CN116966157B - Theophylline sustained release tablet and preparation method thereof - Google Patents
Theophylline sustained release tablet and preparation method thereof Download PDFInfo
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- CN116966157B CN116966157B CN202311226686.1A CN202311226686A CN116966157B CN 116966157 B CN116966157 B CN 116966157B CN 202311226686 A CN202311226686 A CN 202311226686A CN 116966157 B CN116966157 B CN 116966157B
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- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 title claims abstract description 142
- 229960000278 theophylline Drugs 0.000 title claims abstract description 71
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 239000007939 sustained release tablet Substances 0.000 title claims abstract description 39
- 239000001856 Ethyl cellulose Substances 0.000 claims abstract description 21
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims abstract description 21
- 235000019325 ethyl cellulose Nutrition 0.000 claims abstract description 21
- 229920001249 ethyl cellulose Polymers 0.000 claims abstract description 21
- 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 19
- 229960004977 anhydrous lactose Drugs 0.000 claims abstract description 19
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims abstract description 17
- 239000011575 calcium Substances 0.000 claims abstract description 17
- 229910052791 calcium Inorganic materials 0.000 claims abstract description 17
- 239000000463 material Substances 0.000 claims abstract description 16
- 239000002994 raw material Substances 0.000 claims abstract description 15
- 239000000203 mixture Substances 0.000 claims abstract description 13
- 239000000853 adhesive Substances 0.000 claims abstract description 11
- 230000001070 adhesive effect Effects 0.000 claims abstract description 11
- 239000000945 filler Substances 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 8
- 239000000080 wetting agent Substances 0.000 claims abstract description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 53
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 34
- 238000002156 mixing Methods 0.000 claims description 28
- 238000001035 drying Methods 0.000 claims description 19
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 18
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 17
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 17
- 235000019359 magnesium stearate Nutrition 0.000 claims description 17
- 239000007779 soft material Substances 0.000 claims description 15
- 239000008187 granular material Substances 0.000 claims description 12
- 239000002245 particle Substances 0.000 claims description 12
- 239000003826 tablet Substances 0.000 claims description 12
- 238000013268 sustained release Methods 0.000 claims description 7
- 239000012730 sustained-release form Substances 0.000 claims description 6
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 5
- 229920003156 Eudragit® RL PO Polymers 0.000 claims 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims 2
- 238000000034 method Methods 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 3
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 239000003814 drug Substances 0.000 description 17
- 229920003134 Eudragit® polymer Polymers 0.000 description 13
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 239000008280 blood Substances 0.000 description 12
- 210000004369 blood Anatomy 0.000 description 12
- 229940079593 drug Drugs 0.000 description 12
- 239000003405 delayed action preparation Substances 0.000 description 11
- 235000019441 ethanol Nutrition 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 239000007788 liquid Substances 0.000 description 6
- 230000000291 postprandial effect Effects 0.000 description 6
- 238000005550 wet granulation Methods 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 230000001225 therapeutic effect Effects 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 239000002552 dosage form Substances 0.000 description 3
- 239000000523 sample Substances 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 230000002459 sustained effect Effects 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Chemical compound 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 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- FQPFAHBPWDRTLU-UHFFFAOYSA-N aminophylline Chemical compound NCCN.O=C1N(C)C(=O)N(C)C2=C1NC=N2.O=C1N(C)C(=O)N(C)C2=C1NC=N2 FQPFAHBPWDRTLU-UHFFFAOYSA-N 0.000 description 2
- 208000006673 asthma Diseases 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012738 dissolution medium Substances 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 239000002609 medium Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- 230000001105 regulatory effect Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- KMEBCRWKZZSRRT-UHFFFAOYSA-N 2-methyl-7h-purine Chemical compound CC1=NC=C2NC=NC2=N1 KMEBCRWKZZSRRT-UHFFFAOYSA-N 0.000 description 1
- 235000007627 Caesalpinia Nutrition 0.000 description 1
- 241000522234 Caesalpinia Species 0.000 description 1
- 101000939517 Homo sapiens Ubiquitin carboxyl-terminal hydrolase 2 Proteins 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010033557 Palpitations Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 102100029643 Ubiquitin carboxyl-terminal hydrolase 2 Human genes 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N acetonitrile Substances CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 229960003556 aminophylline Drugs 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 201000009267 bronchiectasis Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- -1 hydroxypropyl Chemical group 0.000 description 1
- 230000036039 immunity Effects 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000011068 loading method Methods 0.000 description 1
- FYYHWMGAXLPEAU-OUBTZVSYSA-N magnesium-25 atom Chemical group [25Mg] FYYHWMGAXLPEAU-OUBTZVSYSA-N 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000010008 shearing Methods 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 229910001220 stainless steel Inorganic materials 0.000 description 1
- 239000010935 stainless steel Substances 0.000 description 1
- 238000013179 statistical model Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 238000010998 test method Methods 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
- A61K31/52—Purines, e.g. adenine
- A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
-
- 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
- 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
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/06—Antiasthmatics
Abstract
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a theophylline sustained release tablet and a preparation method thereof. The theophylline sustained release tablet comprises the following raw materials in parts by weight: 20-60 parts of theophylline, 10-40 parts of slow release material, 5-40 parts of filler, 5-15 parts of adhesive, 0.1-2.0 parts of lubricant and 15-25 parts of wetting agent; the slow release material is ethyl cellulose and Ettky ® Is a mixture of (a) and (b); the filler is a mixture of anhydrous calcium hydrophosphate and anhydrous lactose. Compared with the preparation process of the reference preparation, the preparation process of the invention has simple process, can meet the production requirement by adopting general equipment, and has low equipment requirement.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a theophylline sustained release tablet and a preparation method thereof.
Background
Theophylline (Theophylline) is a methylpurine medicine and has definite effects in treating bronchiectasis, resisting inflammation, regulating immunity and the like. The dosage form commonly used in clinic is aminophylline tablet (100 mg/tablet), which is required to be taken 3 times a day, and frequent administration often causes the phenomena of large fluctuation of blood concentration, unstable curative effect and the like in a patient; in addition, when the blood concentration of theophylline exceeds 20. Mu.g/mL, adverse reactions such as nausea, palpitations, arrhythmia and the like are caused, and thus it is necessary to administer the theophylline in a sustained and controlled release dosage form. The traditional medicine is designed into a sustained and controlled release preparation, so that the duration of effective blood concentration can be prolonged, adverse reactions caused by sudden release of the medicine can be reduced, and the medication compliance of patients can be improved.
The theophylline is used as a representative drug for treating asthma, and the theophylline sustained release tablet is a very effective drug for stably treating asthma and has good curative effect. However, regarding the theophylline sustained release tablets in the current market, the preparation process is to add adhesive for granulating after uniformly mixing retarder and other raw materials, and the mixing effect among powders is poor in the mixing process, so that the release degree difference of the theophylline sustained release tablets among tablets or among batches is large, the release degree difference of the theophylline sustained release tablets in each batch is large, and the release linearity in different time is poor, so that the stable therapeutic effect of the theophylline is not exerted.
The Sustained Release Preparation (SRP) is a preparation which can reduce the absorption rate of the drug into the body by delaying the drug release rate from the dosage form, thereby playing a better therapeutic effect, but the release rate of the drug from the preparation is influenced by factors such as PH and the like. The sustained release preparation is a preparation which is prepared by slowly releasing oral medicines in a regulated release medium according to the requirement and has the dosage reduced from 3-4 times to 1-2 times per 24h compared with other corresponding common preparations. The oral sustained release preparation is also divided into sustained release preparation and controlled release preparation according to the first order kinetics and zero kinetics equation in accordance with the drug release process. The sustained and controlled release preparation mainly comprises two types of skeleton type and reservoir type. The sustained-release capacity of the skeleton sustained-release preparation is slightly poorer than that of a reservoir type, and the process is simple; the reservoir type sustained-release agent has good sustained-release capability, complex preparation process, uneven loading of the coated medicament possibly caused by the existence of blank particles in the coating process, poor reproducibility among batches and higher requirement on the preparation process.
The traditional preparation process of the current theophylline sustained release tablet comprises the following steps: mixing retarder and other raw materials, adding adhesive, and granulating. The mixing effect among the powders in the mixing process of the preparation process is poor, so that the release degree difference of the theophylline sustained release tablets among tablets or among batches is large, the release linearity in different time is poor, particularly, the accumulated release degree in 12 hours is only about 80%, the requirement of the 2015 edition of Chinese pharmacopoeia (the accumulated release degree in 12 hours is more than 70%) can be just met, and the stable therapeutic effect of the theophylline cannot be ensured.
Chinese patent application CN103239419a discloses a preparation method of theophylline sustained release tablet, (1) adding retarder into wet granulator, adding solvent of retarder to prepare adhesive, stirring and shearing at normal temperature; (2) Adding theophylline, an adhesive and a filler into a wet granulator to prepare a soft material; (3) After the granulator is replaced by a stainless steel net with 16-20 meshes, granulating by the granulator; (4) And (3) sucking wet particles into a boiling bed for drying by using vacuum, then granulating by using a crushing and granulating machine, adding a lubricant, mixing, and tabletting to obtain the theophylline sustained-release tablet. The method can release at a constant speed, has stable quality, safety, simple process and good process stability, but has low release degree, and can not completely release theophylline.
Therefore, a preparation method of the theophylline sustained release tablet with good sustained release capability, good batch-to-batch reproducibility and simple preparation process needs to be developed.
Disclosure of Invention
Based on the defects in the prior art, the invention provides a theophylline sustained release tablet and a preparation method thereof. The sustained release capacity is good, the batch reproducibility is good, the preparation process is simple, the production requirement can be met by adopting general equipment, and the equipment requirement is low.
In order to achieve the above purpose, the technical scheme adopted by the invention is as follows:
the invention provides a theophylline sustained release tablet, which comprises the following raw materials in parts by weight: 20-60 parts of theophylline, 10-40 parts of slow release material, 5-40 parts of filler, 5-15 parts of adhesive, 0.1-2.0 parts of lubricant and 15-25 parts of wetting agent; the slow release material is ethyl cellulose and Ettky ® Is a mixture of (a) and (b).
Preferably, the ethylcellulose and Ettky ® The mass ratio of (2) is 1:0.8-1.2, preferably 1:1.
Preferably, the filler is selected from one or more of anhydrous dibasic calcium phosphate, lactose and microcrystalline cellulose; the adhesive is hydroxypropyl cellulose; the lubricant is magnesium stearate; the wetting agent is ethanol.
Further preferably, the filler is a mixture of anhydrous dibasic calcium phosphate and anhydrous lactose, the mass ratio of anhydrous dibasic calcium phosphate to anhydrous lactose being 1:0.4-1.5, preferably 1:1.2-1.5.
Further preferably, the ethanol is selected from any one of ethanol with a mass concentration of 70%, ethanol with a mass concentration of 90% and absolute ethanol.
Still further preferably, the ethanol is absolute ethanol.
The invention also relates to a preparation method of the theophylline sustained release tablet, which comprises the following steps:
(1) Mixing theophylline and slow release material, adding ethanol, and preparing soft material;
(2) Granulating the soft material, and drying to obtain dry granules;
(3) And (3) finishing the dry granules, adding a filler, an adhesive and a lubricant, mixing, and tabletting to obtain the theophylline sustained release tablet.
Preferably, the mixing apparatus in step (1) is a wet granulator; the ethanol adding time is 120-240s.
Preferably, the granulating equipment in the step (2) is a square-hole sieve with the diameter of 4-5mm multiplied by 4-5mm, the drying equipment is a fluidized bed, and the drying temperature is less than 40 ℃; the moisture of the dry particles is less than 1.0%.
Preferably, the screen pore size of the granule in step (3) is 1.4-1.6mm, and the rotation speed of the granule is 400-600rpm.
Preferably, the rotational speed of the mixing in step (3) is 10-15rpm and the mixing time is 5-15min. The hardness of the pressed sheet is 100-160N.
Compared with the prior art, the invention has the following beneficial effects:
(1) Compared with the preparation process of the reference preparation, the self-developing agent has simple process, can meet the production requirement by adopting general equipment, and has low equipment requirement;
(2) Compared with the prior art, the prescription process can completely release the medicine;
(3) The product is a narrow therapeutic window drug, the blood concentration influences the drug effect and the safety of patients, and the product prepared by the technical means provided by the invention has a more similar drug release curve with a reference preparation.
Drawings
FIG. 1 is a dissolution comparison curve of examples 1-6 with a reference reagent;
FIG. 2 is a dissolution comparison curve of comparative examples 1-4 with a reference reagent.
Detailed Description
The technical solutions of the embodiments of the present invention are further clearly described, and the described embodiments are only a part of the present invention, which are used to explain the present invention, but not to limit the present invention, so that other embodiments obtained by other persons skilled in the art without creative efforts fall within the protection scope of the present invention.
Reference formulation, trade name: theolone, specification: 0.1g, purchased from Eisai co., ltd. (japan guard);
eud special ® The trade name is Uttky RL PO, purchased from Shangji specialty Chemie (Shanghai) Co., ltd;
ethylcellulose, 20cps, available from Nutrition & Biosciences USA 1, llc;
hydroxypropyl cellulose (L-HPC), available from Nippon Caesalpinia;
the reagents not specifically described below are all conventional reagents and commercially available.
Example 1
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 10 parts of Eudragit ® 10 parts of ethylcellulose, 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 18 parts of absolute ethyl alcohol.
The preparation method of the product comprises the following steps:
(1) Theophylline, eudragit ® Pouring the mixture and ethyl cellulose into wet granulation for mixing, adding absolute ethyl alcohol after mixing uniformly, and adding liquid for 180 seconds to prepare a soft material;
(2) Granulating the soft material by adopting a square hole sieve with the diameter of 5mm multiplied by 5 mm; drying the wet particles by adopting a fluidized bed, controlling the temperature of the materials to be 38 ℃ in the drying process, and drying until the moisture of the materials is 0.7%, thus obtaining dry particles;
(3) The dry granules are granulated by adopting a 1.5mm screen with the rotating speed of 500rpm, then are added into a mixer together with anhydrous calcium hydrophosphate, anhydrous lactose, hydroxypropyl cellulose and magnesium stearate to be mixed for 10 minutes at the rotating speed of 12rpm, and then are tabletted, wherein the tablet hardness is 130N.
Example 2
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 16 parts of anhydrous calcium hydrophosphate and 15 parts of Eudragit ® 15 parts of ethyl cellulose, 11 parts of hydroxypropyl cellulose, 0.1 part of magnesium stearate and 15 parts of absolute ethyl alcohol.
The preparation method of the product comprises the following steps:
(1) Theophylline, eudragit ® Pouring the mixture and ethyl cellulose into wet granulation for mixing, adding absolute ethyl alcohol after mixing uniformly, and adding liquid for 120s to prepare a soft material;
(2) Granulating the soft material by adopting a square hole sieve with the diameter of 5mm multiplied by 5 mm; drying the wet particles by adopting a fluidized bed, controlling the temperature of the materials to be 35 ℃ in the drying process, and drying until the moisture of the materials is 0.8%, thus obtaining dry particles;
(3) The dry granules are granulated by adopting a 1.4mm screen mesh at the rotation speed of 400rpm, then are added into a mixer together with anhydrous calcium hydrophosphate, anhydrous lactose, hydroxypropyl cellulose and magnesium stearate to be mixed for 15min at the rotation speed of 10rpm, and then are tabletted, wherein the tablet hardness is 100N.
Example 3
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 36 parts of anhydrous calcium hydrophosphate and 5 parts of Eudragit ® 5 parts of ethyl cellulose, 11 parts of hydroxypropyl cellulose, 0.1 part of magnesium stearate and 15 parts of absolute ethyl alcohol.
The preparation method of the product comprises the following steps:
(1) Theophylline, eudragit ® Pouring the mixture and ethyl cellulose into wet granulation for mixing, adding absolute ethyl alcohol after mixing uniformly, and adding liquid for 240s to prepare a soft material;
(2) Granulating the soft material by adopting a square hole sieve with the diameter of 4mm multiplied by 4 mm; drying the wet particles by adopting a fluidized bed, controlling the temperature of the materials to be 39 ℃ in the drying process, and drying until the moisture of the materials is 0.5%, thus obtaining dry particles;
(3) The dry granules are granulated by adopting a 1.6mm screen with the rotating speed of 600rpm, then are added into a mixer together with anhydrous calcium hydrophosphate, anhydrous lactose, hydroxypropyl cellulose and magnesium stearate to be mixed for 5 minutes at the rotating speed of 15rpm, and then are tabletted, wherein the tablet hardness is 160N.
Example 4
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 18 parts of anhydrous calcium hydrophosphate and 10 parts of Eudragit ® 10 parts of ethyl cellulose, 11 parts of hydroxypropyl cellulose, 8 parts of anhydrous lactose, 0.1 part of magnesium stearate and 18 parts of absolute ethyl alcohol.
The process for the preparation of the product was identical to that of example 1.
Example 5
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 12 parts of Eudragit ® 10 parts of ethylcellulose, 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 25 parts of 70% ethanol.
The process for the preparation of the product was identical to that of example 1.
Example 6
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 8 parts of Eudragit ® 10 parts of ethyl cellulose and 11 parts of hydroxypropyl fiberVitamin, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 20 parts of 90% ethanol.
The process for the preparation of the product was identical to that of example 1.
Comparative example 1
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 10 parts of Eudragit ® And 10 parts of ethylcellulose, 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 12 parts of purified water.
The preparation method of the product comprises the following steps:
(1) Pouring theophylline and hydroxypropyl cellulose into wet granulation for mixing, adding purified water after mixing uniformly, and adding liquid for 120s to prepare a soft material;
(2) Granulating the soft material by adopting a square hole sieve with the diameter of 5mm multiplied by 5 mm; drying the wet particles by adopting a fluidized bed, controlling the temperature of the materials to be 38 ℃ in the drying process, and drying until the moisture of the materials is 0.7%, thus obtaining dry particles;
(3) The dry granules were sized with a 1.5mm screen at 500rpm and then with Uttky ® Ethyl cellulose, anhydrous calcium hydrophosphate, anhydrous lactose and magnesium stearate are added into a mixer and mixed for 10 minutes at a speed of 12rpm, and then the mixture is tabletted, wherein the tablet hardness is 130N.
Comparative example 2
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 10 parts of Eudragit ® 10 parts of ethyl cellulose, 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose and 0.1 part of magnesium stearate.
The preparation method of the product comprises the following steps:
theophylline, ethylcellulose, anhydrous calcium hydrophosphate, anhydrous lactose, hydroxypropyl cellulose and magnesium stearate are added into a mixer and mixed for 10 minutes at a speed of 12rpm, and then the mixture is tabletted, wherein the tablet hardness is 100N.
Comparative example 3
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate, 20 parts of ethylcellulose, 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 18 parts of absolute ethyl alcohol.
The preparation method of the product comprises the following steps:
(1) Pouring theophylline and ethyl cellulose into wet granulation for mixing, adding absolute ethyl alcohol after mixing uniformly, and adding liquid for 180 seconds to prepare a soft material;
steps (2) and (3) were identical to example 1.
Comparative example 4
The theophylline sustained-release tablet comprises the following raw materials in parts by weight: 43 parts of theophylline, 11 parts of anhydrous calcium hydrophosphate and 20 parts of Eudragit ® 11 parts of hydroxypropyl cellulose, 15 parts of anhydrous lactose, 0.1 part of magnesium stearate and 18 parts of absolute ethyl alcohol.
The preparation method of the product comprises the following steps:
(1) Theophylline and Eudragit ® Mixing in wet granulation, adding absolute ethanol, and adding liquid for 180s to obtain soft material;
steps (2) and (3) were identical to example 1.
Effect testing
Test example 1 dissolution test
Dissolution rate measurement method: XUltimate XB-C18 (4.6X105 mm,5 um) column, and 0.0lmol/L sodium acetate solution (pH value is adjusted to 4.50.05 with 2.0mol/L acetic acid solution) -acetonitrile (volume ratio of 88:12) as mobile phase; detection wavelength: 271nm; the flow rate is 1.0mL/min; column temperature is 30 ℃; the sample injection amount was 20. Mu.L.
The dissolution condition refers to USP2 method, 900mL of pH1.2 medium is taken as dissolution medium, the temperature is 37+/-0.5 ℃, the rotating speed is 50 revolutions per minute, 10mL is sampled at 0.5h, 1h, 2h, 3h, 4h, 6h, 8h, 10h and 12h, and the dissolution medium with the same volume and the temperature of 37+/-0.5 ℃ is timely supplemented, so as to obtain the sample solution. The test results are shown in fig. 1, fig. 2 and table 1.
TABLE 1 dissolution results for examples 1-6, comparative examples 1-4 and reference formulations
Test example 2 postprandial biological efficacy test
Postprandial biological effectiveness test method: the postprandial test uses a random, open, three-preparation, three-sequence, three-cycle design. Healthy subjects were tested for 9 cases after meal. The dosage of the drug is 100 mg/tablet, the cleaning period is 5 days, and 9 subjects complete the test. Test blood collection time point: venous blood was collected at 23 blood collection sites for a total of 0h before dosing (1 h before dosing) and 1, 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 10, 12, 14, 24, 36, 48 hours after dosing. All blood samples were shipped to the testing party after all three cycles of testing were completed. The non-parametric statistical model method is used for calculating the pharmacokinetic parameters, and the geometric mean ratio 90% confidence interval is calculated after logarithmic conversion based on the principal pharmacokinetic parameters (Cmax and AUC).
AUC represents the area under the blood concentration-time curve; c (C) max Represents peak blood concentration (maximum blood concentration); AUC (AUC) 0-t The area under the blood concentration-time curve representing the sample collection time t from the moment 0 to the last concentration can be accurately measured; AUC (AUC) 0-∞ The area under the plasma concentration-time curve from time 0 to the time when all of the original drug was eliminated for this period of time is indicated.
Equivalence criterion: c (C) max And the geometric mean ratio of AUC 90% confidence interval falls within the range of 80.00% -125.00%.
The sample prepared in example 1 was selected for postprandial bioefficacy test since the similarity factor between example 1 and the reference preparation was maximized, and the results showed postprandial bioequivalence, and the results are shown in Table 2.
Table 2 example 1 results of postprandial bioavailability test of theophylline sustained release tablets
According to the result of the pre-test, T 1 C of R max 、AUC 0-t And AUC 0-∞ Is in the interval of 80-125% and the geometric mean ratio difference is about 5%.
The foregoing detailed description is directed to one of the possible embodiments of the present invention, which is not intended to limit the scope of the invention, but is to be accorded the full scope of all such equivalents and modifications so as not to depart from the scope of the invention.
Claims (7)
1. The theophylline sustained release tablet is characterized by comprising the following raw materials in parts by weight: 20-60 parts of theophylline, 10-40 parts of slow release material, 5-40 parts of filler, 5-15 parts of adhesive, 0.1-2.0 parts of lubricant and 15-25 parts of wetting agent; the slow release material is a mixture of ethyl cellulose and Eudragit RL PO;
the mass ratio of the ethyl cellulose to the Eudragit RL PO is 1:0.8-1.2;
the adhesive is hydroxypropyl cellulose;
the filler is one or two selected from anhydrous calcium hydrophosphate and anhydrous lactose; the lubricant is magnesium stearate; the wetting agent is ethanol;
the preparation method of the theophylline sustained release tablet comprises the following steps:
(1) Mixing theophylline and slow release material, adding ethanol, and preparing soft material;
(2) Granulating the soft material, and drying to obtain dry granules;
(3) And (3) finishing the dry granules, adding a filler, an adhesive and a lubricant, mixing, and tabletting to obtain the theophylline sustained release tablet.
2. The theophylline sustained-release tablet according to claim 1, wherein the filler is a mixture of anhydrous calcium hydrogen phosphate and anhydrous lactose, and the mass ratio of the anhydrous calcium hydrogen phosphate to the anhydrous lactose is 1:0.4-1.5.
3. The theophylline sustained release tablet of claim 1, wherein the ethanol is selected from any one of ethanol with a mass concentration of 70%, ethanol with a mass concentration of 90% and absolute ethanol.
4. A sustained-release theophylline tablet according to any one of claims 1 to 3, wherein the mixing equipment in step (1) is a wet granulator; the ethanol adding time is 120-240s.
5. The theophylline sustained-release tablet according to claim 1, wherein in the preparation method of the theophylline sustained-release tablet, the granulating equipment in the step (2) is a square-hole sieve with the diameter of 4-5mm multiplied by 4-5mm, the drying equipment is a fluidized bed, and the drying temperature is less than 40 ℃; the moisture of the dry particles is less than 1.0%.
6. The theophylline sustained-release tablet according to claim 1, wherein in the preparation method of the theophylline sustained-release tablet, the mesh diameter of the granule finishing in the step (3) is 1.4-1.6mm, and the rotation speed of the granule finishing is 400-600rpm.
7. The theophylline sustained-release tablet according to claim 1, wherein the rotational speed of the mixing in the step (3) is 10-15rpm, the mixing time is 5-15min, and the hardness of the tablet is 100-160N.
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