CN111759820B - Oxcarbazepine tablet and preparation method thereof - Google Patents
Oxcarbazepine tablet and preparation method thereof Download PDFInfo
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- CTRLABGOLIVAIY-UHFFFAOYSA-N oxcarbazepine Chemical compound C1C(=O)C2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 CTRLABGOLIVAIY-UHFFFAOYSA-N 0.000 title claims abstract description 88
- 229960001816 oxcarbazepine Drugs 0.000 title claims abstract description 81
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims abstract description 27
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims abstract description 26
- 229940083575 sodium dodecyl sulfate Drugs 0.000 claims abstract description 25
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 20
- 239000002994 raw material Substances 0.000 claims abstract description 18
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims abstract description 16
- 239000007888 film coating Substances 0.000 claims abstract description 16
- 238000009501 film coating Methods 0.000 claims abstract description 16
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 10
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims abstract description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 9
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 9
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims abstract description 9
- 239000008108 microcrystalline cellulose Substances 0.000 claims abstract description 9
- 229940016286 microcrystalline cellulose Drugs 0.000 claims abstract description 9
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 8
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 5
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims abstract description 5
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 5
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 5
- 239000011248 coating agent Substances 0.000 claims description 26
- 238000000576 coating method Methods 0.000 claims description 26
- 239000002245 particle Substances 0.000 claims description 23
- 238000002156 mixing Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 19
- 239000000463 material Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 235000010469 Glycine max Nutrition 0.000 claims description 8
- 244000068988 Glycine max Species 0.000 claims description 8
- 238000001035 drying Methods 0.000 claims description 8
- GOMNOOKGLZYEJT-UHFFFAOYSA-N isoflavone Chemical compound C=1OC2=CC=CC=C2C(=O)C=1C1=CC=CC=C1 GOMNOOKGLZYEJT-UHFFFAOYSA-N 0.000 claims description 8
- CJWQYWQDLBZGPD-UHFFFAOYSA-N isoflavone Natural products C1=C(OC)C(OC)=CC(OC)=C1C1=COC2=C(C=CC(C)(C)O3)C3=C(OC)C=C2C1=O CJWQYWQDLBZGPD-UHFFFAOYSA-N 0.000 claims description 8
- 235000008696 isoflavones Nutrition 0.000 claims description 8
- 239000007788 liquid Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 238000010008 shearing Methods 0.000 claims description 7
- 238000009826 distribution Methods 0.000 claims description 5
- 238000001914 filtration Methods 0.000 claims description 4
- 238000010902 jet-milling Methods 0.000 claims description 2
- 239000007916 tablet composition Substances 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 15
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 49
- 239000008187 granular material Substances 0.000 description 17
- 239000003814 drug Substances 0.000 description 14
- 239000011162 core material Substances 0.000 description 13
- 238000000034 method Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 230000000052 comparative effect Effects 0.000 description 9
- 238000005469 granulation Methods 0.000 description 8
- 230000003179 granulation Effects 0.000 description 8
- 239000008213 purified water Substances 0.000 description 7
- 230000008569 process Effects 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 5
- 238000001727 in vivo Methods 0.000 description 5
- 238000004519 manufacturing process Methods 0.000 description 5
- 239000000203 mixture Substances 0.000 description 5
- 239000007935 oral tablet Substances 0.000 description 4
- 238000005086 pumping Methods 0.000 description 4
- 239000004094 surface-active agent Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 210000001035 gastrointestinal tract Anatomy 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 235000003687 soy isoflavones Nutrition 0.000 description 3
- 239000002671 adjuvant Substances 0.000 description 2
- 239000001961 anticonvulsive agent Substances 0.000 description 2
- 229960003965 antiepileptics Drugs 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000008119 colloidal silica Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000010438 heat treatment Methods 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 238000005303 weighing Methods 0.000 description 2
- 102000001399 Kallikrein Human genes 0.000 description 1
- 108060005987 Kallikrein Proteins 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 229960000623 carbamazepine Drugs 0.000 description 1
- FFGPTBGBLSHEPO-UHFFFAOYSA-N carbamazepine Chemical compound C1=CC2=CC=CC=C2N(C(=O)N)C2=CC=CC=C21 FFGPTBGBLSHEPO-UHFFFAOYSA-N 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 238000011161 development Methods 0.000 description 1
- 230000004069 differentiation Effects 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 230000005611 electricity Effects 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 231100000683 possible toxicity Toxicity 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 238000007613 slurry method Methods 0.000 description 1
- 230000003068 static effect Effects 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000009827 uniform distribution Methods 0.000 description 1
Classifications
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
-
- 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
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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- 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
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- 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
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- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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Abstract
The invention provides an oxcarbazepine tablet and a preparation method thereof, relating to the field of pharmaceutical preparations, wherein the oxcarbazepine tablet comprises a film coating premix and an oxcarbazepine tablet core; the oxcarbazepine tablet core comprises the following raw materials in percentage by weight: 60 to 80 percent of oxcarbazepine, 13 to 22 percent of microcrystalline cellulose, 3 to 5 percent of hydroxypropyl methylcellulose, 2 to 8 percent of croscarmellose sodium, 0.5 to 1 percent of colloidal silicon dioxide, 1 to 3 percent of sodium dodecyl sulfate and 0.5 to 1 percent of magnesium stearate. The oxcarbazepine tablet prepared by optimizing the components, the proportion and the preparation method can be produced commercially, is environment-friendly and economical, has better dissolution rate in a short time and is easy to be absorbed by human bodies.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to oxcarbazepine tablets and a preparation method thereof.
Background
Oxcarbazepine is the second generation antiepileptic drug, and is a derivative of the first generation antiepileptic drug carbamazepine. The drug acts primarily through its pharmacologically active metabolite (10-monohydroxy derivative, MHD). The quality of the oxcarbazepine tablets sold in China is uneven, whether the oxcarbazepine tablets are clinically equivalent to the original product is not clear, and the quality of the oxcarbazepine tablets needs to be improved through consistency evaluation. However, the preparation technology adopted by the existing oxcarbazepine tablet invention has various defects, such as:
the method disclosed in the chinese patent (oxcarbazepine pharmaceutical preparation and the preparation method thereof, application No. 2007800023534.8) requires the use of a broad and multimodal particle size distribution of the bulk drug oxcarbazepine, which is practically only available in laboratories and by technicians trained in good expertise, and is cumbersome and costly in procedures and cannot be used for the commercial production of oxcarbazepine tablet preparations.
The method disclosed in the chinese patent (an oxcarbazepine sustained release tablet and a method for preparing the same, application No. 201510823709.6) requires the use of KG-802 compound, and the bulk drug is pulverized several times during the pulverization process. The yield of micronized raw material medicines is very low easily due to multiple times of crushing, and the raw material medicines after multiple times of crushing are likely to have two-pole differentiation (double peaks) of particle sizes, so that the target particle size range and uniform distribution of the raw material medicines are difficult to control, and the in-vivo absorption is difficult. The possibility of practical application of this scheme to commercial production is 0. The purpose of the patent is to prepare the oxcarbazepine sustained release tablet, which is different from the oxcarbazepine quick release tablet prepared by the invention.
Oxcarbazepine is a BCS4 compound, has poor solubility and permeability, and is added with a proper amount of surfactant to improve the dissolution speed of oxcarbazepine in gastrointestinal tract, promote absorption in vivo and improve bioavailability. Sodium dodecyl sulfate is a surfactant which can be added into oral tablets, and an FDA (food and drug administration) adjuvant toxicity database shows that the maximum dosage of the sodium dodecyl sulfate for the oral tablets is single dose (tablet) 51.69mg, but no method for improving release and bioavailability of oxcarbazepine by using the sodium dodecyl sulfate is searched in Chinese patent on oxcarbazepine preparations.
Aiming at the problems of the difficult-to-dissolve and hypotonic biopharmaceutics characteristics of oxcarbazepine and the difficulty in converting most preparation methods in the prior art into a prescription process for practical production, the development of an environment-friendly and economical oxcarbazepine tablet production prescription process which can be commercially produced and is beneficial to in vivo absorption is needed.
Disclosure of Invention
The invention provides an oxcarbazepine tablet and a preparation method thereof, aiming at the problems in the prior art. The preparation method can be used for commercial production, is environment-friendly and economical, and the prepared oxcarbazepine tablet has excellent dissolution rate in a short time and is easy to be absorbed by human bodies.
In order to achieve the purpose, the technical scheme adopted by the invention is as follows:
the invention provides an oxcarbazepine tablet, which comprises a film coating premix and an oxcarbazepine tablet core; the oxcarbazepine tablet core comprises the following raw materials: oxcarbazepine, microcrystalline cellulose, hypromellose, croscarmellose sodium, colloidal silicon dioxide, sodium lauryl sulfate, and magnesium stearate.
Further, the oxcarbazepine tablet core comprises the following raw materials in percentage by weight:
preferably, the oxcarbazepine tablet core comprises the following raw materials in percentage by weight:
oxcarbazepine 72%
Microcrystalline cellulose 15.85%
4 percent of hydroxypropyl methylcellulose
Croscarmellose sodium 5%
0.65 percent of colloidal silicon dioxide
Sodium dodecyl sulfate 1.85%
0.65 percent of magnesium stearate.
Further, the weight of the film coating premix accounts for 2-4% of the total weight of the oxcarbazepine core.
Further, the weight ratio of the colloidal silicon dioxide to the sodium dodecyl sulfate is 0.5-1: 1-3. Preferably 0.65: 1.85.
Further, the oxcarbazepine tablet further comprises soy isoflavones.
Further, the content of the soybean isoflavone accounts for 2-5% of the total weight of the oxcarbazepine tablet core.
In some specific embodiments, the oxcarbazepine core comprises the following raw materials in weight percent:
preferably, the oxcarbazepine tablet core comprises the following raw materials in percentage by weight:
oxcarbazepine 70%
Microcrystalline cellulose 15.55%
Hydroxypropyl methylcellulose 3.8%
4.6 percent of croscarmellose sodium
0.7 percent of colloidal silicon dioxide
Sodium dodecyl sulfate 1.65%
Magnesium stearate 0.7%
3 percent of soybean isoflavone.
The invention also provides a preparation method of the oxcarbazepine tablet, which comprises the following steps:
(1) premixing: uniformly mixing oxcarbazepine, sodium dodecyl sulfate and colloidal silicon dioxide;
(2) micronization: performing jet milling on the premixed mixed material, and controlling the particle size distribution after milling;
(3) and (3) granulating: stirring and shearing the micronized mixed material, microcrystalline cellulose and hydroxypropyl methylcellulose, mixing uniformly, and adding pure water for granulation;
(4) drying;
(5) finishing the grains;
(6) totally mixing;
(7) tabletting: tabletting to obtain an oxcarbazepine core;
(8) coating: mixing the film coating premix and pure water, stirring until the film coating premix and the pure water are completely dissolved, filtering to obtain a coating solution, and coating the oxcarbazepine tablet core by using the coating solution.
Further, when the soybean isoflavone is added, the step (1) mixes the soybean isoflavone with oxcarbazepine, sodium dodecyl sulfate, and colloidal silicon dioxide.
Further, the adding amount of the pure water in the step (3) is 15-25% of the weight of the granulated dry powder feeding material.
Further, the solid content of the coating liquid in the step (8) is 10-15%.
Further, in some specific embodiments, the oxcarbazepine tablet is prepared by a process comprising the steps of:
(1) premixing: the oxcarbazepine raw material medicine, sodium dodecyl sulfate and colloidal silicon dioxide in the prescription amount are put into a mixer and mixed evenly.
(2) Micronization: and (3) carrying out air flow crushing on the premixed mixed material, and controlling the particle size distribution after crushing.
(3) And (3) granulating: and sequentially adding the micronized mixture, microcrystalline cellulose and hydroxypropyl methylcellulose into a high-shear wet granulator. Stirring and shearing are started, mixing is carried out until the mixture is uniform, and sampling is carried out to detect the content uniformity. Stirring and shearing are started, and a proper amount of purified water is added into the granulator for granulation.
(4) And (3) drying: drying with a fluidized bed dryer, starting steam to enter a system, lifting the hopper after the hopper is positioned, and pumping the prepared wet particles into a fluidized bed dryer bin to start drying. When the moisture of the particles reaches the control range, the heating is stopped. And (4) connecting the dry granules to a conveying hose of the bin granulator, and pumping the dry granules to the bin granulator for granulation through the conveying hose.
(5) Straightening: and (3) granulating the dry particles by using a bin granulator, starting a vacuum feeder of the bin granulator, setting granulation frequency, hermetically conveying the dry particles in the bin of the fluidized dryer into the bin of the bin granulator, and finally starting a motor of the bin granulator to start granulation. The appearance granularity of the checking particles is uniform and has no foreign matters. The particles are loaded in a lifting and feeding special barrel and are transported to a total mixing chamber.
(6) Total mixing: lifting the whole granules by a hydraulic lifter, aligning the whole granules with a feed inlet of a total mixing tank of a high-efficiency three-dimensional motion mixer, connecting and fastening a flexible connection, opening a valve, and enabling the whole granules to enter the total mixing tank in a free-falling mode. And after all the whole granules are added, closing the opening of the tank and starting the machine. The granules were checked for their behavior after the total mixing and were visually checked for light yellow granules and powder.
(7) Tabletting: and calculating the theoretical tablet weight according to the content of the prepared particles, and adding a lifting and feeding special barrel filled with the prepared particles into a blanking bin of the tablet press in a lifting and feeding mode. Normal compression was started to give tablet cores.
(8) Coating: taking the tablet core, weighing the film coating premix by using an electronic counting scale, and filling into a clean medicinal plastic bag. According to the proportion of the solid content of the coating liquid being 10 percent, the purified water quantity required to be added in each part is obtained, weighed by an electronic scale and poured into a premixing stirring tank. And adding the weighed film coating premix into weighed purified water, stirring until the film coating premix is completely dissolved, and filtering by using a 100-target standard sample sieve for later use. When in use, the filtrate is poured into a stirring tank of a coating machine, and the stirring paddle is started to stir slowly. The received plain tablets are coated in a coating operation room by a high-efficiency coating machine, and coating is started.
The technical effects obtained by the invention are as follows:
1. the invention combines the surface activity of the sodium dodecyl sulfate and the huge specific surface area of the silicon dioxide with the mixed micro powder of the bulk drug, the sodium dodecyl sulfate and the colloidal silicon dioxide, thereby reducing the material flow difficulty and the electrostatic aggregation when the oxcarbazepine is micronized at one stroke, and leading the oxcarbazepine micronization to be efficient and economic. The oxcarbazepine tablet has the oxcarbazepine content of 60-80% and poor flowability, so that micronization is difficult to feed and long in micronization time, and the oxcarbazepine tablet is easy to aggregate after micronization. The colloidal silicon dioxide has extremely large specific surface area and is commonly used as a glidant, so that the micronization feeding and crushing process can be accelerated when the colloidal silicon dioxide is mixed into the oxcarbazepine bulk drug. Meanwhile, the sodium dodecyl sulfate has better hydrophilicity and surface activity, is beneficial to eliminating static electricity and improving the state of the micronized raw material medicine. In addition, in the research, a small amount of soybean isoflavone is additionally added into the raw materials, so that the accelerated dissolution of the oxcarbazepine tablets can be promoted.
2. Oxcarbazepine is a BCS4 compound, has poor solubility and permeability, and is added with a proper amount of surfactant to improve the dissolution speed of oxcarbazepine in gastrointestinal tract, promote absorption in vivo and improve bioavailability. Sodium dodecyl sulfate is a surfactant which can be added into oral tablets, and an FDA (food and drug administration) adjuvant toxicity database shows that the maximum dosage of the sodium dodecyl sulfate for the oral tablets is single dose (tablet) 51.69mg, but no method for improving release and bioavailability of oxcarbazepine by using the sodium dodecyl sulfate is searched in Chinese patent on oxcarbazepine preparations. The invention adopts sodium dodecyl sulfate as one of the tablet core auxiliary materials, the dosage of the sodium dodecyl sulfate does not exceed the specification of an FDA (food and drug administration) auxiliary material maximum dosage database (IIG), the potential toxicity hazard is avoided, the dissolution speed of the oxcarbazepine in gastrointestinal tracts is improved, the in-vivo absorption is promoted, and the bioavailability is improved.
Detailed Description
It should be noted that the film coating premix used in the present invention is opadry produced by kallikrein, and the other raw materials are all common commercial products, so the source thereof is not particularly limited.
The oxcarbazepine core materials and the corresponding amounts added in examples 1-6 are shown in table 1:
TABLE 1
Example 1
A process for the preparation of oxcarbazepine tablets comprising the steps of:
(1) premixing: the oxcarbazepine raw material medicine, sodium dodecyl sulfate and colloidal silicon dioxide in the prescription amount are put into a mixer and mixed evenly.
(2) Micronization: and (3) carrying out air flow crushing on the premixed mixed material, and controlling the particle size distribution after crushing.
(3) And (3) granulating: and sequentially adding the micronized mixture, microcrystalline cellulose and hydroxypropyl methylcellulose into a high-shear wet granulator. Stirring and shearing are started, mixing is carried out until the mixture is uniform, and sampling is carried out to detect the content uniformity. Stirring and shearing are started, and a proper amount of purified water is added into the granulator to granulate, wherein the adding amount of the purified water is 25 percent of the weight of the granulated dry powder.
(4) And (3) drying: drying with a fluidized bed dryer, starting steam to enter a system, lifting the hopper after the hopper is positioned, and pumping the prepared wet particles into a fluidized bed dryer bin to start drying. When the moisture of the particles reaches the control range, the heating is stopped. And (4) connecting the dry granules to a conveying hose of the bin granulator, and pumping the dry granules to the bin granulator for granulation through the conveying hose.
(5) Straightening: and (3) granulating the dry particles by using a bin granulator, starting a vacuum feeder of the bin granulator, setting granulation frequency, hermetically conveying the dry particles in the bin of the fluidized dryer into the bin of the bin granulator, and finally starting a motor of the bin granulator to start granulation. The appearance granularity of the checking particles is uniform and has no foreign matters. The particles are loaded in a lifting and feeding special barrel and are transported to a total mixing chamber.
(6) Total mixing: lifting the whole granules by a hydraulic lifter, aligning the whole granules with a feed inlet of a total mixing tank of a high-efficiency three-dimensional motion mixer, connecting and fastening a flexible connection, opening a valve, and enabling the whole granules to enter the total mixing tank in a free-falling mode. And after all the whole granules are added, closing the opening of the tank and starting the machine. The granules were checked for their behavior after the total mixing and were visually checked for light yellow granules and powder.
(7) Tabletting: and calculating the theoretical tablet weight according to the content of the prepared particles, and adding a lifting and feeding special barrel filled with the prepared particles into a blanking bin of the tablet press in a lifting and feeding mode. Normal compression was started to give tablet cores.
(8) Coating: taking the tablet core, weighing the film coating premix by using an electronic counting scale, and filling into a clean medicinal plastic bag. According to the proportion of the solid content of the coating liquid being 10 percent, the purified water quantity required to be added in each part is obtained, weighed by an electronic scale and poured into a premixing stirring tank. And adding the weighed film coating premix into weighed purified water, stirring until the film coating premix is completely dissolved, and filtering by using a 100-target standard sample sieve for later use. When in use, the filtrate is poured into a stirring tank of a coating machine, and the stirring paddle is started to stir slowly. The received plain tablets are coated in a coating operation room by a high-efficiency coating machine, and coating is started.
Example 2
The preparation method is different from the example 1 only in that the adding amount of the pure water in the step (3) is 25 percent of the weight of the fed granulating dry powder, and the solid content of the coating liquid in the step (8) is 15 percent.
Example 3
The preparation method is different from the example 1 only in that the adding amount of the pure water in the step (3) is 20 percent of the weight of the fed granulating dry powder, and the solid content of the coating liquid in the step (8) is 12 percent.
Example 4
In the step (1), soybean isoflavone, oxcarbazepine, sodium dodecyl sulfate and colloidal silicon dioxide are mixed together, and the other preparation methods are the same as those in example 1.
Example 5
The preparation method is different from the example 4 only in that the adding amount of the pure water in the step (3) is 25 percent of the weight of the fed granulating dry powder, and the solid content of the coating liquid in the step (8) is 15 percent.
Example 6
The preparation method is different from the example 4 only in that the adding amount of the pure water in the step (3) is 20 percent of the weight of the fed granulating dry powder, and the solid content of the coating liquid in the step (8) is 12 percent.
Example 7
The only difference from example 6 is that no soy isoflavones were present (no soy isoflavones were added in step (1) of the preparation process) and the amounts of the remaining raw materials (parts by weight rather than percentages) were identical to example 6.
Comparative example 1
The difference from example 3 is only that the oxcarbazepine core comprises the following raw materials in weight percent:
comparative example 2
The difference from example 6 is only that the oxcarbazepine core comprises the following raw materials in weight percent:
comparative example 3
The only difference from example 3 is that the weight ratio of colloidal silica to sodium dodecylsulfate is 1.2:0.8 (the total weight of both is in accordance with example 3).
Comparative example 4
The only difference from example 6 is that the weight ratio of colloidal silica to sodium dodecylsulfate is 1.2:0.8 (the total weight of both is in accordance with example 6).
Oxcarbazepine tablet dissolution test of the present invention
Test subjects: oxcarbazepine tablets prepared in examples 1 to 7 and comparative examples 1 to 4, reference formulation (600 mg of nordstrand).
The test method comprises the following steps: the dissolution of oxcarbazepine tablets and reference tablets in different examples at different times was examined (the measurement method refers to the second method of 0931 in the appendix of the fourth part of the 'Chinese pharmacopoeia 2020 edition', and the measurement conditions refer to the dissolution curve determination conditions of oxcarbazepine tablets recommended by the US FDA, namely aqueous medium, 1% SDS, 60rpm, and slurry method), and the test results were counted in Table 1 and a dissolution similarity factor was calculated (f 2).
TABLE 1
As can be seen from table 1, the dissolution conditions of the oxcarbazepine tablets in the examples of the present invention reach more than 60 f2 compared with the reference preparation, which indicates that the oxcarbazepine tablets of the present invention have bioavailability consistent with the original imported product, and the oxcarbazepine tablets in the examples of the present invention can reach better dissolution rate in a shorter time. The dissolution conditions of comparative example 1 and comparative example 3 are inferior to those of example 3, and the dissolution conditions of comparative example 2, comparative example 4 and example 7 are inferior to those of example 6, so that the components and contents of the oxcarbazepine tablet greatly influence the dissolution conditions of the oxcarbazepine tablet, and the dissolution conditions are better within the protection range of the present invention.
Finally, it should be noted that the above-mentioned contents are only used for illustrating the technical solutions of the present invention, and not for limiting the protection scope of the present invention, and that the simple modifications or equivalent substitutions of the technical solutions of the present invention by those of ordinary skill in the art can be made without departing from the spirit and scope of the technical solutions of the present invention.
Claims (4)
1. Oxcarbazepine tablet formulation characterized by: consists of a film coating premix and an oxcarbazepine tablet core; the oxcarbazepine tablet core comprises the following raw materials in percentage by weight:
65 to 73 percent of oxcarbazepine
Microcrystalline cellulose 14.8% -20.4%
Hydroxypropyl methylcellulose 3.5% -4.5%
4 to 6 percent of croscarmellose sodium
0.6 to 0.8 percent of colloidal silicon dioxide
Sodium dodecyl sulfate 1.5-2.5%
Magnesium stearate 0.6-0.8%
2-5% of soybean isoflavone;
the weight ratio of the colloidal silicon dioxide to the sodium dodecyl sulfate is 0.5-1:1-3;
the weight of the film coating premix accounts for 2-4% of the total weight of the oxcarbazepine tablet core;
the preparation method of the oxcarbazepine tablet comprises the following steps:
(1) premixing: uniformly mixing the soybean isoflavone, oxcarbazepine, sodium dodecyl sulfate and colloidal silicon dioxide;
(2) micronization: performing jet milling on the premixed mixed material, and controlling the particle size distribution of the milled mixed material to be D90 which is less than or equal to 15 mu m;
(3) and (3) granulating: stirring and shearing the micronized mixed material, microcrystalline cellulose and hydroxypropyl methylcellulose, mixing uniformly, adding pure water, and granulating by starting stirring and shearing.
2. Oxcarbazepine tablet according to claim 1, wherein: the preparation method of the oxcarbazepine tablet further comprises the following steps:
(4) drying;
(5) finishing the grains;
(6) totally mixing;
(7) tabletting: tabletting to obtain an oxcarbazepine core;
(8) coating: mixing the film coating premix and pure water, stirring until the film coating premix and the pure water are completely dissolved, filtering to obtain a coating solution, and coating the oxcarbazepine tablet core by using the coating solution.
3. Oxcarbazepine tablet according to claim 1, wherein: and (3) adding the pure water in an amount which is 15-25% of the weight of the granulated dry powder.
4. Oxcarbazepine tablet according to claim 2, wherein: the solid content of the coating liquid in the step (8) is 10-15%.
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Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522140A (en) * | 2001-05-18 | 2004-08-18 | 兰贝克赛实验室有限公司 | Oxcarbazepine dosage forms |
| WO2007011349A1 (en) * | 2005-07-15 | 2007-01-25 | Teva Pharmaceutical Industries Ltd. | Novel granulation process and granulate produced therefrom |
| WO2007133476A2 (en) * | 2006-05-08 | 2007-11-22 | Scolr Pharma, Inc. | Competitive substrate inhibition to increase drug bioavailability |
| WO2008037044A1 (en) * | 2006-09-27 | 2008-04-03 | Medley S.A. Indústria Farmacêutica | Oxcarbazepine-containing oral formulation and a process to obtain the same |
| CN106794986A (en) * | 2014-09-02 | 2017-05-31 | 布平德尔·辛格 | Deuterate or non-deuterate molecule and pharmaceutical preparation |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB0221956D0 (en) * | 2002-09-20 | 2002-10-30 | Novartis Ag | Organic compounds |
| WO2006046105A1 (en) * | 2004-10-25 | 2006-05-04 | Ranbaxy Laboratories Limited | Oxcarbazepine dosage forms |
| CA2603235A1 (en) * | 2005-03-28 | 2006-10-05 | Bioresponse, Llc | Diindolylmethane-based compositions and methods of use thereof for promoting oral mucosal and bone health |
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Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1522140A (en) * | 2001-05-18 | 2004-08-18 | 兰贝克赛实验室有限公司 | Oxcarbazepine dosage forms |
| WO2007011349A1 (en) * | 2005-07-15 | 2007-01-25 | Teva Pharmaceutical Industries Ltd. | Novel granulation process and granulate produced therefrom |
| WO2007133476A2 (en) * | 2006-05-08 | 2007-11-22 | Scolr Pharma, Inc. | Competitive substrate inhibition to increase drug bioavailability |
| WO2008037044A1 (en) * | 2006-09-27 | 2008-04-03 | Medley S.A. Indústria Farmacêutica | Oxcarbazepine-containing oral formulation and a process to obtain the same |
| CN106794986A (en) * | 2014-09-02 | 2017-05-31 | 布平德尔·辛格 | Deuterate or non-deuterate molecule and pharmaceutical preparation |
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