CN1839871A - Azithromycin enteric coated microsphere and preparation method thereof - Google Patents
Azithromycin enteric coated microsphere and preparation method thereof Download PDFInfo
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- CN1839871A CN1839871A CN200610037717.9A CN200610037717A CN1839871A CN 1839871 A CN1839871 A CN 1839871A CN 200610037717 A CN200610037717 A CN 200610037717A CN 1839871 A CN1839871 A CN 1839871A
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- azithromycin
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- 229960004099 azithromycin Drugs 0.000 title claims abstract description 78
- MQTOSJVFKKJCRP-BICOPXKESA-N azithromycin Chemical compound O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)N(C)C[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 MQTOSJVFKKJCRP-BICOPXKESA-N 0.000 title claims abstract description 78
- 239000004005 microsphere Substances 0.000 title claims abstract description 40
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 239000000463 material Substances 0.000 claims abstract description 38
- 239000004014 plasticizer Substances 0.000 claims abstract description 23
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 7
- 229920000642 polymer Polymers 0.000 claims abstract 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- 238000001694 spray drying Methods 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 19
- 238000000034 method Methods 0.000 claims description 15
- 229920001577 copolymer Polymers 0.000 claims description 12
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 9
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 239000000741 silica gel Substances 0.000 claims description 9
- 229910002027 silica gel Inorganic materials 0.000 claims description 9
- 230000008569 process Effects 0.000 claims description 6
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000002253 acid Substances 0.000 claims description 5
- 229920002678 cellulose Polymers 0.000 claims description 5
- 235000010980 cellulose Nutrition 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 4
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- -1 carboxymethyl ethyl Chemical group 0.000 claims description 3
- 229920002301 cellulose acetate Polymers 0.000 claims description 3
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 239000002861 polymer material Substances 0.000 claims 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 claims 2
- 239000011347 resin Substances 0.000 claims 2
- 229920005989 resin Polymers 0.000 claims 2
- 239000001856 Ethyl cellulose Substances 0.000 claims 1
- 239000000853 adhesive Substances 0.000 claims 1
- 230000000181 anti-adherent effect Effects 0.000 claims 1
- 239000004359 castor oil Substances 0.000 claims 1
- 235000019438 castor oil Nutrition 0.000 claims 1
- 238000001035 drying Methods 0.000 claims 1
- 150000002148 esters Chemical class 0.000 claims 1
- 235000019325 ethyl cellulose Nutrition 0.000 claims 1
- 229920001249 ethyl cellulose Polymers 0.000 claims 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims 1
- 125000005591 trimellitate group Chemical group 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 12
- 239000000203 mixture Substances 0.000 abstract description 9
- 230000000844 anti-bacterial effect Effects 0.000 abstract description 4
- 235000019658 bitter taste Nutrition 0.000 abstract description 3
- 229940079593 drug Drugs 0.000 abstract description 3
- 210000004051 gastric juice Anatomy 0.000 abstract description 3
- 238000010521 absorption reaction Methods 0.000 abstract description 2
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- 210000001035 gastrointestinal tract Anatomy 0.000 abstract description 2
- 239000000825 pharmaceutical preparation Substances 0.000 abstract description 2
- 230000004936 stimulating effect Effects 0.000 abstract 1
- 229920002521 macromolecule Polymers 0.000 description 26
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 22
- 238000005303 weighing Methods 0.000 description 17
- 230000000968 intestinal effect Effects 0.000 description 15
- 239000012530 fluid Substances 0.000 description 13
- 239000003960 organic solvent Substances 0.000 description 8
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 7
- 239000002775 capsule Substances 0.000 description 7
- ULGZDMOVFRHVEP-RWJQBGPGSA-N Erythromycin Chemical group O([C@@H]1[C@@H](C)C(=O)O[C@@H]([C@@]([C@H](O)[C@@H](C)C(=O)[C@H](C)C[C@@](C)(O)[C@H](O[C@H]2[C@@H]([C@H](C[C@@H](C)O2)N(C)C)O)[C@H]1C)(C)O)CC)[C@H]1C[C@@](C)(OC)[C@@H](O)[C@H](C)O1 ULGZDMOVFRHVEP-RWJQBGPGSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- 239000003120 macrolide antibiotic agent Substances 0.000 description 4
- 229960003276 erythromycin Drugs 0.000 description 3
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 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 description 3
- 208000015181 infectious disease Diseases 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- YHVUVJYEERGYNU-UHFFFAOYSA-N 4',8-Di-Me ether-5,7,8-Trihydroxy-3-(4-hydroxybenzyl)-4-chromanone Natural products COC1(C)CC(O)OC(C)C1O YHVUVJYEERGYNU-UHFFFAOYSA-N 0.000 description 2
- 230000000845 anti-microbial effect Effects 0.000 description 2
- 230000008901 benefit Effects 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- AJSDVNKVGFVAQU-BIIVOSGPSA-N cladinose Chemical compound O=CC[C@@](C)(OC)[C@@H](O)[C@H](C)O AJSDVNKVGFVAQU-BIIVOSGPSA-N 0.000 description 2
- 238000004132 cross linking Methods 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 230000000638 stimulation Effects 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 206010000087 Abdominal pain upper Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 206010059866 Drug resistance Diseases 0.000 description 1
- 241000588914 Enterobacter Species 0.000 description 1
- 241000588724 Escherichia coli Species 0.000 description 1
- 206010070840 Gastrointestinal tract irritation Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000001828 Gelatine Substances 0.000 description 1
- 102000002067 Protein Subunits Human genes 0.000 description 1
- 108010001267 Protein Subunits Proteins 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 230000009471 action Effects 0.000 description 1
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- 238000003556 assay Methods 0.000 description 1
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- 238000005516 engineering process Methods 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
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- 239000008273 gelatin Substances 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 239000007791 liquid phase Substances 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002572 peristaltic effect Effects 0.000 description 1
- 210000001539 phagocyte Anatomy 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 210000002345 respiratory system Anatomy 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及药物制剂领域，具体涉及阿奇霉素肠溶微球及其制备方法。其特征是由阿奇霉素、高分子肠溶材料、抗粘剂和增塑剂组成。以上组成优选的重量百分比为阿奇霉素8～32％，高分子肠溶材料28～60％，抗粘剂15～34％和增塑剂5～25％；本发明掩蔽了阿奇霉素的苦味，减少了阿奇霉素在胃液中的释放，避免了其对胃粘膜的刺激作用，使其在肠道内溶解、释放，从而提高药物的吸收速度，提高其生物利用度，发挥更好的抗菌作用。The invention relates to the field of pharmaceutical preparations, in particular to azithromycin enteric-coated microspheres and a preparation method thereof. It is characterized by the composition of azithromycin, polymer enteric material, anti-tacking agent and plasticizer. The preferred weight percentage of the above composition is 8-32% of azithromycin, 28-60% of polymer enteric material, 15-34% of anti-sticking agent and 5-25% of plasticizer; the present invention masks the bitter taste of azithromycin and reduces the The release in the gastric juice avoids its stimulating effect on the gastric mucosa, and makes it dissolve and release in the intestinal tract, thereby increasing the absorption rate of the drug, improving its bioavailability, and exerting a better antibacterial effect.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to Azithromycin enteric casing microsphere and preparation method thereof.
Background technology
Azithromycin (Azithronycin) is a kind of Macrolide broad ectrum antibiotic that the erythromycin structure obtains after modified, mainly by suppressing the synthetic antibacterial action that reaches of ribosome 50s protein subunit matter in the bacterial cell.Be widely used at present the infection of gastrointestinal tract, genito-urinary system, respiratory tract and others, curative effect is obvious, is not prone to drug resistance.Absorb rapidly behind the azithromycin oral, can be distributed in the many organs and tissues of whole body rapidly, make tissue concentration be higher than 10～100 times of blood concentrations, and sustainable several days.Azithromycin can also be absorbed rapidly by phagocyte simultaneously, is carried into infection site, makes infection site concentration higher, has unique pharmacokinetic characteristics and broad-spectrum antibacterial activity.This medicine has also that effect is strong in addition, long half time, antimicrobial spectrum be than advantages such as erythromycin are wide, except the antimicrobial spectrum of erythromycin, can also suppress the escherichia coli of multiple aerobic and anaerobism gram-positive cocci, especially hemophilus influenza and Enterobacter.Therefore, azithromycin is at present domestic and international clinical quite valued broad spectrum antibiotic.
The existing peroral dosage form of azithromycin has granule, dispersible tablet, capsule, powder, dry suspension and syrup.But macrolide antibiotics and capsule shells produce the crosslinked action with chemical reaction, make the amino generation cross-linking reaction in the gelatin of azithromycin and capsule shells kind, change the dissolubility of gelatine capsule shell, make the azithromycin capsule agent not meet quality standard at external dissolubility.Azithromycin belongs to macrolide antibiotics in addition, and this class medicine mouthfeel is extremely bitter, and ubiquity the side effect of GI irritation, untoward reaction the most common for feel sick, untoward reaction such as diarrhoea, stomachache, dizziness.Recent research also shows, azithromycin is degraded 68% in 30 minutes in the 0.1mol/L hydrochloric acid solution, and this shows that azithromycin is unstable in gastric juice, and degradation speed is fast, medicine under one's belt major part be damaged, obviously influence clinical efficacy.According to another bibliographical information, behind the oral azithromycin, be degraded to the amount of taking off the cladinose azithromycin and be about about 15% of dosage, and behind the azithromycin of intravenous injection Isodose, take off the cladinose azithromycin the quantity not sufficient dosage 0.5%, further proved the destruction of gastric acid to azithromycin, cause the bioavailability of azithromycin common oral preparation lower, bibliographical information only is between 37～46%, thereby has influenced the clinical efficacy of azithromycin.
Though reported some enteric coated preparation in the prior art about azithromycin, there are problems such as intravital bioavailability is lower, onset slow, the pharmaceutical adjunct consumption is big, and taking dose is bigger usually in disclosed enteric coated preparation in that but discovery is used at present and the prior art.At present still need a kind of new enteric coated preparation that azithromycin is discharged rapidly at enteral, improve the infiltration rate of medicine, reduce dosage, the shortening medicine improves bioavailability to the onset time of patient part.
Summary of the invention
The objective of the invention is at the problems referred to above, provide a kind of and can improve patient's medication compliance, reduce medicine to gastric stimulation, avoid stomach acids destroy, shelter the bitterness of azithromycin, the Azithromycin enteric casing microsphere that make that medicine dissolves rapidly at intestinal, release, absorption, bioavailability is significantly improved, and enteric-coated microsphere that can suitability for industrialized production.
The invention discloses a kind of Azithromycin enteric casing microsphere, it is made up of azithromycin, macromolecule enteric material, antiplastering aid and plasticizer.More than forming preferred percentage by weight is azithromycin 8～32%, macromolecule enteric material 28～60%, antiplastering aid 15～34% and plasticizer 5～25%; Preferred percentage by weight is an azithromycin 10～24%, macromolecule enteric material 40～48%, antiplastering aid 18～32% and plasticizer 10～22%.
Macromolecule enteric material of the present invention is preferably resinae or cellulose family macromolecule material.In wherein said resinae macromolecular material preferable methyl acrylic acid-methylmethacrylate copolymer (the strange L100 of You Te), the methacrylic acid-methylmethacrylate copolymer (the strange S100 of You Te) one or both and above mixture.Described cellulose family macromolecule material is selected from one or both and the above mixture in Hydroxypropyl Methylcellulose Phathalate (HPMCP) or cellulose acetate-phthalate (CAP), the carboxylic first and second basic celluloses (CMEC), the cellulose acetate benzenetricarboxylic acid ester (CAT).More preferably methacrylic acid-methylmethacrylate copolymer (the strange L100 of You Te), methacrylic acid-methylmethacrylate copolymer (the strange S100 of You Te) or its mixture, preferred equal proportion mixture.
The mixture of one or both materials in the preferred micropowder silica gel of antiplastering aid of the present invention, magnesium stearate or the Pulvis Talci, more preferably micropowder silica gel.Antiplastering aid effect in the present invention is the generation that reduces wall sticking phenomenon in spray-drying process, improves the flowability of Azithromycin enteric casing microsphere, and improves its yield.
Plasticizer is preferably from Oleum Ricini, glycerol, Polyethylene Glycol or diethyl phthalate, more preferably Oleum Ricini.The adding plasticizer can increase the plasticity of Azithromycin enteric casing microsphere, improves its pliability, avoids the broken phenomenon of Azithromycin enteric casing microsphere to take place, and improves its yield.
The preparation method of Azithromycin enteric casing microsphere of the present invention comprises: the macromolecule enteric material is dissolved in acetone, ethanol or the methanol equal solvent, and the concentration of ethanol, methanol is preferred 80～95%, preferred 95% ethanol water.Get azithromycin and be dissolved in the macromolecule enteric material solution, add plasticizer and stir; Add an amount of antiplastering aid again, under stirring condition, carry out spray drying and promptly get enteric-coated microsphere.
The concentration of macromolecule enteric material is controlled at 1.5～2.5% during preparation, and preferred 2%.Too rare as concentration, then the enteric material balling-up is very difficult, is difficult to the medicine azithromycin is wrapped up into, and is too big as concentration, then more serious the and easy plug nozzle of wall sticking phenomenon when spray drying.
The amount of antiplastering aid and plasticizer controls that effect is better within the scope of the invention, and amount has been lacked and do not reached anti-stick and plastifying purpose, too many content of dispersion that can the reduction Azithromycin enteric casing microsphere.
Preparation method of the present invention is to adopt the spray drying method for preparation Azithromycin enteric casing microsphere.
The process conditions of spray drying method of the present invention are preferably: inlet temperature is controlled at 70 ℃～90 ℃, leaving air temp is controlled at 50 ℃～70 ℃, charging rate: 20ml/min, throughput 600nl/h, wherein best inlet temperature is controlled at 80 ± 2 ℃, and best leaving air temp is controlled at 65 ± 2 ℃.Low excessively as intake air temperature, many drops do not have dry to adhere on the inwall of hothouse fully, and plug nozzle very easily, causing spraying to interrupt.On the contrary, too high as intake air temperature, then solvent evaporates is rapid, and the microsphere of preparation adheres to each other in a short time easily, mobile variation.
It is a physical process that spray drying prepares microsphere, and it is lower to the requirement of equipment, and technological parameter (inlet temperature, leaving air temp, atomization speed, charging rate etc.) is control easily.Because hydrojet is input to certain speed in the airtight relatively system through peristaltic pump (constant flow pump) carries out spray drying for treating of preparation can being finished; need not to add all ingredients, adjuvant in the spray-drying process; therefore do not exist midway shut down, operation such as dismounting; only need after preparation is finished; the taking-up of powder in the catcher is got final product, and it is very easy therefore to operate.Therefore help industrialized great production, this is that spray drying prepares the big advantage of microsphere with respect to other method.
The Azithromycin enteric casing microsphere outward appearance that makes with the inventive method is loose sprills, is viewed as spherical shape under the optical microscope, and adhesion is few.Carry out release research in the hydrochloric acid solution of 0.1mol/L and simulated intestinal fluid, the result is as follows:
1. release experiment in the acid
With reference to Chinese Pharmacopoeia drug release determination method first method, be dissolution medium with the hydrochloric acid solution 250ml of 0.1mol/L, temperature (37 ± 0.5 ℃), rotating speed 50r/min.Precision takes by weighing the 0.5g enteric-coated microsphere and puts in the little stripping rotor, draw solution 10ml behind the sample point 2h of regulation, behind 220 μ m filtering with microporous membranes, adopt high performance liquid chromatography to carry out the assay of azithromycin, calculate release, should be according to release regulation release in the acid of Chinese Pharmacopoeia enteric coated preparation less than 10%.Wherein high-efficient liquid phase chromatogram condition is: Diamonsil C
18Post (4.6mm * 150mm, 5 μ m); The 0.067mol/L potassium dihydrogen phosphate of mobile phase: pH 4.0-second eyeball (75: 25); Detect wavelength 210nm flow velocity: 1.0ml/min; Column temperature: 40 ℃; Sample size: 20 μ L.
2. release experiment in the simulated intestinal fluid
Release medium in the release experiment in the acid is changed into the simulated intestinal fluid of pH 6.8, and other experimental technique is identical, investigates the release of Azithromycin enteric casing preparation in simulated intestinal fluid.
Release experiment result shows, prescription consists of azithromycin 8～32% by weight percentage, macromolecule enteric material 28～60%, antiplastering aid 15～34% and plasticizer 5～25%, making Azithromycin enteric casing microsphere release behind the 2h in the hydrochloric acid solution of 0.1mol/L by spray drying is 2.963～6.751%, and the release in simulated intestinal fluid behind the 2h is 91.284～97.574% (n=3).Meet the pharmacopeia regulation requirement of enteric coated preparation fully.
The obtained technological progress of the present invention is:
Integrated artistic step of the present invention is simple, utilize the Azithromycin enteric casing microsphere of method preparation of the present invention can be processed into oral formulations such as capsule, tablet, suspensoid and dry suspension, sheltered the bitterness of azithromycin, reduced the release of azithromycin in gastric juice, avoided its stimulation to gastric mucosa, make it in intestinal, dissolve, discharge, thereby improve the infiltration rate of medicine, improve its bioavailability, bring into play better antibacterial action, and the common process preparation easily realizes suitability for industrialized production.Also avoided simultaneously the cross-linking reaction of azithromycin, adopted this method also to can be used for other macrolide antibiotics and prepare enteric-coated microsphere with capsule shells.
The specific embodiment
Embodiment 1
Precision takes by weighing the macromolecule enteric material---and methacrylic acid-methylmethacrylate copolymer (the strange L100 of You Te) 6.0 grams are dissolved in 95% ethanol of 300ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 1.2g and is dissolved in the macromolecule enteric material, after adding plasticizer Oleum Ricini 4.5ml stirs, add micropowder silica gel 3.0g again, under stirring condition, by 82 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 3.015 ± 2.379% (n=3); Release in simulated intestinal fluid behind (pH 6.8) 2h is 92.141 ± 2.379% (n=3).
Embodiment 2
Precision takes by weighing the macromolecule enteric material---and methacrylic acid-methylmethacrylate copolymer (strange L100 of You Te and the strange S100 equal proportion of You Te mixture) 4.5 grams are dissolved in 95% ethanol of 300ml, get 1.5% enteric material solution, and are standby.Precision takes by weighing azithromycin 3.0g and is dissolved in the macromolecule enteric material, after adding plasticizer Oleum Ricini 1.5ml stirs, add micropowder silica gel 0.5g again, under stirring condition, by 81 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 6.015 ± 2.451% (n=3); Release in simulated intestinal fluid behind (pH 6.8) 2h is 94.285 ± 2.258% (n=3).
Embodiment 3
Precision takes by weighing the macromolecule enteric material---and Hydroxypropyl Methylcellulose Phathalate 2.5 grams are dissolved in 80% ethanol of 65ml, get 1.5% enteric material solution, and are standby.Precision takes by weighing azithromycin 1.2g and is dissolved in the macromolecule enteric material, after adding plasticizer Oleum Ricini 3.0ml stirs, add micropowder silica gel 2.2g again, under stirring condition, by 82 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 8.623 ± 1.584% (n=3); Release in simulated intestinal fluid (pH 6.8) behind the 2h is 93.854 ± 2.584% (n=3).
Embodiment 4
Precision takes by weighing the macromolecule enteric material---and Hydroxypropyl Methylcellulose Phathalate 4.8 grams are dissolved in 90% ethanol of 240ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 2.4g and is dissolved in the macromolecule enteric material, after adding plasticizer Oleum Ricini 1.2ml stirs, add Pulvis Talci 1.9g again, under stirring condition, by 82 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 3.954 ± 1.271% (n=3); Release in simulated intestinal fluid (pH 6.8) behind the 2h is 95.875 ± 3.015% (n=3).
Embodiment 5
Precision takes by weighing the macromolecule enteric material---and cellulose acetate-phthalate 4 grams are dissolved in 95% ethanol of 200ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 1g and is dissolved in the macromolecule enteric material, after adding plasticizer Polyethylene Glycol 2.0g stirs, add micropowder silica gel 2.2g again, under stirring condition, by 79 ℃ of inlet temperature, leaving air temp: 60 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 4.218 ± 1.354% (n=3); Release in simulated intestinal fluid (pH 6.8) behind the 2h is 93.262 ± 3.532% (n=3).
Embodiment 6
Precision takes by weighing the macromolecule enteric material---and methacrylic acid-methylmethacrylate copolymer (the strange L100 of You Te) 5 grams are dissolved in 90% ethanol of 250ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 1.6g and is dissolved in the macromolecule enteric material, after adding plasticizer Polyethylene Glycol 4.0g stirs, add micropowder silica gel 2.0g again, under stirring condition, by 81 ℃ of inlet temperature, leaving air temp: 60 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 3.748 ± 1.187% (n=3); Release in simulated intestinal fluid (pH 6.8) behind the 2h is 95.224 ± 3.574% (n=3).
Embodiment 7
Precision takes by weighing the macromolecule enteric material---and cellulose acetate benzenetricarboxylic acid ester 7 grams are dissolved in 95% ethanol of 350ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 1g and is dissolved in the macromolecule enteric material, after adding plasticizer Polyethylene Glycol 2.5g stirs, add Pulvis Talci 1.5g again, under stirring condition, by 82 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 6.512 ± 1.648% (n=3); Release in simulated intestinal fluid (pH 6.8) behind the 2h is 95.355 ± 2.642% (n=3).
Embodiment 8
Precision takes by weighing the macromolecule enteric material---and methacrylic acid-methylmethacrylate copolymer (the strange L100 of You Te) 6.0 grams are dissolved in 95% ethanol of 300ml, get 2% enteric material solution, and are standby.Precision takes by weighing azithromycin 2g and is dissolved in the macromolecule enteric material, after adding plasticizer Oleum Ricini 3ml stirs, add micropowder silica gel 2.5g again, under stirring condition, by 82 ℃ of inlet temperature, leaving air temp: 61 ℃, charging rate: 20ml/min, throughput 600nl/h with its spray drying, remove organic solvent and promptly obtain Azithromycin enteric casing microsphere.
Release in the hydrochloric acid solution of 0.1mol/L behind the 2h is 2.804 ± 1.058% (n=3); Release in simulated intestinal fluid behind (pH 6.8) 2h is 96.574 ± 2.461% (n=3).
Claims (10)
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390848B (en) * | 2008-11-12 | 2010-04-21 | 浙江丽水众益药业有限公司 | Medicine composition azithromycin enteric-coated capsules |
| CN102813633A (en) * | 2011-06-10 | 2012-12-12 | 塔科敏斯基制药厂波尔法合资公司 | Method for preparing pharmaceutical composition containing macrolides antibiotics by using wet granulation |
| CN109181884A (en) * | 2018-07-16 | 2019-01-11 | 苏州华龙化工有限公司 | A kind of preparation method of the crease-resistant effervescent detergent of cotton |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1255098C (en) * | 2003-12-15 | 2006-05-10 | 上海中医药大学 | Ophiopogonin enteric coated microsphere preparation and preparing process thereof |
| CN1264520C (en) * | 2004-04-23 | 2006-07-19 | 石家庄制药集团欧意药业有限公司 | Enteric-coated azithromycin preparation and its preparing process |
| CN1284540C (en) * | 2004-07-30 | 2006-11-15 | 浙江大德药业集团有限公司 | Azithromycin enteric casing preparation and its preparing process |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101390848B (en) * | 2008-11-12 | 2010-04-21 | 浙江丽水众益药业有限公司 | Medicine composition azithromycin enteric-coated capsules |
| CN102813633A (en) * | 2011-06-10 | 2012-12-12 | 塔科敏斯基制药厂波尔法合资公司 | Method for preparing pharmaceutical composition containing macrolides antibiotics by using wet granulation |
| CN109181884A (en) * | 2018-07-16 | 2019-01-11 | 苏州华龙化工有限公司 | A kind of preparation method of the crease-resistant effervescent detergent of cotton |
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