CN113081986A - Cefaclor sustained-release composition and preparation method thereof - Google Patents
Cefaclor sustained-release composition and preparation method thereof Download PDFInfo
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- CN113081986A CN113081986A CN202110436564.XA CN202110436564A CN113081986A CN 113081986 A CN113081986 A CN 113081986A CN 202110436564 A CN202110436564 A CN 202110436564A CN 113081986 A CN113081986 A CN 113081986A
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- 229960005361 cefaclor Drugs 0.000 title claims abstract description 87
- QYIYFLOTGYLRGG-GPCCPHFNSA-N cefaclor Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3C(=C(Cl)CS[C@@H]32)C(O)=O)=O)N)=CC=CC=C1 QYIYFLOTGYLRGG-GPCCPHFNSA-N 0.000 title claims abstract description 86
- 239000000203 mixture Substances 0.000 title claims abstract description 45
- 238000013268 sustained release Methods 0.000 title claims abstract description 27
- 239000012730 sustained-release form Substances 0.000 title claims abstract description 27
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 37
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 28
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 15
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims abstract description 14
- 229930195725 Mannitol Natural products 0.000 claims abstract description 14
- 235000021355 Stearic acid Nutrition 0.000 claims abstract description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 14
- 239000000594 mannitol Substances 0.000 claims abstract description 14
- 235000010355 mannitol Nutrition 0.000 claims abstract description 14
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims abstract description 14
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims abstract description 14
- 239000008117 stearic acid Substances 0.000 claims abstract description 14
- 239000003826 tablet Substances 0.000 claims description 19
- 239000011248 coating agent Substances 0.000 claims description 18
- 238000000034 method Methods 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 238000000576 coating method Methods 0.000 claims description 15
- 238000003756 stirring Methods 0.000 claims description 15
- 238000001035 drying Methods 0.000 claims description 8
- 238000007873 sieving Methods 0.000 claims description 8
- 229920003135 Eudragit® L 100-55 Polymers 0.000 claims description 5
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 238000013270 controlled release Methods 0.000 claims description 2
- 239000007891 compressed tablet Substances 0.000 claims 1
- 239000000463 material Substances 0.000 abstract description 28
- 238000004090 dissolution Methods 0.000 abstract description 15
- 239000003795 chemical substances by application Substances 0.000 abstract description 12
- 239000003405 delayed action preparation Substances 0.000 abstract description 6
- 239000003814 drug Substances 0.000 abstract description 6
- 230000000694 effects Effects 0.000 abstract description 5
- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 3
- 206010067484 Adverse reaction Diseases 0.000 abstract description 2
- 230000006838 adverse reaction Effects 0.000 abstract description 2
- 238000001727 in vivo Methods 0.000 abstract description 2
- 230000002035 prolonged effect Effects 0.000 abstract description 2
- 239000007939 sustained release tablet Substances 0.000 description 43
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 28
- 239000008187 granular material Substances 0.000 description 6
- 239000002994 raw material Substances 0.000 description 6
- 229960004841 cefadroxil Drugs 0.000 description 5
- NBFNMSULHIODTC-CYJZLJNKSA-N cefadroxil monohydrate Chemical compound O.C1([C@@H](N)C(=O)N[C@H]2[C@@H]3N(C2=O)C(=C(CS3)C)C(O)=O)=CC=C(O)C=C1 NBFNMSULHIODTC-CYJZLJNKSA-N 0.000 description 5
- 239000000843 powder Substances 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 238000013461 design Methods 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 239000011253 protective coating Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 241000191967 Staphylococcus aureus Species 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000194017 Streptococcus Species 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- YEFOAORQXAOVJQ-RZFZLAGVSA-N schisandrol a Chemical compound C1[C@H](C)[C@@](C)(O)CC2=CC(OC)=C(OC)C(OC)=C2C2=C1C=C(OC)C(OC)=C2OC YEFOAORQXAOVJQ-RZFZLAGVSA-N 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 239000004925 Acrylic resin Substances 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 241000304886 Bacilli Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 241000192125 Firmicutes Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- 241000588747 Klebsiella pneumoniae Species 0.000 description 1
- 108010087702 Penicillinase Proteins 0.000 description 1
- 241000191963 Staphylococcus epidermidis Species 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000002671 adjuvant Substances 0.000 description 1
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 description 1
- 229960000723 ampicillin Drugs 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 238000012512 characterization method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002354 daily effect Effects 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 229940047650 haemophilus influenzae Drugs 0.000 description 1
- 230000002949 hemolytic effect Effects 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000003999 initiator Substances 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 230000002147 killing effect Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229940124588 oral cephalosporin Drugs 0.000 description 1
- 229950009506 penicillinase Drugs 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 230000001360 synchronised effect Effects 0.000 description 1
- 238000012795 verification Methods 0.000 description 1
- YEFOAORQXAOVJQ-UHFFFAOYSA-N wuweizischun A Natural products C1C(C)C(C)(O)CC2=CC(OC)=C(OC)C(OC)=C2C2=C1C=C(OC)C(OC)=C2OC YEFOAORQXAOVJQ-UHFFFAOYSA-N 0.000 description 1
- 229910052727 yttrium Inorganic materials 0.000 description 1
- VWQVUPCCIRVNHF-UHFFFAOYSA-N yttrium atom Chemical compound [Y] VWQVUPCCIRVNHF-UHFFFAOYSA-N 0.000 description 1
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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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
-
- 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
-
- 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
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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
- A61K9/2853—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers, poly(lactide-co-glycolide)
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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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a cefaclor sustained-release composition and a preparation method thereof, belonging to the technical field of medicine preparation. The cefaclor sustained-release composition comprises the following components in parts by weight: 375 parts of cefaclor, 28-35 parts of mannitol, 90-130 parts of HPMC and/or HPC, 100-555-20 parts of Eiteqi L, 2-5 parts of stearic acid and 1-5 parts of magnesium stearate. The cefaclor sustained-release composition has high fitting degree with a reference agent Hicliro dissolution curve, does not produce burst release in alcohol, and has biological equivalence with the reference agent Hicliro. Because the sustained-release preparation is adopted, the administration times can be reduced, and the enteric material is applied, the in vivo release is prolonged to the intestinal tract, and the adverse reaction of the medicine to the gastrointestinal tract is reduced, thereby improving the compliance of patients, further improving the curative effect and having important medical value.
Description
Technical Field
The invention belongs to the technical field of medicine preparation, and particularly relates to a cefaclor sustained-release composition and a preparation method thereof.
Background
The cefaclor sustained-release preparation belongs to the second generation oral cephalosporin and has strong killing effect on various gram-positive bacteria and gram-negative bacteria. The activity on penicillinase-producing staphylococcus aureus, group A hemolytic streptococcus, viridans streptococcus and staphylococcus epidermidis is the same as that of cefadroxil, and the antibacterial effect on non-enzyme-producing staphylococcus aureus and pneumococcus is 2-4 times stronger than that of cefadroxil. The activity to gram-negative bacilli including Escherichia coli and Klebsiella pneumoniae is stronger than cefadroxil, similar to cefadroxil, and stronger than cefadroxil. The cefaclor sustained-release preparation with the concentration of 2.9-8 mg/L can inhibit all haemophilus influenzae, including ampicillin-resistant strains.
CN102028667A discloses a cefaclor sustained release tablet (/ preparation) and a preparation method thereof; the dispersible sustained-release preparation using sodium carboxymethyl starch as a disintegrant and HPMC as a framework material is easy to cause burst release of the medicament because the sustained-release preparation needs to use the disintegrant to erode the framework and then diffuse.
CN101897678A discloses a cefaclor sustained-release composition, which takes acrylic resin as a retardant, takes HPMC with high viscosity as a framework material, and similarly takes sodium carboxymethyl starch as a disintegrant, which is required to be completely released in 4-8 hours; the release profile of the reference agent which cumulatively reaches a release of more than 90% over 4 hours (see the schild release).
The compositions and the preparation processes disclosed in the prior art all use high-viscosity materials as frameworks, the release target does not meet the requirement of the Xilao design of a reference agent, the medicament is released in a delayed manner at a low pH position and is completely released at the upper end of a small intestine to achieve the aim of maintaining the therapeutic blood concentration to a certain degree, and the problems that the release time is too long and the aim of maintaining the therapeutic blood concentration cannot be achieved exist.
Disclosure of Invention
In order to solve at least one of the above technical problems, the technical solution provided by the present invention is as follows:
the invention provides a cefaclor sustained-release composition in a first aspect, which comprises the following components in parts by weight: 375 parts of cefaclor, 28-35 parts of mannitol, 90-130 parts of HPMC and/or HPC, 100-555-20 parts of Eiteqi L, 2-5 parts of stearic acid and 1-5 parts of magnesium stearate.
In the invention, the HPMC is selected from at least one of HPMC-E5, HPMC-E50, HPMC-K4, HPMC-K15 and HPMC-K100. Further, the HPMC is of a low viscosity type (LV), a high molecular weight type (M), or a controlled release type (CR).
In some embodiments of the invention, the HMPC is selected from at least one of HPMC-E5, HPMC-E50 and HPMC-K100, preferably the HMPC is of the low viscosity type.
In some embodiments of the invention, the HPMC is HPMC-E5; in other embodiments of the invention, the HPMC is HPMC-E50; in still other embodiments of the present invention, the HPMC is HPMC-K100. In some preferred embodiments of the invention, the HPMC are HPMC-E50 and HPMC-K100 LV.
In the present invention, the HPC is selected from at least one of HPC-HXF, HPC-MXF, HPC-GXF, HPC-JXF, HPC-LXF, HPC-EXF and HPC-ELF.
In some embodiments of the invention, the HPC is HPC-HXF.
In some embodiments of the invention, the cefaclor sustained-release composition comprises cefaclor 375 parts, mannitol 30 parts, HPMC-E5073.2 parts, HPC-HXF 50 parts, Eiteqi L100-5519.4 parts, stearic acid 3.5 parts, and magnesium stearate 2.5 parts.
In other embodiments of the present invention, the cefaclor sustained-release composition comprises 375 parts of cefaclor, 30 parts of mannitol, 534 parts of HPMC-E, 61.3 parts of HPC-HXF, 100-557.5 parts of Yttrium L, 4 parts of stearic acid and 3 parts of magnesium stearate.
In still other embodiments of the present invention, the cefaclor sustained-release composition comprises cefaclor 375 parts, mannitol 30 parts, HPMC-K100LV 76.6.6 parts, HPMC-E5021.5 parts, Eiteqi L100-557.1 parts, stearic acid 3.2 parts, and magnesium stearate 2.1 parts.
In some embodiments of the present invention, the cefaclor sustained-release composition further comprises 15-20 parts of a coating agent. In some embodiments of the invention, the coating agent is an opadry blue coating powder.
A second aspect of the present invention provides a process for the preparation of a cefaclor sustained release composition as defined in the first aspect of the present invention, comprising the steps of:
s1, sieving cefaclor, mannitol, HPMC and/or HPC respectively, and mixing to obtain a first mixture;
s2, dissolving the Eudragit L100-55 in ethanol, and slowly stirring until the solution is completely dissolved and clarified to obtain a first solution;
s3, adding the first mixture obtained in the step S1 into a granulator, stirring for 1-5min, adding the first solution obtained in the step S2 into the granulator, and continuing stirring for 1-5min to obtain a second mixture;
s4, drying the second mixture obtained in the step S3 until the water content is lower than 4%;
s5, adding stearic acid and magnesium stearate into the second mixture dried in the step S5, and mixing to obtain the cefaclor sustained-release composition.
In some embodiments of the invention, in step S3, the first solution is added in atomized form to a granulator. In some preferred embodiments of the invention, the first solution is added to the granulator in its entirety within 2 min.
In some embodiments of the invention, further comprising:
s6, tabletting the cefaclor sustained-release composition on a tablet press.
In some embodiments of the invention, further comprising:
and S7, coating the tablet compressed in the step S6.
The invention has the advantages of
Compared with the prior art, the invention has the following beneficial effects:
the cefaclor sustained-release composition has high fitting degree with a reference agent, namely a Schizochralski dissolution curve, and has very high fitting degree in a hydrochloric acid medium or a hydrochloric acid medium containing ethanol.
The cefaclor sustained-release composition has biological equivalence with a reference agent of Schizochralski, and can be used for replacing the Schizochralski.
The cefaclor sustained-release composition is a sustained-release preparation, can make up the defect of more daily administration times of patients, reduces the administration times, can keep stable and effective blood concentration only by taking the composition orally twice every day and one tablet at a time, and adopts enteric-coated materials, so that the in-vivo release is prolonged to the intestinal part, the adverse reaction of the medicine to the gastrointestinal tract is reduced, the compliance of the patients is improved, and the curative effect is further improved.
The cefaclor sustained-release composition does not cause the possibility of burst release in alcohol and has higher safety.
Drawings
FIG. 1 shows the dissolution profiles of cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 of the present invention in a 0.1mol/L hydrochloric acid medium.
FIG. 2 shows the dissolution profiles of cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 of the present invention in a 0.1mol/L hydrochloric acid medium containing 5% ethanol.
FIG. 3 shows the dissolution profiles of cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 of the present invention in a 0.1mol/L hydrochloric acid medium containing 20% ethanol.
FIG. 4 shows the dissolution profiles of cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 of the present invention in a 0.1mol/L hydrochloric acid medium containing 40% ethanol.
Fig. 5 shows the pharmacokinetics of cefaclor in plasma of subjects after taking respectively the cefaclor sustained release tablet (/) #1(T) prepared in example 1 of the present invention and the reference formulation schildol (R).
Detailed Description
Unless otherwise indicated, implied from the context, or customary in the art, all parts and percentages herein are by weight and the testing and characterization methods used are synchronized with the filing date of the present application. Where applicable, the contents of any patent, patent application, or publication referred to in this application are incorporated herein by reference in their entirety and their equivalent family patents are also incorporated by reference, especially as they disclose definitions relating to synthetic techniques, products and process designs, polymers, comonomers, initiators or catalysts, and the like, in the art. To the extent that a definition of a particular term disclosed in the prior art is inconsistent with any definitions provided herein, the definition of the term provided herein controls.
The numerical ranges in this application are approximations, and thus may include values outside of the ranges unless otherwise specified. A numerical range includes all numbers from the lower value to the upper value, in increments of 1 unit, provided that there is a separation of at least 2 units between any lower value and any higher value. For example, if a compositional, physical, or other property (e.g., molecular weight, melt index, etc.) is recited as 100 to 1000, it is intended that all individual values, e.g., 100, 101, 102, etc., and all subranges, e.g., 100 to 166, 155 to 170, 198 to 200, etc., are explicitly recited. For ranges containing a numerical value less than 1 or containing a fraction greater than 1 (e.g., 1.1, 1.5, etc.), then 1 unit is considered appropriate to be 0.0001, 0.001, 0.01, or 0.1. For ranges containing single digit numbers less than 10 (e.g., 1 to 5), 1 unit is typically considered 0.1. These are merely specific examples of what is intended to be expressed and all possible combinations of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application.
In addition, unless explicitly stated otherwise, the use of the terms "a", "an" or "the" are intended to include the plural forms thereof. The terms "comprising," "including," "having," and derivatives thereof do not exclude the presence of any other component, step or procedure, and are not intended to exclude the presence of other elements, steps or procedures not expressly disclosed herein. To the extent that any doubt is eliminated, all compositions herein containing, including, or having the term "comprise" may contain any additional additive, adjuvant, or compound, unless expressly stated otherwise. Rather, the term "consisting essentially of … …" excludes any other components, steps or processes from the scope of any of the terms hereinafter recited, insofar as such terms are necessary for performance. The term "consisting of … …" does not include any components, steps or processes not specifically described or listed. Unless explicitly stated otherwise, the term "or" refers to the listed individual members or any combination thereof.
In order to make the technical problems, technical solutions and advantageous effects solved by the present invention more apparent, the present invention is further described in detail below with reference to the following embodiments.
Examples
The following examples are used herein to demonstrate preferred embodiments of the invention. It will be appreciated by those of skill in the art that the techniques disclosed in the examples which follow represent techniques discovered by the inventor to function in the invention, and thus can be considered to constitute preferred modes for its practice. Those of skill in the art should, in light of the present disclosure, appreciate that many changes can be made in the specific embodiments which are disclosed and still obtain a like or similar result without departing from the spirit or scope of the invention.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs and the disclosures and references cited herein and the materials to which they refer are incorporated by reference.
Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments of the invention described herein. Such equivalents are intended to be encompassed by the following claims.
The experimental methods not specifically described in the following examples are conventional methods unless otherwise specified. The instruments used in the following examples are, unless otherwise specified, laboratory-standard instruments; the test materials used in the following examples were purchased from a conventional biochemical reagent store unless otherwise specified.
Example 1 Cefaclor sustained release tablet (/) #1 and method of making the same
This example provides a cefaclor sustained release tablet (/) #1 as a tablet, comprising per 1000 tablets as follows:
| composition (I) | Content (g) | Function(s) |
| Cefaclor | 375 | 73.26％ |
| Mannitol | 30 | 5.86％ |
| HPMC-E50 | 73.2 | 10.28％ |
| HPC- |
50 | 8.13％ |
| Youteqi L100-55 | 19.4 | 1.31％ |
| Stearic acid | 3.5 | 0.68％ |
| Magnesium stearate | 2.5 | 0.49％ |
| Total weight of tablet | 512 | |
| Opadry blue coating powder | 16 | 3.12％ |
The preparation method of the cefaclor sustained release tablet (/) #1 comprises the following steps: sieving raw materials and auxiliary materials, weighing, mixing, granulating, drying, tabletting, coating and the like. The specific process steps are as follows:
step 1: sieving cefaclor raw material, HPC-HXF, HPMC-E50 and mannitol respectively, mixing, and storing;
step 2: dissolving the Eudragit L100-55 in ethanol, slowly stirring until the solution is completely dissolved and clarified, and keeping for later use;
and step 3: pouring the uniformly mixed materials in the step 1 into a granulator, and stirring for 3 minutes;
and 4, step 4: adding the enteric material solution in the step 2 into the continuously mixed material of the granulator in the step 3 in an atomizing mode, finishing the adding within 2 minutes, continuously stirring for 3 minutes, and then starting a cutter for 1 minute;
and 5: taking the materials in the step 4 out of the pot, drying, and controlling the water content of the materials to be lower than 3.8%;
step 6: adding stearic acid, magnesium stearate and HPMC-50 into the dried granules obtained in the step 5 for total mixing, and determining the mixing uniformity until the granules are qualified;
step 7, transferring the material in the step 5 to a tablet press for tabletting;
and 8, transferring the uncoated plain tablets obtained in the step 7 to a high-efficiency coating machine for conventional film protective coating, wherein the coating weight is increased by about 3.12%.
Example 2 Cefaclor sustained release tablet (/) #2 and method of making
This example provides a cefaclor sustained release tablet (/) #2 as a tablet, comprising per 1000 tablets as follows:
| composition (I) | Content (g) | Function(s) |
| Cefaclor | 375 | 72.84％ |
| Mannitol | 30 | 5.83％ |
| HPMC-E5 | 34 | 6.60％ |
| HPC-HXF | 61.3 | 11.91％ |
| Youteqi L100-55 | 7.5 | 1.46％ |
| Stearic acid | 4 | 0.78％ |
| Magnesium stearate | 3 | 0.58％ |
| Total weight of tablet | 514.8 | |
| Opadry blue coating powder | 16 | 3.12％ |
The preparation method of the cefaclor sustained release tablet (/) #2 comprises the following steps: sieving raw materials and auxiliary materials, weighing, mixing, granulating, drying, tabletting, coating and the like. The specific process steps are as follows:
step 1: sieving cefaclor raw material, HPC-HXF, HPMC-E50 and mannitol respectively, mixing, and storing;
step 2: dissolving the Eudragit L100-55 in ethanol, slowly stirring until the solution is completely dissolved and clarified, and keeping for later use;
and step 3: pouring the uniformly mixed materials in the step 1 into a granulator, and stirring for 3 minutes;
and 4, step 4: adding the enteric material solution in the step 2 into the continuously mixed material of the granulator in the step 3 in an atomizing mode, finishing the adding within 2 minutes, continuously stirring for 3 minutes, and then starting a cutter for 1 minute;
and 5: taking the materials in the step 4 out of the pot, drying, and controlling the water content of the materials to be lower than 3.8%;
step 6: adding stearic acid, magnesium stearate and HPMC-50 into the dried granules obtained in the step 5 for total mixing, and determining the mixing uniformity until the granules are qualified;
step 7, transferring the material in the step 5 to a tablet press for tabletting;
and 8, transferring the uncoated plain tablets obtained in the step 7 to a high-efficiency coating machine for conventional film protective coating, wherein the coating weight is increased by about 3.12%.
Example 3 Cefaclor sustained release tablet (/) #3 and method of making the same
This example provides a cefaclor sustained release tablet (/) #3 as a tablet, comprising per 1000 tablets as follows:
| composition (I) | Content (g) | Function(s) |
| Cefaclor | 375 | 72.74％ |
| Mannitol | 30 | 5.82％ |
| HPMC-K100LV | 76.6 | 14.86％ |
| HPMC-E50 | 21.5 | 4.17％ |
| Youteqi L100-55 | 7.1 | 1.38％ |
| Stearic acid | 3.2 | 0.62％ |
| Magnesium stearate | 2.1 | 0.41％ |
| Total weight of tablet | 515.5 | |
| Opadry blue coating powder | 16 | 3.12％ |
The preparation method of the cefaclor sustained release tablet (/) #3 comprises the following steps: sieving raw materials and auxiliary materials, weighing, mixing, granulating, drying, tabletting, coating and the like. The specific process steps are as follows:
step 1: sieving cefaclor raw material, HPC-HXF, HPMC-E50 and mannitol respectively, mixing, and storing;
step 2: dissolving the Eudragit L100-55 in ethanol, slowly stirring until the solution is completely dissolved and clarified, and keeping for later use;
and step 3: pouring the uniformly mixed materials in the step 1 into a granulator, and stirring for 3 minutes;
and 4, step 4: adding the enteric material solution in the step 2 into the continuously mixed material of the granulator in the step 3 in an atomizing mode, finishing the adding within 2 minutes, continuously stirring for 3 minutes, and then starting a cutter for 1 minute;
and 5: taking the materials in the step 4 out of the pot, drying, and controlling the water content of the materials to be lower than 3.8%;
step 6: adding stearic acid, magnesium stearate and HPMC-50 into the dried granules obtained in the step 5 for total mixing, and determining the mixing uniformity until the granules are qualified;
step 7, transferring the material in the step 5 to a tablet press for tabletting;
and 8, transferring the uncoated plain tablets obtained in the step 7 to a high-efficiency coating machine for conventional film protective coating, wherein the coating weight is increased by about 3.12%.
Example 4 examples 1-3 dissolution Properties of Cefaclor sustained Release tablets/
The cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (//# 2 and cefaclor sustained release tablets (//# 3) prepared in examples 1-3 were compared in terms of dissolution performance with respect to the reference agent, schizandrol (ritex).
First, the dissolution curves of cefaclor sustained-release tablets (/) #1, cefaclor sustained-release tablets (/) #2 and cefaclor sustained-release tablets (/) #3 and a reference agent, schidilao, in a 0.1mol/L hydrochloric acid medium containing 5% ethanol, in a 0.1mol/L hydrochloric acid medium containing 20% ethanol and in a 0.1mol/L hydrochloric acid medium containing 40% ethanol were measured by high performance liquid chromatography, respectively, and the results are shown in FIGS. 1 to 4, respectively.
The results showed that the dissolution curve fitness of the cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 and the reference agent, schizandrol, in 0.1mol/L hydrochloric acid medium, respectively, were: 80.4, 74.8 and 66.7; the fit of the dissolution curves in a 0.1mol/L hydrochloric acid medium containing 5% ethanol were: 85.5, 69.9 and 78.1; the fit of the dissolution curves in a 0.1mol/L hydrochloric acid medium containing 20% ethanol were: 77.3, 76.4 and 62.3; the fit of the dissolution curves in a 0.1mol/L hydrochloric acid medium containing 40% ethanol were: 85.7, 62.1 and 69.2.
Therefore, the dissolution curve fitting degree of the cefaclor sustained release tablet (/) #1 of the invention and the reference agent Cichlo in different mediums is higher than that of the cefaclor sustained release tablet (/) #2 and the cefaclor sustained release tablet (/ # 3). Except in a 0.1mol/L hydrochloric acid medium containing 5% ethanol, the dissolution curve of the cefaclor sustained release tablet (/) #2 and a reference agent have higher fitting degree.
Also, the cefaclor sustained release tablets (/ /) #1, cefaclor sustained release tablets (/ /) #2 and cefaclor sustained release tablets (/ /) #3 prepared in examples 1-3 did not cause possibility of burst release in alcohol (ethanol), and had higher safety.
EXAMPLE 5 bioequivalence of Cefaclor sustained release tablet/prepared in example 1
Bioequivalence verification was performed using the cefaclor sustained release tablet (/) #1 prepared in example 1 and schizandra as a reference.
Bioequivalence test Using a two-cycle self-crossover design, 12 male healthy volunteers were randomly divided into A, B groups, group A taking the test formulation-cefaclor sustained release tablet (/) #3(T) for the first time, group B taking the reference formulation Symphoni (R) for the first time, and one week later crossover.
The results are shown in FIG. 5, demonstrating the bioequivalence of the invention and the reference agent.
All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.
Claims (10)
1. The cefaclor sustained-release composition is characterized by comprising the following components in parts by weight: 375 parts of cefaclor, 28-35 parts of mannitol, 90-130 parts of HPMC and/or HPC, 100-555-20 parts of Eiteqi L, 2-5 parts of stearic acid and 1-5 parts of magnesium stearate.
2. The cefaclor sustained-release composition as claimed in claim 1, wherein said HPMC is at least one selected from HPMC-E5, HPMC-E50, HPMC-K4, HPMC-K15 and HPMC-K100.
3. The cefaclor sustained-release composition according to claim 2, wherein HPMC is of low viscosity, high molecular weight or controlled release type.
4. The cefaclor sustained-release composition according to claim 1, wherein the HPC is at least one selected from the group consisting of HPC-HXF, HPC-MXF, HPC-GXF, HPC-JXF, HPC-LXF, HPC-EXF and HPC-ELF.
5. The cefaclor sustained-release composition according to any one of claims 1-4, further comprising 15-20 parts of a coating agent.
6. A process for the preparation of a cefaclor sustained release composition as claimed in claim 1, comprising the steps of:
s1, sieving cefaclor, mannitol, HPMC and/or HPC respectively, and mixing to obtain a first mixture;
s2, dissolving the Eudragit L100-55 in ethanol, and slowly stirring until the solution is completely dissolved and clarified to obtain a first solution;
s3, adding the first mixture obtained in the step S1 into a granulator, stirring for 1-5min, adding the first solution obtained in the step S2 into the granulator, and continuing stirring for 1-5min to obtain a second mixture;
s4, drying the second mixture obtained in the step S3 until the water content is lower than 4%;
s5, adding stearic acid and magnesium stearate into the second mixture dried in the step S5, and mixing to obtain the cefaclor sustained-release composition.
7. The method of claim 6, wherein the first solution is added in an atomized form to the granulator in step S3.
8. The method of claim 7, wherein the first solution is added to the granulator in its entirety within 2 min.
9. The method of any one of claims 6 to 8, further comprising:
s6, tabletting the cefaclor sustained-release composition on a tablet press.
10. The method of manufacturing according to claim 9, further comprising:
and S7, coating the compressed tablet.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968508A (en) * | 1987-02-27 | 1990-11-06 | Eli Lilly And Company | Sustained release matrix |
| CN102579319A (en) * | 2011-01-14 | 2012-07-18 | 海南康虹医药科技开发有限公司 | Slow release composition with cefaclor |
-
2021
- 2021-04-22 CN CN202110436564.XA patent/CN113081986B/en active Active
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4968508A (en) * | 1987-02-27 | 1990-11-06 | Eli Lilly And Company | Sustained release matrix |
| CN102579319A (en) * | 2011-01-14 | 2012-07-18 | 海南康虹医药科技开发有限公司 | Slow release composition with cefaclor |
Non-Patent Citations (2)
| Title |
|---|
| 尹莉芳等: "影响头孢克罗缓释片释药因素的研究", 《中国药科大学学报》 * |
| 王淼等: "羟丙甲纤维素对头孢克洛缓释片释放度的影响", 《中国生化药物杂志》 * |
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Denomination of invention: A sustained-release cefaclor combination and its preparation method Granted publication date: 20220429 Pledgee: Hangzhou United Rural Commercial Bank Co.,Ltd. Xiasha sub branch Pledgor: Hangzhou Hongyou Pharmaceutical Technology Co.,Ltd. Registration number: Y2024980012466 |
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