CN114191400A - Balofloxacin tablet and preparation process thereof - Google Patents

Balofloxacin tablet and preparation process thereof Download PDF

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CN114191400A
CN114191400A CN202111580441.XA CN202111580441A CN114191400A CN 114191400 A CN114191400 A CN 114191400A CN 202111580441 A CN202111580441 A CN 202111580441A CN 114191400 A CN114191400 A CN 114191400A
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balofloxacin
parts
tablet
microcrystalline cellulose
pregelatinized starch
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林裕朗
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Huayu Wuxi Pharmacy Co ltd
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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
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4709—Non-condensed quinolines and containing further heterocyclic rings
    • 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
    • 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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  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Molecular Biology (AREA)
  • Communicable Diseases (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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Abstract

The invention discloses a balofloxacin tablet, which comprises the following components in parts by weight: 100-120 parts of balofloxacin dihydrate, 107-132 parts of microcrystalline cellulose, 104-143 parts of pregelatinized starch and 1-3 parts of magnesium stearate, wherein the preparation process of the tablet comprises the following steps of S1: weighing balofloxacin dihydrate, and screening for later use; weighing microcrystalline cellulose and pregelatinized starch, mixing, and screening the mixed materials for later use; step S2: the balofloxacin dihydrate, the microcrystalline cellulose and the pregelatinized starch are mixed uniformly by a dilution method to obtain mixed powder. Step S3: weighing magnesium stearate and screening for later use; step S4: the preparation method has the advantages that the tablets have excellent in vitro stability and in vivo solubility, the related preparation process avoids redundant and fussy treatment processes, and the preparation method is simple and rapid.

Description

Balofloxacin tablet and preparation process thereof
Technical Field
The invention relates to the technical field of preparation of anti-infective drugs, in particular to a balofloxacin tablet and a preparation process thereof.
Background
Infectious diseases are the most common group of diseases in clinic, involve almost all specialists in clinic, and are one of the most common causes of death of patients. Anti-infective drugs are effective means for combating infectious diseases in humans, are large in number, many in type, and fast in development. According to statistics, the sales of anti-infective drugs accounts for about 15% of the sales of medicines in the world, and is second to cardiovascular drugs. In China, anti-infective drugs account for about 14% of the entire drug market, and are the first of all drug types. Quinolone drugs are antibacterial drugs which are rapidly developed in recent years, account for 18.5% of the world antibiotic market, have an average annual growth rate of 7%, and are one of the most active fields in anti-infective drugs, wherein balofloxacin belongs to fourth-generation quinolone drugs, and the action pharmacology of balofloxacin inhibits bacterial DNA synthesis by inhibiting the activity of bacterial DNA gyrase, so that bacteria die. Currently, polyethylene glycol 8000 and the like are generally used as a binder in the preparation process of balofloxacin tablets to ensure the integrity of the tablets. However, there are the following problems:
1. although the in vitro integrity of the tablet is good, the dissolution speed of the tablet in vivo is reduced, and the onset time of balofloxacin is influenced.
2. The polyethylene glycol can cause diarrhea when being taken orally in large dose, and even cause hemolysis when the concentration of the polyethylene glycol is more than 40 percent; the use of large amounts of excipients also reduces the dosage of balofloxacin in a single tablet.
Disclosure of Invention
In view of the above disadvantages of the prior art, the present invention provides a balofloxacin tablet and a preparation process thereof, which has the advantages that the tablet has excellent in vitro stability and in vivo solubility, and the related preparation process avoids redundant and tedious processing procedures, and is simple and fast.
The technical purpose of the invention is realized by the following technical scheme:
a preparation process of balofloxacin tablets comprises the following steps:
step S1: weighing balofloxacin dihydrate, and screening for later use; weighing microcrystalline cellulose and pregelatinized starch, mixing, and screening the mixed materials for later use;
step S2: the balofloxacin dihydrate, the microcrystalline cellulose and the pregelatinized starch are mixed uniformly by a dilution method to obtain mixed powder.
Step S3: weighing magnesium stearate and screening for later use;
step S4: and uniformly mixing the mixed powder and magnesium stearate, screening the mixture, determining the tablet weight, and tabletting to obtain the tablet.
Further, in step S1, balofloxacin dihydrate is sieved through a 100 mesh sieve.
Further, in step S1, the mixture of microcrystalline cellulose and pregelatinized starch is passed through a 100 mesh screen.
Further, in step S2, the mixture of balofloxacin dihydrate, microcrystalline cellulose and pregelatinized starch was added from the feed inlet and mixed for 20 minutes at a rotation speed of 10 rpm by mixing and diluting with a multi-directional mixer.
Further, in step S3, magnesium stearate is sieved through a 100 mesh screen.
Further, in step S4, after the mixed powder and the magnesium stearate are uniformly mixed, the mixture is sieved by two 80-mesh sieves
The balofloxacin tablet comprises the following components in parts by weight: 100-120 parts of balofloxacin dihydrate, 107-132 parts of microcrystalline cellulose, 104-143 parts of pregelatinized starch and 1-3 parts of magnesium stearate.
Further, the composition comprises the following components in parts by weight: 104-113 parts of balofloxacin dihydrate, 117-124 parts of microcrystalline cellulose, 104-143 parts of pregelatinized starch and 1-3 parts of magnesium stearate.
Further, every 1000 tablets of balofloxacin are prepared, comprising the following components: 109.2g of balofloxacin dihydrate, 120g of microcrystalline cellulose, 120g of pregelatinized starch and 2.0g of magnesium stearate.
In conclusion, the invention has the following beneficial effects:
1. in the preparation of the combination of balofloxacin, a few kinds of auxiliary materials are selected as far as possible, the problem that the medicine effect of balofloxacin is influenced by the auxiliary materials such as polyethylene glycol is avoided, the optimal auxiliary material proportion is selected, the balofloxacin tablet has excellent in vivo solubility and stability in vitro of the tablet, and the single tablet is ensured to have enough dosage.
2. The formula is simplified, and meanwhile, the process flow is simplified, on one hand, the accurate metering of the components is realized, on the other hand, the preparation conditions are reduced, the redundant medicine component treatment process is eliminated, and the formula and the process of the balofloxacin tablet suitable for industrial production in China are obtained.
Drawings
FIG. 1 is a schematic diagram of the process for making balofloxacin tablets.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the following detailed description of the present invention is provided with reference to the accompanying drawings and the detailed description. The advantages and features of the present invention will become more apparent from the following description. It is to be noted that the drawings are in a very simplified form and are all used in a non-precise scale for the purpose of facilitating and distinctly aiding in the description of the embodiments of the present invention. To make the objects, features and advantages of the present invention comprehensible, reference is made to the accompanying drawings. It should be understood that the structures, ratios, sizes, and the like shown in the drawings and described in the specification are only used for matching with the disclosure of the specification, so as to be understood and read by those skilled in the art, and are not used to limit the implementation conditions of the present invention, so that the present invention has no technical significance, and any structural modification, ratio relationship change or size adjustment should still fall within the scope of the present invention without affecting the efficacy and the achievable purpose of the present invention.
Example 1:
a balofloxacin tablet, which is prepared into 1000 tablets in the embodiment, has the formula of balofloxacin dihydrate 101.2g, microcrystalline cellulose 108.2g, pregelatinized starch 104.1g and magnesium stearate 1.5 g. Wherein the microcrystalline cellulose plays a role: excipients, disintegrants; pregelatinized starch functions: excipients, disintegrants; magnesium stearate plays a role: and (3) a lubricant.
As shown in fig. 1, the preparation process comprises the following steps:
step S1: weighing balofloxacin dihydrate, and screening the balofloxacin dihydrate through a 100-mesh sieve for later use; weighing microcrystalline cellulose and pregelatinized starch, mixing, and screening the mixed material through a 100-mesh sieve for later use;
step S2: the method comprises the following steps of uniformly mixing a mixture of balofloxacin dihydrate, microcrystalline cellulose and pregelatinized starch by a dilution method to obtain mixed powder, specifically, mixing and diluting the mixture by a multi-directional motion mixer, adding the mixture of balofloxacin dihydrate, microcrystalline cellulose and pregelatinized starch from a feed inlet, mixing for 20 minutes, and rotating at the speed of 10 revolutions per minute.
Step S3: weighing magnesium stearate, and screening for later use, wherein the magnesium stearate is screened through a 100-mesh screen.
Step S4: and uniformly mixing the mixed powder and the magnesium stearate, screening the mixture, and sieving the mixture through a 100-mesh sieve. Then determining the weight of the tablet, and tabletting to obtain the tablet.
Initial stability study of balofloxacin:
balofloxacin tablets prepared according to the prescription are placed for 5 days under the conditions of illumination of 4500Lx, constant temperature of 60 ℃ and high humidity RH of 92.5 percent, and various indexes are examined, and the results are shown in table 1.
Figure BDA0003426981860000051
TABLE 1
The experimental results are as follows: the product has good stability under various conditions. However, in a high-humidity environment, moisture absorption occurs, which indicates that the product should be stored hermetically under dry conditions.
Example 2:
this example is the same as example 1 except for the prescription of balofloxacin.
In this embodiment, 1000 tablets are prepared, and the specific prescription is: 109.2g of balofloxacin dihydrate, 120g of microcrystalline cellulose, 120g of pregelatinized starch and 2g of magnesium stearate.
Initial stability study of balofloxacin:
balofloxacin tablets prepared according to the prescription are placed for 5 days under the conditions of illumination of 4500Lx, constant temperature of 60 ℃ and high humidity RH of 92.5 percent, and various indexes are examined, and the results are shown in table 2.
Figure BDA0003426981860000052
Figure BDA0003426981860000061
TABLE 2
The experimental results are as follows: the product has good stability under various conditions. However, in a high-humidity environment, moisture absorption occurs, which indicates that the product should be stored hermetically under dry conditions.
Example 3:
this example is the same as example 1 except for the prescription of balofloxacin.
In this embodiment, 1000 tablets are prepared, and the specific prescription is: 119.5g of balofloxacin dihydrate, 130g of microcrystalline cellulose, 130g of pregelatinized starch and 3g of magnesium stearate.
Initial stability study of balofloxacin:
balofloxacin tablets prepared according to the prescription are placed for 5 days under the conditions of light irradiation of 4500Lx, constant temperature of 60 ℃ and high humidity RH of 92.5 percent, and various indexes are examined, and the results are shown in table 3.
Figure BDA0003426981860000062
TABLE 3
The experimental results are as follows: the product has good stability under various conditions. However, in a high-humidity environment, moisture absorption occurs, which indicates that the product should be stored hermetically under dry conditions.
And (3) verification of balofloxacin finished product:
the product was prepared according to the recipe in examples 1-3, and the specifications of the tablets were: 0.1 g/tablet.
The results are shown in Table 4.
Batches of Example 1 Example 2 Example 3
Feed amount Feeding 1000 tablets Feeding 1000 tablets Feeding 1000 tablets
Amount of finished product 983 tablet 988 tablet 993 tablet
Yield of finished products 98.3％ 98.3％ 98.3％
TABLE 4
Pharmacological verification of balofloxacin:
1. absorption of
Balofloxacin was absorbed more rapidly after single oral administration to mice and beagle dogs. There is ethnic variability in the absorption and elimination of balofloxacin from animals, the elimination half-life of beagle dogs is shorter than that of mice, and the AUC of beagle dogs is higher than that of mice administered dose. The mean oral bioavailability for mice, rats and beagle dogs was 19.03,87.50 and 87.73%, respectively. Balofloxacin was almost completely absorbed by single oral doses in rats and beagle dogs, whereas the mice absorbed less after single oral doses.
2. Distribution of
After single oral administration of balofloxacin to rats, the radioactivity of most tissues reaches the maximum value within 1h after administration, and 0.5h after administration, the radioactivity of the tissues is highest by the kidney and the liver, the radioactivity of the spleen, the pancreas, the lung and the mandibular gland contain moderate radioactivity, and the radioactivity of the brain and the cerebellum is lower.
3. Metabolism
After single oral administration of balofloxacin to mice and beagle dogs, the urine drug prototype output of mice and beagle dogs was the majority. Metabolites, the combined product of glucuronic acid of balofloxacin and the demethylation product at the N-position of balofloxacin are excreted in small portions through the urine. Most of the bile or feces of beagle dogs are excreted as a binding product of glucuronic acid. Most of the bile or feces of the mice are excreted with unknown products in addition to the bound products of glucuronic acid.
4. Excretion device
After single oral administration of balofloxacin to mice and beagle dogs, almost all of the radioactivity of the administered dose was excreted in urine and feces. After single-dose intravenous administration of balofloxacin to mice and beagle dogs, the excretion rate of radioactivity of beagle dogs through urine is similar to that of feces, the excretion rate of radioactivity of mice through urine is lower than that of feces, and the excretion route of radioactivity is different from species.
5. Human body drug-induced power experiment
The product is orally taken by a single dose in healthy adult men, and the blood concentration is correspondingly increased along with the dose. The peak concentrations in the 100 and 200mg dose groups were 1 and 2. mu.g/ml, respectively. The peak reaching time is 1.0-1.2h, the half-life period is 7.0-8.3h, and the rapid absorption of the medicine in small intestine and the long plasma retention time are shown. After meal administration, Tmax is prolonged, Cmax is reduced, and the accumulative excretion rate of the medicine in urine is similar to the fasting administration state, so that the medicine absorption is not influenced.
The cumulative excretion rate of the original drug form in urine is 70-80% of the oral dosage 48 hours after administration of different dosages, and 2.8-10.7% of the oral dosage is eliminated from feces. The product is hardly metabolized, the glucuronic acid binding product of balofloxacin is 4%, and the N-position demethylation product of balofloxacin is 0.4%.
The repeated dose administration is carried out by oral administration 1 time per day at 200 or 300mg for 7 days, and the blood concentration reaches a steady state on 2-3 days. The plasma concentrations varied similarly after each administration and were similar to those at the first time. The cumulative urine excretion rates of 200mg and 300mg doses were 71.9 and 86.3%, respectively, and there was no accumulation in vivo.
The technical features of the embodiments described above may be arbitrarily combined, and for the sake of brevity, all possible combinations of the technical features in the embodiments described above are not described, but should be considered as being within the scope of the present specification as long as there is no contradiction between the combinations of the technical features.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present patent shall be subject to the appended claims.

Claims (9)

1. The preparation process of the balofloxacin tablet is characterized by comprising the following steps:
step S1: weighing balofloxacin dihydrate, and screening for later use; weighing microcrystalline cellulose and pregelatinized starch, mixing, and screening the mixed materials for later use;
step S2: the balofloxacin dihydrate, the microcrystalline cellulose and the pregelatinized starch are mixed uniformly by a dilution method to obtain mixed powder.
Step S3: weighing magnesium stearate and screening for later use;
step S4: and uniformly mixing the mixed powder and magnesium stearate, screening the mixture, determining the tablet weight, and tabletting to obtain the tablet.
2. The process for preparing balofloxacin tablets as claimed in claim 1, wherein the steps of: in step S1, balofloxacin dihydrate is sieved through a 100 mesh sieve.
3. The process for preparing balofloxacin tablets as claimed in claim 1, wherein the steps of: in step S1, the mixture of microcrystalline cellulose and pregelatinized starch is passed through a 100 mesh screen.
4. The process for preparing balofloxacin tablets as claimed in claim 1, wherein the steps of: in step S2, the mixture of balofloxacin dihydrate, microcrystalline cellulose and pregelatinized starch was added from the feed inlet and mixed for 20 minutes at a rotation speed of 10 rpm by mixing and dilution in a multi-directional mixer.
5. The process for preparing balofloxacin tablets as claimed in claim 1, wherein the steps of: in step S3, the magnesium stearate is passed through a 100 mesh screen.
6. The process for preparing balofloxacin tablets as claimed in claim 1, wherein the steps of: in step S4, the mixed powder and magnesium stearate are mixed uniformly and then sieved through an 80-mesh sieve twice.
7. The balofloxacin tablet prepared by the preparation process of the balofloxacin tablet as described in any one of claims 1-6, which is characterized by comprising the following components in parts by weight: 100-120 parts of balofloxacin dihydrate, 107-132 parts of microcrystalline cellulose, 104-143 parts of pregelatinized starch and 1-3 parts of magnesium stearate.
8. Balofloxacin tablet according to claim 7, characterized in that: comprises the following components in parts by weight: 104-113 parts of balofloxacin dihydrate, 117-124 parts of microcrystalline cellulose, 104-143 parts of pregelatinized starch and 1-3 parts of magnesium stearate.
9. Balofloxacin tablet according to claim 7, characterized in that: every 1000 tablets of balofloxacin are prepared, which comprises the following components: 109.2g of balofloxacin dihydrate, 120g of microcrystalline cellulose, 120g of pregelatinized starch and 2.0g of magnesium stearate.
CN202111580441.XA 2021-12-22 2021-12-22 Balofloxacin tablet and preparation process thereof Pending CN114191400A (en)

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101627999A (en) * 2009-08-20 2010-01-20 山东罗欣药业股份有限公司 Balofloxacin composition, preparation method thereof and synthesis method of material medicament
US20100029936A1 (en) * 2007-01-24 2010-02-04 Harms Arthur E Quinolone Carboxylic Acids, Derivatives Thereof, and Methods of Making and Using Same
CN107343879A (en) * 2016-05-04 2017-11-14 永信药品工业(昆山)有限公司 Balofloxacin pharmaceutical composition, preparation method and applications
CN107669645A (en) * 2017-10-31 2018-02-09 瑞阳制药有限公司 The preparation method of ciprofloxacin hydrocloride tablets
CN109045034A (en) * 2018-09-29 2018-12-21 哈尔滨珍宝制药有限公司 A kind of moxifloxacin hydrochloride medicinal composition and its preparation method and application

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20100029936A1 (en) * 2007-01-24 2010-02-04 Harms Arthur E Quinolone Carboxylic Acids, Derivatives Thereof, and Methods of Making and Using Same
CN101627999A (en) * 2009-08-20 2010-01-20 山东罗欣药业股份有限公司 Balofloxacin composition, preparation method thereof and synthesis method of material medicament
CN107343879A (en) * 2016-05-04 2017-11-14 永信药品工业(昆山)有限公司 Balofloxacin pharmaceutical composition, preparation method and applications
CN107669645A (en) * 2017-10-31 2018-02-09 瑞阳制药有限公司 The preparation method of ciprofloxacin hydrocloride tablets
CN109045034A (en) * 2018-09-29 2018-12-21 哈尔滨珍宝制药有限公司 A kind of moxifloxacin hydrochloride medicinal composition and its preparation method and application

Non-Patent Citations (2)

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Title
关志宇主编: "《药用制剂辅料与包装材料》", 31 January 2017, 中国医药科技出版社 *
唐星主编: "《药剂学》", 31 December 2019, 中国医药科技出版社 *

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