abstract description 8
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims abstract description 7
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 7
- 229920003081 Povidone K 30 Polymers 0.000 claims abstract description 7
- 238000011049 filling Methods 0.000 claims abstract description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 7
- 229940069328 povidone Drugs 0.000 claims abstract description 7
- 239000002245 particle Substances 0.000 claims description 41
- 238000000034 method Methods 0.000 claims description 28
- 229940079593 drug Drugs 0.000 claims description 20
- 239000000463 material Substances 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 16
- 238000001035 drying Methods 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 108010010803 Gelatin Proteins 0.000 claims description 6
- 239000008273 gelatin Substances 0.000 claims description 6
- 229920000159 gelatin Polymers 0.000 claims description 6
- 235000019322 gelatine Nutrition 0.000 claims description 6
- 235000011852 gelatine desserts Nutrition 0.000 claims description 6
- 238000011068 loading method Methods 0.000 claims description 5
- 238000005507 spraying Methods 0.000 claims description 5
- 238000005303 weighing Methods 0.000 claims description 3
- 238000004090 dissolution Methods 0.000 description 27
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- 230000000052 comparative effect Effects 0.000 description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- 230000001276 controlling effect Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- 201000008482 osteoarthritis Diseases 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 6
- 238000011156 evaluation Methods 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 239000000945 filler Substances 0.000 description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 4
- 239000008186 active pharmaceutical agent Substances 0.000 description 4
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 4
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 4
- 229940088679 drug related substance Drugs 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 230000006378 damage Effects 0.000 description 3
- 238000000227 grinding Methods 0.000 description 3
- 230000009467 reduction Effects 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- 208000006820 Arthralgia Diseases 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- 108010002352 Interleukin-1 Proteins 0.000 description 2
- 210000001188 articular cartilage Anatomy 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- 230000018109 developmental process Effects 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000011361 granulated particle Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 238000010008 shearing Methods 0.000 description 2
- 239000007787 solid Substances 0.000 description 2
- 238000001694 spray drying Methods 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 241000220479 Acacia Species 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 206010023232 Joint swelling Diseases 0.000 description 1
- 235000010643 Leucaena leucocephala Nutrition 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- 208000008589 Obesity Diseases 0.000 description 1
- 208000002193 Pain Diseases 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- -1 anthraquinone compounds Chemical class 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000022159 cartilage development Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000007850 degeneration Effects 0.000 description 1
- 238000001739 density measurement Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 238000011978 dissolution method Methods 0.000 description 1
- 230000002183 duodenal effect Effects 0.000 description 1
- 230000007613 environmental effect Effects 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 238000009478 high shear granulation Methods 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 230000008407 joint function Effects 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 208000015122 neurodegenerative disease Diseases 0.000 description 1
- 229940021182 non-steroidal anti-inflammatory drug Drugs 0.000 description 1
- 235000020824 obesity Nutrition 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001737 promoting effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 238000013112 stability test Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
Classifications
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
- A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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]
Abstract
The invention discloses a diacerein capsule composition and a preparation method thereof. The diacerein capsule composition provided by the invention comprises the following substances in percentage by mass: 16.67% of diacerein, 49.00% -69.00% of 200-mesh lactose, 10% -30% of pregelatinized starch, 30.00% of povidone K and 0.33% of magnesium stearate. The preparation method comprises the following steps: pulverizing diacerein raw material medicine to obtain grain size distribution D90 less than or equal to 60 μm; premixing prescription amount diacerein, lactose of 200 meshes and pregelatinized starch to obtain premixed powder; dissolving povidone K30 in purified water to prepare an adhesive solution with the mass concentration of 20%; granulating by a fluidized bed; finishing; adding magnesium stearate into the granules after finishing, and mixing; and filling the capsule.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a diacerein capsule composition and a preparation method thereof.
Background
Osteoarthritis is a degenerative disease, and as people age, various factors such as obesity, strain, wound and the like of the body cause degeneration, damage or hyperplasia of articular cartilage, and clinical manifestations of joint pain, tenderness, stiffness, joint swelling, limited movement, joint deformity and the like of slow development are extremely high, so that the incidence rate of middle-aged and elderly people is extremely high. According to the statistics of the related data, the situation that the activity of the osteoarthritis patients exceeding 4/5 is limited can occur, and the osteoarthritis patients exceeding 1/4 cannot autonomously complete the main daily activities, so that the burden of families and society is increased.
In general, non-steroidal anti-inflammatory drugs and analgesics are the most prominent drugs in the traditional clinical treatment of osteoarthritis, however, prolonged administration of these drugs can result in very serious kidney damage and gastric and duodenal damage in patients. Therefore, relief of joint pain and repair of damaged articular cartilage are the most fundamental treatments, and are also important ways to improve the quality of life of patients.
Diacerein with molecular formula C 19 H 12 O 8 Is an important inhibitor of osteoarthritis IL-1, has the chemical name of diacetyl rhein and belongs to anthraquinone compounds. The product can induce cartilage formation, has analgesic, antiinflammatory and antipyretic effects, and can also be used for remarkably improving joint function, delaying disease course, relieving pain, improving life quality, and improving safety, and can be used for treating Osteoarthritis (OA) to exert antibacterial effect.
Diacerein (Diacerein), an inhibitor of osteoarthritis IL-1 developed by swiss praise Bei Chen pharmaceutical company (TRB CHEMEDICA) research. Currently, diacerein capsules are marketed in the countries and regions such as the Czech republic of China, brazil, austria, russia, etc., and are marketed in China 1 month 4 days 2005 under the trade name of "An Biding" with a specification of 50mg.
The diacerein is orange yellow crystalline powder, is dissolved in dimethyl sulfoxide and dimethylacetamide, is almost insoluble in water, methanol, acetonitrile and ethanol, and is unstable to light, heat, acid, alkali and oxygen.
CN201610612501.4 discloses a diacerein capsule preparation and a preparation method thereof, the active ingredient of the capsule is diacerein, the auxiliary materials are lactose, aerosil, magnesium stearate, disintegrating agent and adhesive, and the preparation process is a wet mixing granulator for granulation.
CN202110806396.9 discloses a diacerein granule containing diacerein, a filler, a glidant, an acrylic resin and polyethylene glycol, a process for preparing the same, and a solid preparation patent containing the diacerein granule; the process adopts fluidized bed granulation, and high-concentration ethanol is used in the process.
CN202210449016.5 discloses a diacerein capsule with high bioavailability and a preparation method thereof, the capsule comprises a content and a capsule shell, wherein the content comprises enteric medicament particles, a filler, a disintegrating agent and a lubricant, and the enteric medicament particles are obtained by uniformly mixing, hot-melting extrusion and crushing.
CN202210739554.8 discloses a diacerein capsule, a preparation method and an application patent thereof, wherein the capsule content comprises diacerein, sodium citrate, hydroxypropyl methylcellulose phthalate, acacia and other pharmaceutical excipients in a specific proportion; the process is a spray drying process, and a mixed solvent of acetone and propylene glycol is used in the process.
In summary, the present domestic diacerein patent mainly aims to solve the problems of stability and bioavailability of diacerein solid preparations. However, in the prior art, the wet mixing granulator is used for granulation, and the prepared granules have poor wettability and nonuniform granules; secondly, the spray drying technology and the hot melt extrusion technology are adopted, the preparation process is relatively complex, organic solvents such as ethanol, acetone and the like are used in the process, and the high temperature is used in the process condition, so that the production safety and the product quality are at great risk; in addition, the use of special pharmaceutical equipment, such as hot melt extruders, is expensive, which would also indirectly result in increased production costs.
Disclosure of Invention
The invention aims to provide a diacerein capsule composition and a preparation method thereof, wherein the composition formula is obtained by optimizing the range of the particle size distribution D90 of raw materials and the dosage of pregelatinized starch. The preparation method comprises the steps of premixing raw material medicines diacerein, lactose of 200 meshes as a filler and pregelatinized starch as a filler/disintegrating agent, performing fluidized bed granulation by using a povidone K30 solution as an adhesive, and controlling the granulation parameters of the fluidized bed to realize simple and controllable process, cost reduction, efficiency improvement and stable quality of the product.
The diacerein capsule composition provided by the invention comprises the following substances in percentage by mass: 16.67% of diacerein, 49.00% -69.00% of 200-mesh lactose, 10% -30% of pregelatinized starch, 30.00% of povidone K and 0.33% of magnesium stearate.
Preferably, the diacerein capsule composition consists of the following substances in percentage by mass: 16.67% of diacerein, 59.00% of 200-mesh lactose, 20% of pregelatinized starch, 30.00% of povidone K and 0.33% of magnesium stearate.
Specifically, the diacerein capsule composition is filled in a hollow capsule of No. 1 gelatin at 300mg, and the specific composition is as follows: 50mg of diacerein, 177mg of lactose of 200 meshes, 60mg of pregelatinized starch, 30 mg of povidone K and 1.0mg of magnesium stearate.
Preferably, the granularity distribution D90 of the diacerein bulk drug is less than or equal to 60 mu m, preferably 10 mu m to 30 mu m.
The preparation method of the diacerein capsule composition provided by the invention comprises the following steps:
(1) Pretreatment: pulverizing diacerein raw material medicine, and controlling pulverizing parameters to obtain pulverized raw material medicine grain size distribution D90 less than or equal to 60 micrometers;
(2) Premixing: premixing prescription amount diacerein, lactose of 200 meshes and pregelatinized starch to obtain premixed powder;
(3) Granulating by a fluidized bed:
a. preparing an adhesive solution: weighing purified water, and dissolving povidone K30 in the purified water to prepare an adhesive solution with the mass concentration of 10-30%;
b. granulating: placing the premixed powder in a fluidized bed, setting the air inlet temperature to be 60-70 ℃, starting preheating materials, spraying the adhesive solution when the temperature of the materials is increased to be more than 45 ℃, and controlling the temperature of the materials to be 30-40 ℃; continuously drying the adhesive solution after spraying, and controlling the moisture content of the particles to be less than or equal to 2%;
c. finishing: the dried granules are crushed and granulated by a crushing granulator and are granulated by a screen mesh of 1.0 mm;
(4) Total mixing: adding magnesium stearate into the granules after finishing, and mixing to obtain total mixed granules;
(5) Filling the capsule: the total mixed granules were filled into 1# gelatin hollow capsules with a theoretical loading of 300 mg/granule.
In the step (2), the mixing is performed in a hopper mixer, the mixing speed of the hopper mixer is set to be 8-15 rpm, and the mixing is performed for 5-15 min.
In the step (4), the mixing is performed in a hopper mixer, the mixing speed of the hopper mixer is set to be 8-15 rpm, and the mixing is performed for 5-10 min.
Compared with the prior art, the invention has the following beneficial technical effects:
1. in the invention, the granularity distribution D90 of diacerein bulk drug is controlled to be less than or equal to 60 mu m, preferably 10 mu m to 30 mu m, and the dissolution similarity of the diacerein bulk drug and the original research agent can be obviously improved.
2. In the invention, pregelatinized starch is controlled to account for 10% -30% (mg/mg), preferably 20% (mg/mg) of the prescription proportion of the capsule content, and the rapid disintegration of the granule is realized under the condition that super-disintegrants (crosslinked sodium carboxymethyl cellulose) added in the original grinding preparation are not used; meanwhile, the prepared particles have uniform size and good fluidity, and the filling of the capsules is smoothly carried out and is stable under the condition of not additionally using a glidant (colloidal silicon dioxide).
3. The invention adopts the fluidized bed granulation, the actual material temperature is controlled to be 30-40 ℃ in the stage of the fluidized bed granulation, and the moisture of the granules is controlled to be less than or equal to 2% at the drying end point after the granulation is finished.
Drawings
Fig. 1 shows capsules prepared in examples 1, 2, 3 and 1 according to the present invention, respectively, and the capsules were prepared with a conventional agent (trade name:lot 97837) dissolution profile versus graph;
fig. 2 shows capsules prepared in examples 1, 4 and 5 according to the present invention, respectively, together with a raw developer (trade name:lot 97837).
Detailed Description
The invention will be further illustrated with reference to the following specific examples, but the invention is not limited to the following examples. The methods are conventional methods unless otherwise specified. The starting materials are available from published commercial sources unless otherwise specified.
Example 1: diacerein capsule composition and preparation thereof
Pulverizing the raw materials, and the particle size distribution D90 is about 15 μm; pregelatinized starch is used in an amount of 20% (mg/mg)
Prescription composition:
the preparation method comprises the following steps:
(1) Pretreatment: the diacerein crude drug is crushed, the crushing parameter is controlled to obtain the particle size distribution D90 of the crushed crude drug of about 15 mu m, the particle size is measured by a laser particle sizer, and the result of the particle size D90 is 15.83 mu m.
(2) Premixing: placing the prescription amount of diacerein, lactose 200 meshes and pregelatinized starch into a hopper mixer, setting the mixing speed to be 10rpm, and mixing for 10min to obtain premixed powder.
(3) Granulating by a fluidized bed:
a. preparing an adhesive solution: weighing purified water, and dissolving povidone K30 in the purified water to prepare a binder solution with the concentration of 20% (g/g);
b. granulating: placing the premixed powder into a fluidized bed, setting the air inlet temperature to be 60-70 ℃, starting preheating materials, spraying adhesive solution when the temperature of the materials is increased to be more than 45 ℃, and controlling the temperature of the materials to be 30-40 ℃; continuously drying after the binder solution is sprayed, and controlling the moisture content of the particles to be less than or equal to 2 percent (moisture meter, 105 ℃/5 min);
c. finishing: the dried granules are crushed and granulated by a crushing granulator and are granulated by a 1.0mm screen.
(4) Total mixing: and (3) placing the granulated particles into a hopper mixer, adding magnesium stearate according to the yield of the particles, setting the mixing speed to be 10rpm, and mixing for 10min to obtain total mixed particles.
(5) Filling the capsule: the total mixed granules were filled into 1# gelatin hollow capsules with a theoretical loading of 300 mg/granule.
Example 2: diacerein capsule composition and preparation thereof
Pulverizing the raw materials, and the particle size distribution D90 is about 30 μm; pregelatinized starch is used in an amount of 20% (mg/mg)
Prescription composition: as in example 1.
The preparation method comprises the following steps: the process steps were the same as in example 1 except that the process "pretreatment in step (1)" was different. In this example, diacerein was pulverized, and the pulverized crude drug was obtained by controlling the pulverizing parameters to have a particle size D90 of about 30 μm, and the particle size was measured by a laser particle sizer, with the result that the particle size D90 was 27.45 μm.
Example 3: diacerein capsule composition and preparation thereof
Sieving the crude drug, and the particle size distribution D90 is about 60 μm; pregelatinized starch is used in an amount of 20% (mg/mg)
Prescription composition: as in example 1.
The preparation method comprises the following steps: the process steps were the same as in example 1, except that the process step "(1) pretreatment" was different. In this example diacerein drug substance was sieved to obtain a particle size D90 of about 60 μm, which was measured using a laser particle sizer, with a particle size D90 of 50.65 μm.
Example 4: diacerein capsule composition and preparation thereof
Pulverizing the raw materials, and the particle size distribution D90 is about 30 μm; pregelatinized starch is used in an amount of 10% (mg/mg)
Prescription composition:
the preparation method comprises the following steps: as in example 1.
Example 5: diacerein capsule composition and preparation thereof
Pulverizing the raw materials, and the particle size distribution D90 is about 30 μm; pregelatinized starch is used in an amount of 30% (mg/mg)
Prescription composition:
the preparation method comprises the following steps: as in example 1.
Comparative example 1: diacerein capsule composition and preparation thereof
The crude drug is not treated, and the particle size distribution D90 is about 100 mu m; pregelatinized starch is used in an amount of 20% (mg/mg)
Prescription composition: as in example 1.
The preparation method comprises the following steps: the process steps are the same as in example 1 except that the process "pretreatment in step (1)" is different. The diacerein crude drug of this example was not pretreated, and its particle size was measured by a laser particle sizer, and the result of particle size D90 was 99.12. Mu.m. Comparative example 2: diacerein capsule composition and preparation thereof
Pulverizing the raw materials, and the particle size distribution D90 is about 30 μm; the granulating mode adopts a wet mixing granulator
Prescription composition: as in example 1.
The preparation method comprises the following steps:
(1) Pretreatment: the diacerein crude drug is crushed, the crushing parameter is controlled to obtain the crushed crude drug with the granularity D90 of about 30 mu m, the granularity is measured by a laser particle sizer, and the result of the granularity D90 is 27.45 mu m.
(2) Premixing: the prescription dose of diacerein, lactose 200 meshes, pregelatinized starch and povidone K30 are placed in a wet mixing granulator, the stirring speed is set to be 4r/s, the shearing speed is set to be 4r/s, and the mixture is mixed for 5min, so as to obtain premixed powder.
(3) High shear granulation: adding purified water accounting for 30% of the weight of the premixed powder into a wet mixing granulator, setting stirring speed to be 4r/s, shearing speed to be 24r/s, granulating for 3min, preparing a soft material, and granulating by a 4X 4mm square screen of a crushing granulator.
(4) Drying and granulating: drying the wet granules by using a fluidized bed, controlling the moisture of the granules to be less than or equal to 2 percent (moisture meter, 105 ℃/5 min), ending the drying, and sieving the granules by using a crushing and sieving machine through a 1.0mm sieve.
(5) Total mixing: and (3) placing the granulated particles into a hopper mixer, adding magnesium stearate according to the yield of the particles, setting the mixing speed to be 10rpm, and mixing for 10min to obtain total mixed particles.
(6) Filling the capsule: the total mixed granules were filled into 1# gelatin hollow capsules with a theoretical loading of 300 mg/granule. Comparative example 3: pulverizing the raw materials, and the particle size distribution D90 is about 30 μm; prescription of original preparation
Prescription composition:
the preparation method comprises the following steps: as in comparative example 2.
The invention achieves the technical effects that
1. The process is simple and controllable, is beneficial to industrialized mass production, and realizes cost reduction and synergy.
According to the technical scheme, a fluidized bed granulation process is adopted, two process steps of granulating and drying are finished in a fluidized bed for continuous operation, and compared with the process of granulating by adopting a wet mixing granulator, the process steps are reduced, the operation is simpler, and the labor intensity is reduced.
The bulk density and tap density of examples 1, 4, 5 and 2, 3, and ampdines were measured according to the general rule "0993 bulk density and tap density measurement" in chinese pharmacopoeia 2020, and the compressibility index and hausner ratio were determined to evaluate the flowability of the granules, and the results were compared as follows:
TABLE 1 flowability evaluation
| Evaluation index | Example 1 | Example 4 | Example 5 | Comparative example 2 | Comparative example 3 | An Biding x |
| Bulk Density (g/ml) | 0.626 | 0.623 | 0.630 | 0.646 | 0.637 | 0.650～0.683 |
| Tap Density (g/ml) | 0.725 | 0.721 | 0.732 | 0.820 | 0.811 | 0.748～0.834 |
| Compressibility index (%) | 13.7 | 13.6 | 13.9 | 21.2 | 21.5 | 9.3～20.5 |
| Haosner ratio | 1.158 | 1.157 | 1.162 | 1.269 | 1.273 | 1.102～1.258 |
| Flowability evaluation | Good quality | Good quality | Good quality | Qualified product | Qualified product | Good to qualified |
| Difference in loading (%) | -2.9～3.5 | -3.1～3.8 | -2.6～3.3 | -6.2～6.8 | -6.8～7.5 | -3.3～6.6 |
Note that: * The above table is the original grinding preparation, trade nameSummary of data for four batches.
TABLE 2 correspondence of compressibility index, haosner ratio and flowability
As can be seen from the flowability evaluation results in table 1, the flowability of the granules prepared in the fluidized bed granulation methods in examples 1, 4 and 5 is significantly better than that of the granules prepared in comparative examples 2 and 3 by using a wet mixing granulator; the pregelatinized starch used in examples 1, 4 and 5 was 20%,10% and 30%, respectively, and the resulting capsule contents were good in flowability without significant differences. Furthermore, comparing the difference in the contents in the above table, it is apparent that the capsule contents prepared by the fluid bed granulation have smaller difference in the contents than those prepared by the wet mixing granulator, indicating that the former is more stable to fill and the latter is liable to fluctuate in the filling stability. Therefore, the fluidized bed granulation process is easier to realize mass production, the process is more controllable, and the quality is more stable.
Meanwhile, compared with the prescription composition of the original grinding preparation of the comparative example 3, the super-disintegrant crosslinked sodium carboxymethyl cellulose and the glidant colloidal silicon dioxide are not used in the examples 1 to 5, so that the types of auxiliary materials are reduced, and the auxiliary material cost is also reduced. The industry knows that the cross-linked sodium carboxymethyl cellulose and the colloidal silicon dioxide are superior to imported auxiliary materials for a long time, and the price of the cross-linked sodium carboxymethyl cellulose and the colloidal silicon dioxide is tens to tens times that of domestic pregelatinized starch. The cost reduction and synergy are one of survival strategies of imitation medicine enterprises under the large environmental background of increasingly vigorous competition of imitation medicine markets. For the domestic auxiliary material company, the auxiliary material realizes domestic substitution import and is beneficial to promoting the development of the domestic auxiliary material company.
2. Controlling granularity of raw materials, and improving similarity of dissolution of product and original developer
In the technical scheme of the invention, the granularity distribution D90 of diacerein bulk drug is controlled to be 10-30 mu m, a fluidized bed granulation process is used, povidone K30 aqueous solution is used as an adhesive, and the air inlet temperature of a fluidized bed is regulated during granulation so as to control the material temperature to be 30-40 ℃. The process is simple and controllable, does not introduce organic solvent, realizes the similarity of dissolution curves of the product and the original developer, and reduces the risk of in vivo absorption inequivalence.
According to the four-part rule "0931 dissolution and release degree determination method" of Chinese pharmacopoeia 2020 edition, a basket device is adopted, the rotating speed is 100r/min, and 900ml of phosphate buffer with pH of 6.0 is used as a dissolution medium for dissolution curve determination. The capsules prepared in example 1, example 2, example 3, and comparative example 1 were prepared separately from the original developer (trade name:lot 97837) was subjected to dissolution profile comparison. The particle size comparison of the crude drugs is shown in Table 3, and the dissolution curve results are shown in Table 4.
Table 3 summary of drug substance particle size
| Evaluation object | Example 1 | Example 2 | Example 3 | Comparative example 1 |
| Particle size D90 of crude drug | About 15 μm | About 30 μm | About 60 μm | About 100 μm |
TABLE 4 comparison of dissolution profiles
From the dissolution profile results in table 4, it is clear that diacerein particle size has a significant effect on the dissolution profile, and that the smaller the drug substance particle size, the faster the dissolution. As can be seen from the similarity factor f2 between comparative examples 1, 2, 3 and 1 and the original preparation, the prepared capsules are similar to the original preparation when the granularity D90 of the raw materials is less than or equal to 60 mu m, and particularly the similarity factor between the prepared capsules and the original preparation is higher when the granularity D90 is 10 mu m to 30 mu m; however, when the drug substance is not treated and the measured particle size D90 is close to 100 μm, the capsule prepared is dissimilar to the original preparation.
3. Optimizing pregelatinized starch dosage and improving similarity of dissolution of product and original developer
In the technical scheme of the invention, pregelatinized starch is used as a filling agent and a disintegrating agent, and the pregelatinized starch also has the functions of flow and self lubrication. In order to further improve the similarity of dissolution curves of the self-product and the original developer, the dosage of pregelatinized starch is optimized and inspected, and the tolerance of the composition prescription is improved.
The capsules prepared in examples 1, 4 and 5 were prepared by the dissolution method described above, respectively, and the capsules were prepared by mixing with the original developer (trade name:lot 97837) was subjected to dissolution profile comparison. The comparison of the amounts of pregelatinized starch is shown in Table 5 and the dissolution profile results are shown in Table 6.
TABLE 5 comparison of pregelatinized starch levels
| Evaluation object | Example 1 | Example 4 | Example 5 |
| Pregelatinized starch dosage | 20％ | 10％ | 30％ |
TABLE 6 comparison of dissolution profiles
From the results of the dissolution profile in Table 6, it is seen that the amount of pregelatinized starch affects the dissolution profile, and at 10% the overall dissolution rate is slowed, which may be associated with a reduced disintegration after a reduced amount of pregelatinized starch, and an extended dissolution time of the particles, thereby slowing dissolution. When the amount is 30%, the overall dissolution rate also tends to be slow, which may be accompanied by an increase in the amount of pregelatinized starch, which may be due to its viscosity upon dissolution, forming a weak gel, thereby slowing the dissolution of the drug. From this, it is presumed that when the amount of pregelatinized starch is further reduced (< 10%) or increased (> 30%), there may be cases where the dissolution profile of the capsule produced is not similar to that of the original formulation, so that when the amount of pregelatinized starch is in the range of 10 to 30%, the dissolution profile is ensured to be similar to that of the original formulation, and particularly when the amount is 20%, the similarity factor is the highest.
4. Stability investigation
According to the requirements of four parts of 9001 raw material medicaments and preparation stability test guidelines in the Chinese pharmacopoeia 2020, the method is used for inspecting 6 months under the conditions of the temperature of 40+/-2 ℃ and the humidity of 75+/-5%, and sampling at 1 st, 3 rd and 6 th months respectively to detect the change condition of related substances. The diacerein capsules prepared in examples 1, 2, 4 and 5 of the present invention were subjected to an acceleration test with the original developer (lot number 97837), and the results of the detection of the substances are shown in Table 7.
TABLE 7 comparison of results of substances involved in the accelerated test
As can be seen from the results of the related substances in the accelerated test, the diacerein capsules prepared in the examples 1, 2, 4 and 5 are placed for 6 months under the accelerated test condition, and compared with the original preparation, the increase level of the total impurities of the diacerein related substances is equivalent, so that the diacerein capsules prepared in the invention have the stability consistent with the original preparation.
Claims (7)
1. The diacerein capsule composition consists of the following substances in percentage by mass: 16.67% of diacerein, 49.00% -69.00% of 200-mesh lactose, 10% -30% of pregelatinized starch, 30.00% of povidone K and 0.33% of magnesium stearate.
2. The diacerein capsule composition according to claim 1, characterized in that: the diacerein capsule composition consists of the following substances in percentage by mass: 16.67% of diacerein, 59.00% of 200-mesh lactose, 20% of pregelatinized starch, 30.00% of povidone K and 0.33% of magnesium stearate.
3. Diacerein capsule composition according to claim 2, characterized in that:
the diacerein capsule composition is filled in a hollow capsule of No. 1 gelatin in an amount of 300mg, and the specific composition is as follows: 50mg of diacerein, 177mg of lactose of 200 meshes, 60mg of pregelatinized starch, 30 mg of povidone K and 1.0mg of magnesium stearate.
4. A diacerein capsule composition according to any one of claims 1-3, characterized in that: the granularity distribution D90 of the diacerein bulk drug is less than or equal to 60 mu m, preferably 10 mu m to 30 mu m.
5. A process for the preparation of a diacerein capsule composition according to any one of claims 1 to 4, comprising the steps of:
(1) Pretreatment: pulverizing diacerein raw material medicine, and controlling pulverizing parameters to obtain pulverized raw material medicine grain size distribution D90 less than or equal to 60 micrometers;
(2) Premixing: premixing diacerein, lactose of 200 meshes and pregelatinized starch according to a proportion to obtain premixed powder;
(3) Granulating by a fluidized bed:
a. preparing an adhesive solution: weighing purified water, and dissolving povidone K30 in the purified water to prepare an adhesive solution with the mass concentration of 10-30%;
b. granulating: placing the premixed powder in a fluidized bed, setting the air inlet temperature to be 60-70 ℃, starting preheating materials, spraying the adhesive solution when the temperature of the materials is increased to be more than 45 ℃, and controlling the temperature of the materials to be 30-40 ℃; continuously drying the adhesive solution after spraying, and controlling the moisture content of the particles to be less than or equal to 2%;
c. finishing: the dried granules are crushed and granulated by a crushing granulator and are granulated by a screen mesh of 1.0 mm;
(4) Total mixing: adding magnesium stearate into the granules after finishing, and mixing to obtain total mixed granules;
(5) Filling the capsule: the total mixed granules were filled into 1# gelatin hollow capsules with a theoretical loading of 300 mg/granule.
6. The method of manufacturing according to claim 5, wherein: in the step (2), the mixing is performed in a hopper mixer, the mixing speed of the hopper mixer is set to be 8-15 rpm, and the mixing is performed for 5-15 min.
7. The method of manufacturing according to claim 5 or 6, characterized in that: in the step (4), the mixing is performed in a hopper mixer, the mixing speed of the hopper mixer is set to be 8-15 rpm, and the mixing is performed for 5-10 min.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009040702A2 (en) * | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| CN114796149A (en) * | 2022-04-27 | 2022-07-29 | 苏州中化药品工业有限公司 | Diacerein capsule with high bioavailability and preparation method thereof |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009040702A2 (en) * | 2007-09-27 | 2009-04-02 | Wockhardt Research Centre | Pharmaceutical compositions of rhein or diacerein |
| CN114796149A (en) * | 2022-04-27 | 2022-07-29 | 苏州中化药品工业有限公司 | Diacerein capsule with high bioavailability and preparation method thereof |
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