CN113081987B - Fluorocytosine tablet and preparation method thereof - Google Patents
Fluorocytosine tablet and preparation method thereof Download PDFInfo
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- CN113081987B CN113081987B CN202110474497.0A CN202110474497A CN113081987B CN 113081987 B CN113081987 B CN 113081987B CN 202110474497 A CN202110474497 A CN 202110474497A CN 113081987 B CN113081987 B CN 113081987B
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- XRECTZIEBJDKEO-UHFFFAOYSA-N flucytosine Chemical compound NC1=NC(=O)NC=C1F XRECTZIEBJDKEO-UHFFFAOYSA-N 0.000 title claims abstract description 89
- 238000002360 preparation method Methods 0.000 title claims abstract description 14
- 229960004413 flucytosine Drugs 0.000 claims abstract description 70
- WZPBZJONDBGPKJ-UHFFFAOYSA-N Antibiotic SQ 26917 Natural products O=C1N(S(O)(=O)=O)C(C)C1NC(=O)C(=NOC(C)(C)C(O)=O)C1=CSC(N)=N1 WZPBZJONDBGPKJ-UHFFFAOYSA-N 0.000 claims abstract description 30
- WZPBZJONDBGPKJ-VEHQQRBSSA-N aztreonam Chemical compound O=C1N(S([O-])(=O)=O)[C@@H](C)[C@@H]1NC(=O)C(=N/OC(C)(C)C(O)=O)\C1=CSC([NH3+])=N1 WZPBZJONDBGPKJ-VEHQQRBSSA-N 0.000 claims abstract description 30
- 229960003644 aztreonam Drugs 0.000 claims abstract description 30
- 229920002472 Starch Polymers 0.000 claims abstract description 25
- 239000006041 probiotic Substances 0.000 claims abstract description 25
- 235000018291 probiotics Nutrition 0.000 claims abstract description 25
- 229910052708 sodium Inorganic materials 0.000 claims abstract description 25
- 239000011734 sodium Substances 0.000 claims abstract description 25
- 235000019698 starch Nutrition 0.000 claims abstract description 25
- 239000008107 starch Substances 0.000 claims abstract description 25
- 150000001875 compounds Chemical class 0.000 claims abstract description 24
- 235000007164 Oryza sativa Nutrition 0.000 claims abstract description 21
- 240000004808 Saccharomyces cerevisiae Species 0.000 claims abstract description 21
- 235000014680 Saccharomyces cerevisiae Nutrition 0.000 claims abstract description 21
- 235000009566 rice Nutrition 0.000 claims abstract description 21
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 20
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 20
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 20
- 229920002774 Maltodextrin Polymers 0.000 claims abstract description 18
- 239000005913 Maltodextrin Substances 0.000 claims abstract description 18
- JCQLYHFGKNRPGE-FCVZTGTOSA-N lactulose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 JCQLYHFGKNRPGE-FCVZTGTOSA-N 0.000 claims abstract description 18
- 229960000511 lactulose Drugs 0.000 claims abstract description 18
- PFCRQPBOOFTZGQ-UHFFFAOYSA-N lactulose keto form Natural products OCC(=O)C(O)C(C(O)CO)OC1OC(CO)C(O)C(O)C1O PFCRQPBOOFTZGQ-UHFFFAOYSA-N 0.000 claims abstract description 18
- 229940035034 maltodextrin Drugs 0.000 claims abstract description 18
- 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 9
- 238000003756 stirring Methods 0.000 claims description 44
- 239000000203 mixture Substances 0.000 claims description 39
- 238000002156 mixing Methods 0.000 claims description 36
- 238000001035 drying Methods 0.000 claims description 30
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 22
- 229940032147 starch Drugs 0.000 claims description 21
- 241000209094 Oryza Species 0.000 claims description 20
- 239000002245 particle Substances 0.000 claims description 20
- 239000008187 granular material Substances 0.000 claims description 15
- 238000007873 sieving Methods 0.000 claims description 14
- 239000000725 suspension Substances 0.000 claims description 14
- 235000012054 meals Nutrition 0.000 claims description 13
- 229960003943 hypromellose Drugs 0.000 claims description 11
- 230000000529 probiotic effect Effects 0.000 claims description 8
- 241001608472 Bifidobacterium longum Species 0.000 claims description 7
- 244000199885 Lactobacillus bulgaricus Species 0.000 claims description 7
- 235000013960 Lactobacillus bulgaricus Nutrition 0.000 claims description 7
- 241000194020 Streptococcus thermophilus Species 0.000 claims description 7
- 229940009291 bifidobacterium longum Drugs 0.000 claims description 7
- 229940004208 lactobacillus bulgaricus Drugs 0.000 claims description 7
- 229940083542 sodium Drugs 0.000 claims description 7
- 238000005507 spraying Methods 0.000 claims description 7
- 239000011363 dried mixture Substances 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims 1
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- 229940079593 drug Drugs 0.000 abstract description 10
- 239000003814 drug Substances 0.000 abstract description 10
- 206010059866 Drug resistance Diseases 0.000 abstract description 9
- 241000233866 Fungi Species 0.000 abstract description 8
- 239000000843 powder Substances 0.000 abstract description 6
- 230000000857 drug effect Effects 0.000 abstract description 3
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- 230000007774 longterm Effects 0.000 abstract description 3
- 240000007594 Oryza sativa Species 0.000 abstract 1
- 230000000694 effects Effects 0.000 description 7
- 241000699670 Mus sp. Species 0.000 description 5
- 231100000331 toxic Toxicity 0.000 description 4
- 230000002588 toxic effect Effects 0.000 description 4
- 241000222120 Candida <Saccharomycetales> Species 0.000 description 3
- 241000222122 Candida albicans Species 0.000 description 3
- 206010007134 Candida infections Diseases 0.000 description 3
- 201000003984 candidiasis Diseases 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 239000013589 supplement Substances 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- 241001337994 Cryptococcus <scale insect> Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 201000009906 Meningitis Diseases 0.000 description 2
- 208000001647 Renal Insufficiency Diseases 0.000 description 2
- 229930003270 Vitamin B Natural products 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 230000002950 deficient Effects 0.000 description 2
- 230000000797 effect on infection Effects 0.000 description 2
- 206010014665 endocarditis Diseases 0.000 description 2
- 235000013312 flour Nutrition 0.000 description 2
- 230000000968 intestinal effect Effects 0.000 description 2
- 201000006370 kidney failure Diseases 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 235000019156 vitamin B Nutrition 0.000 description 2
- 239000011720 vitamin B Substances 0.000 description 2
- OBXUXLBEGTZOSY-UHFFFAOYSA-N 4-amino-1-fluoropyrimidin-2-one Chemical compound NC=1C=CN(F)C(=O)N=1 OBXUXLBEGTZOSY-UHFFFAOYSA-N 0.000 description 1
- 206010067484 Adverse reaction Diseases 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
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- 206010008803 Chromoblastomycosis Diseases 0.000 description 1
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- 208000000857 Hepatic Insufficiency Diseases 0.000 description 1
- 206010022653 Intestinal haemorrhages Diseases 0.000 description 1
- 206010028080 Mucocutaneous candidiasis Diseases 0.000 description 1
- 208000031888 Mycoses Diseases 0.000 description 1
- 206010040047 Sepsis Diseases 0.000 description 1
- 206010042566 Superinfection Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 201000000839 Vitamin K Deficiency Bleeding Diseases 0.000 description 1
- 206010047634 Vitamin K deficiency Diseases 0.000 description 1
- 230000006838 adverse reaction Effects 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000000843 anti-fungal effect Effects 0.000 description 1
- 229940121375 antifungal agent Drugs 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 230000004064 dysfunction Effects 0.000 description 1
- 230000002538 fungal effect Effects 0.000 description 1
- 208000014951 hematologic disease Diseases 0.000 description 1
- 208000018706 hematopoietic system disease Diseases 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 231100000915 pathological change Toxicity 0.000 description 1
- 230000036285 pathological change Effects 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002685 pulmonary effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 208000013223 septicemia Diseases 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 208000019206 urinary tract infection Diseases 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 208000016794 vitamin K deficiency hemorrhagic disease Diseases 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
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- 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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- 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
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K31/425—Thiazoles
- A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
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- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
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- A61K35/66—Microorganisms or materials therefrom
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- A61K35/745—Bifidobacteria
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- A61K35/747—Lactobacilli, e.g. L. acidophilus or L. brevis
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Abstract
The invention discloses a flucytosine tablet and a preparation method thereof, and the flucytosine tablet comprises the following components of 31.2-67.8 parts of flucytosine, 4.7-13.2 parts of aztreonam, 20-30 parts of maltodextrin, 14-18 parts of pea powder, 10-15 parts of rice bran, 6-9 parts of beer yeast, 3-6 parts of lactulose, 3-6 parts of compound probiotics, 9-16 parts of sodium carboxymethyl starch and 3-7 parts of hydroxypropyl methylcellulose; wherein, in each tablet of fluorocytosine: the content of the fluorocytosine is 31.0 to 36.0 percent, and the content of the aztreonam is 4.5 to 7.0 percent. The flucytosine tablet can improve drug resistance of fungi caused by long-term administration of flucytosine, reduce administration frequency and administration dosage, has a simple and reliable preparation method, and has a smooth surface, so that the quality and the stability of the drug effect of the prepared tablet are effectively ensured, and the drug can be rapidly dispersed, dissolved and absorbed in the gastrointestinal tract.
Description
Technical Field
The invention relates to a flucytosine tablet and a preparation method thereof, belonging to the technical field of medicines.
Background
Flucytosine, used for treating fungal infections caused by cryptococcus and candida, such as fungal septicemia, endocarditis, meningitis and pulmonary and urinary tract infection antifungal drugs, mainly used for mucocutaneous candidiasis, candida endocarditis, candida arthritis, cryptococcus meningitis and chromomycosis; however, the blood phase should be checked regularly during administration, and patients with liver and renal insufficiency such as blood disease and pregnant women should be cautiously administered, and patients with severe renal insufficiency should be prohibited. The existing flucytosine products are generally capsule preparations, injection and tablets, and because the fungi easily generate drug resistance to the flucytosine, the drug resistance phenomenon of the fungi can be found in a long treatment course, so that the drug resistance frequently occurs, and the monotherapy using the flucytosine has limitation. Therefore, the flucytosine tablet can improve the drug resistance of fungi caused by long-term administration of flucytosine, reduce the administration frequency, lower the administration dosage and reduce the toxic and side effects.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a flucytosine tablet and a preparation method thereof, the flucytosine tablet can reduce the administration frequency and the administration dosage, improve the drug resistance of fungi caused by long-term administration of flucytosine, reduce the toxic and side effects, has simple and reliable preparation method, smooth surface of the prepared tablet, effectively ensures the quality and the stability of the drug effect, and ensures that the drug can be rapidly dispersed, dissolved and absorbed in the gastrointestinal tract.
In order to achieve the purpose, the invention adopts the following technical scheme: a fluorocytosine tablet is characterized by comprising the following components of 31.2-67.8 parts of fluorocytosine, 4.7-13.2 parts of aztreonam, 20-30 parts of maltodextrin, 14-18 parts of pea flour, 10-15 parts of rice bran, 6-9 parts of beer yeast, 3-6 parts of lactulose, 3-6 parts of compound probiotic, 9-16 parts of sodium carboxymethyl starch and 3-7 parts of hydroxypropyl methylcellulose; wherein, in each tablet of fluorocytosine: the content of the fluorocytosine is 31.0-36.0%, and the content of the aztreonam is 4.5-7.0%.
Preferably, the flucytosine tablet comprises 49 parts of flucytosine, 8.9 parts of aztreonam, 25.5 parts of maltodextrin, 16 parts of pea powder, 13.5 parts of rice bran, 7.5 parts of beer yeast, 4.5 parts of lactulose, 4.5 parts of compound probiotic, 13 parts of sodium carboxymethyl starch and 6 parts of hydroxypropyl methylcellulose; wherein, in each tablet of fluorocytosine: the content of flucytosine is 33.0 percent and the content of aztreonam is 6.0 percent.
Preferably, the compound probiotic is prepared by mixing bifidobacterium longum, lactobacillus bulgaricus and streptococcus thermophilus.
Wherein the weight ratio of the bifidobacterium longum to the lactobacillus bulgaricus to the streptococcus thermophilus is 10:1: 1.
The invention also provides a preparation method of the flucytosine tablet, which comprises the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing aztreonam, pea meal, rice bran, beer yeast and compound probiotics, adding the mixture into pure water with the weight of 1.5-2.5 times of that of the mixture, fully stirring and uniformly dispersing the mixture, drying the mixture by a fluidized bed at the temperature of 50-55 ℃, and crushing the dried mixture to 80-100 meshes to obtain a mixture A;
(3) mixing flucytosine, maltodextrin and lactulose, adding the mixture into pure water with the weight of 3-3.5 times of that of the mixture, fully stirring and uniformly dispersing the mixture, adding one third of sodium carboxymethyl starch, and stirring and uniformly dispersing the mixture to obtain a suspension B;
(4) spraying the mixture A into the suspension B under stirring, continuously stirring and mixing to prepare wet particles, and drying to obtain particles C;
(5) and mixing the hydroxypropyl methylcellulose and the rest sodium carboxymethyl starch, adding the mixture into pure water with the weight of 0.5-0.6 times of that of the hydroxypropyl methylcellulose, fully stirring and uniformly dispersing, adding the granules C, uniformly mixing to obtain final granules, and drying and tabletting the final granules to obtain the flucytosine tablet.
Preferably, the drying temperature of the fluidized bed in the step (2) is 50-55 ℃.
Preferably, the stirring speed in the stirring state in the step (4) is 500-800 r/min, and the drying temperature under the drying condition is 40-45 ℃.
Preferably, the drying temperature of the drying condition in the step (5) is 30 to 35 ℃.
The invention has the beneficial effects.
1. Aztreonam added into the fluorocytosine tablet disclosed by the invention has a synergistic antibacterial effect with fluorocytosine, so that the treatment effect on infection is improved, and rice bran, beer yeast, pea flour and compound probiotics are used as auxiliary materials to synergistically supplement deficient nutrient elements, so that the administration frequency can be reduced, the administration dosage can be reduced, the drug resistance of fungi on the fluorocytosine can be weakened, and the toxic and side effects can be reduced.
2. The rice bran and the beer yeast contain rich nutrient vitamin B families, can supplement vitamin B families which are deficient due to flucytosine and aztreonam in an auxiliary way, and avoid causing superinfection; the pea meal contains rich nutrient vitamin K, can assist in supplementing vitamin K deficiency caused by flucytosine and aztreonam, and avoids intestinal bleeding.
3. The compound probiotic preparation is prepared by mixing bifidobacterium longum, lactobacillus bulgaricus and streptococcus thermophilus, can effectively supplement normal probiotic groups deleted in vivo, improve intestinal canal imbalance, avoid the condition of channel dysfunction or adverse reaction, and reduce fungi with drug resistance to flucytosine.
4. The preparation method of the flucytosine tablet is simple and reliable, and the prepared tablet has smooth surface, effectively ensures the quality and the stability of the drug effect, and ensures that the drug can be rapidly dispersed, dissolved and absorbed in the gastrointestinal tract.
Detailed Description
In order to more clearly and completely illustrate the present invention, the following examples are given by way of illustration of the present invention, and are not intended to limit the present invention.
The compound probiotic agent is prepared by mixing bifidobacterium longum, lactobacillus bulgaricus and streptococcus thermophilus, adding a proper amount of pure water, fully and uniformly stirring, granulating and drying; wherein the weight ratio of the bifidobacterium longum to the lactobacillus bulgaricus to the streptococcus thermophilus is 10:1: 1.
Example 1
A flucytosine tablet is prepared by the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing 4.7g of aztreonam, 14g of pea meal, 10g of rice bran, 6g of beer yeast and 3g of compound probiotics, adding into 57g of pure water, fully stirring and uniformly dispersing, drying by a fluidized bed at the temperature of 50-55 ℃, and crushing to 80-100 meshes to obtain a mixture A;
(3) mixing 31.2g of flucytosine, 20g of maltodextrin and 3g of lactulose, adding the mixture into 163g of pure water, fully stirring and uniformly dispersing, adding 3g of one third of sodium carboxymethyl starch, and stirring and uniformly dispersing to obtain a suspension B;
(4) spraying the mixture A into the suspension B under the stirring state at the speed of 500-800 r/min, continuously stirring and mixing to prepare wet particles, and drying at the temperature of 40-45 ℃ to obtain particles C;
(5) mixing 3g of hypromellose and 6g of the rest sodium carboxymethyl starch, adding into 5g of pure water, fully stirring and uniformly dispersing, adding the particles C, uniformly mixing to obtain final particles, drying the final particles at the temperature of 30-35 ℃, and tabletting to obtain 101 flucytosine tablets, wherein each flucytosine tablet is 1 +/-0.008 g, the content of flucytosine is 30.0%, and the content of aztreonam is 4.5%.
Example 2
A flucytosine tablet is prepared by the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing 13.2g of aztreonam, 18g of pea powder, 15g of rice bran, 9g of beer yeast and 6g of compound probiotics, adding into 153g of pure water, fully stirring and uniformly dispersing, drying by a fluidized bed at the temperature of 50-55 ℃, and crushing to 80-100 meshes to obtain a mixture A;
(3) mixing 67.8g of flucytosine, 30g of maltodextrin and 6g of lactulose, adding the mixture into 363g of pure water, fully stirring and uniformly dispersing, adding 5g of one third of sodium carboxymethyl starch, and stirring and uniformly dispersing to obtain a suspension B;
(4) spraying the mixture A into the suspension B under the stirring state at the speed of 500-800 r/min, continuously stirring and mixing to prepare wet particles, and drying at the temperature of 40-45 ℃ to obtain particles C;
(5) mixing 7g of hypromellose and 11g of the rest sodium carboxymethyl starch, adding into 9g of pure water, fully stirring and uniformly dispersing, adding the granule C, uniformly mixing to obtain final granules, drying the final granules at the temperature of 30-35 ℃, and tabletting to obtain flucytosine tablets, wherein the weight of each flucytosine tablet is 1 +/-0.006 g, the content of flucytosine is 36.0%, and the content of aztreonam is 7.0%.
Example 3
A flucytosine tablet is prepared by the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing 7.2g of aztreonam, 15g of pea powder, 12g of rice bran, 7g of beer yeast and 4g of compound probiotics, adding the mixture into 82g of pure water, fully stirring and uniformly dispersing, drying by a fluidized bed at the temperature of 50-55 ℃, and crushing to 80-100 meshes to obtain a mixture A;
(3) mixing 41.3g of flucytosine, 24g of maltodextrin and 3g of lactulose, adding the mixture into 140g of pure water, fully stirring and uniformly dispersing, adding one third of 4g of sodium carboxymethyl starch, and stirring and uniformly dispersing to obtain a suspension B;
(4) spraying the mixture A into the suspension B under the stirring state at the speed of 500-800 r/min, continuously stirring and mixing to prepare wet particles, and drying at the temperature of 40-45 ℃ to obtain particles C;
(5) 5g of hypromellose and 8g of the rest sodium carboxymethyl starch are mixed and then added into 7g of pure water, the mixture is fully stirred and uniformly dispersed, particles C are added and uniformly mixed to obtain final particles, the final particles are dried at the temperature of 30-35 ℃ and then tabletted to obtain 128 flucytosine tablets, the weight of each flucytosine tablet is 1 +/-0.005 g, the content of the flucytosine is 31.6 percent, and the content of the aztreonam is 5.5 percent.
Example 4
A flucytosine tablet is prepared by the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing 10.6g of aztreonam, 17g of pea powder, 14g of rice bran, 8g of beer yeast and 5g of compound probiotics, adding into 125.5g of pure water, fully stirring and uniformly dispersing, drying by a fluidized bed at the temperature of 50-55 ℃, and crushing to 80-100 meshes to obtain a mixture A;
(3) mixing flucytosine 55.7g, maltodextrin 27g and lactulose 5g, adding into pure water 180g
Fully stirring and uniformly dispersing, then adding 3.5g of one third of sodium carboxymethyl starch, and stirring and uniformly dispersing to obtain a suspension B;
(4) spraying the mixture A into the suspension B under the stirring state at the speed of 500-800 r/min, continuously stirring and mixing to prepare wet particles, and drying at the temperature of 40-45 ℃ to obtain particles C;
(5) mixing 6.5g of hydroxypropyl methylcellulose and 10.5g of the rest sodium carboxymethyl starch, adding the mixture into 10g of pure water, fully stirring and uniformly dispersing, adding the granules C, uniformly mixing to obtain final granules, drying the final granules at the temperature of 30-35 ℃, and tabletting to obtain flucytosine tablets, wherein 160 flucytosine tablets are obtained, the weight of each flucytosine tablet is 1 +/-0.004 g, the content of flucytosine is 34.2%, and the content of aztreonam is 6.5%.
Example 5
A flucytosine tablet is prepared by the following steps:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing 8.9g of aztreonam, 16g of pea powder, 13.5g of rice bran, 7.5g of beer yeast and 4.5g of compound probiotics, adding the mixture into 105g of pure water, fully stirring and uniformly dispersing, drying by a fluidized bed at the temperature of 50-55 ℃, and crushing to 80-100 meshes to obtain a mixture A;
(3) 49g of flucytosine, 25.5g of maltodextrin and 4.5g of lactulose are mixed and added into 161g of pure water, fully stirred and uniformly dispersed, then one third of sodium carboxymethyl starch is added, and stirred and uniformly dispersed to obtain a suspension B;
(4) spraying the mixture A into the suspension B under the stirring state at the speed of 500-800 r/min, continuously stirring and mixing to prepare wet particles, and drying at the temperature of 40-45 ℃ to obtain particles C;
(5) mixing 6g of hypromellose and 10g of the rest sodium carboxymethyl starch, adding into 9g of pure water, fully stirring and uniformly dispersing, adding the granule C, uniformly mixing to obtain final granules, drying the final granules at the temperature of 30-35 ℃, and tabletting to obtain flucytosine tablets, wherein 147 tablets are obtained, the weight of each flucytosine tablet is 1 +/-0.003 g, the content of flucytosine is 33.0%, and the content of aztreonam is 6.0%.
And (3) testing results:
1. disintegration test
The fluorocytosine tablets prepared in the above examples 1 to 5 are subjected to disintegration test, and 1 fluorocytosine tablet is put into 100ml of 0.1mol/L hydrochloric acid at 25-30 ℃, and the disintegration time, solution clarity, taste stability and drug property are measured, as shown in Table 1:
TABLE 1
From the above table 1, it is found that the fluorocytosine tablet of the present invention is smooth, can be rapidly disintegrated, and the solution after dissolution is clear and transparent, and has no sticking, dispersion effect, drug quality, and drug efficacy stability.
2. Clinical trials in candidiasis mice
Selecting 18 constipated mice, and dividing 3 mice into 6 groups; the flucytosine tablets of examples 1 to 5 correspond to a group of candidiasis mice, respectively; control group: selecting the raw materials and the dosage for preparation in example 5, and removing pea meal, rice bran, beer yeast and compound probiotics to prepare flucytosine tablets, wherein the flucytosine tablets correspond to a group of candidiasis mice; the pathological changes, the medication and the total number of beneficial bacteria after the medication are observed, as shown in table 2:
TABLE 2
From the table 2, it is found that the flucytosine tablet provided by the invention has the advantages that the treatment effect on infection is improved, the administration frequency can be reduced, the administration dosage can be reduced, the intestinal flora can be adjusted, the curative effect is good, the phenomenon of no dosage dependence is avoided, the drug resistance of fungi on flucytosine is weakened, the toxic and side effects are reduced, and the flucytosine tablet prepared in example 5 has a better effect.
Finally, it should be noted that the above embodiments are only used for illustrating and not limiting the technical solutions of the present invention, and although the present invention has been described in detail with reference to the above embodiments, it should be understood by those skilled in the art that modifications or equivalent substitutions can be made to the present invention without departing from the spirit and scope of the present invention, and all modifications or partial substitutions should be covered by the scope of the claims of the present invention.
Claims (6)
1. The flucytosine tablet is characterized by comprising 49 parts of flucytosine, 8.9 parts of aztreonam, 25.5 parts of maltodextrin, 16 parts of pea meal, 13.5 parts of rice bran, 7.5 parts of beer yeast, 4.5 parts of lactulose, 4.5 parts of compound probiotic, 13 parts of sodium carboxymethyl starch and 6 parts of hydroxypropyl methylcellulose; wherein, in each tablet of fluorocytosine: the content of flucytosine is 33.0 percent and the content of aztreonam is 6.0 percent.
2. A fluorocytosine tablet in accordance with claim 1, wherein the compound probiotic is prepared by mixing bifidobacterium longum, lactobacillus bulgaricus and streptococcus thermophilus.
3. A flucytosine tablet according to claim 2, wherein the bifidobacterium longum, lactobacillus bulgaricus and streptococcus thermophilus are in a weight ratio of 10:1: 1.
4. A process for the preparation of a fluorocytosine tablet according to claim 1, comprising the steps of:
(1) respectively sieving flucytosine, maltodextrin, sodium carboxymethyl starch, lactulose and hypromellose with a sieve of 80-100 meshes, respectively crushing aztreonam, pea meal, rice bran, beer yeast and compound probiotics and sieving with a sieve of 200-230 meshes;
(2) mixing aztreonam, pea meal, rice bran, beer yeast and compound probiotics, adding the mixture into pure water with the weight of 1.5-2.5 times of that of the mixture, fully stirring and uniformly dispersing the mixture, drying the mixture by a fluidized bed at the temperature of 50-55 ℃, and crushing the dried mixture to 80-100 meshes to obtain a mixture A;
(3) mixing flucytosine, maltodextrin and lactulose, adding the mixture into pure water with the weight of 3-3.5 times of that of the mixture, fully stirring and uniformly dispersing the mixture, adding one third of sodium carboxymethyl starch, and stirring and uniformly dispersing the mixture to obtain a suspension B;
(4) spraying the mixture A into the suspension B under stirring, continuously stirring and mixing to prepare wet particles, and drying to obtain particles C;
(5) and mixing the hydroxypropyl methylcellulose and the rest sodium carboxymethyl starch, adding the mixture into pure water with the weight of 0.5-0.6 times of that of the hydroxypropyl methylcellulose, fully stirring and uniformly dispersing, adding the granules C, uniformly mixing to obtain final granules, and drying and tabletting the final granules to obtain the flucytosine tablet.
5. A fluorocytosine tablet production method according to claim 4, wherein the stirring speed in the stirring state in the step (4) is 500 to 800r/min, and the drying temperature under the drying condition is 40 to 45 ℃.
6. A fluorocytosine tablet preparation method according to claim 4, wherein the drying temperature of the drying condition in step (5) is 30 to 35 ℃.
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| CN111848834A (en) * | 2019-04-30 | 2020-10-30 | 苏州大学 | Application of cationic polymer modified by fluorine-containing compound in preparing transmucosal drug delivery of drug |
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| CN111848834A (en) * | 2019-04-30 | 2020-10-30 | 苏州大学 | Application of cationic polymer modified by fluorine-containing compound in preparing transmucosal drug delivery of drug |
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