CN112190558A - Levofloxacin composition - Google Patents
Levofloxacin composition Download PDFInfo
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- CN112190558A CN112190558A CN202011122897.7A CN202011122897A CN112190558A CN 112190558 A CN112190558 A CN 112190558A CN 202011122897 A CN202011122897 A CN 202011122897A CN 112190558 A CN112190558 A CN 112190558A
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- sodium acetate
- citric acid
- levofloxacin hydrochloride
- levofloxacin
- magnesium stearate
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K31/5375—1,4-Oxazines, e.g. morpholine
- A61K31/5383—1,4-Oxazines, e.g. morpholine ortho- or peri-condensed with heterocyclic ring systems
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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
- A61K9/2009—Inorganic compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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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
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention relates to a levofloxacin hydrochloride composition, belonging to the technical field of pharmaceutical preparations. Every 1000 tablets of the levofloxacin hydrochloride composition contain 100g of levofloxacin hydrochloride, 10-14g of citric acid, a proper amount of sodium acetate, 60-80g of superfine silica gel powder, 60-120g of microcrystalline cellulose, 8-15g of crospovidone and 1-2g of magnesium stearate. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.8-2.2. The invention provides a stable levofloxacin composition.
Description
Technical Field
The invention relates to a levofloxacin hydrochloride composition, belonging to the technical field of pharmaceutical preparations.
Background
Levofloxacin has a chemical name of (S) - (-) -9-fluoro-2, 3-dihydro-3-methyl-10- [ 4-methyl-1-piperazinyl ] -7-oxo-7-hydropyrido [1,2,3-de ] - [1,4] benzoxazine-6-carboxylic acid, and a fluoroquinolone antibacterial drug developed by first pharmaceutical co-Ltd of Japan is a first-line clinical antibacterial drug, and belongs to a national basic drug.
Levofloxacin hydrochloride is slightly soluble in water, and in order to improve the dissolution rate, a surfactant is often added into the prescription. Stability tests show that the levofloxacin hydrochloride oral preparation has the degradation problem in the storage process, the increase of the impurity E is positively correlated with the storage time, and certain potential safety hazard is brought to clinical medication.
201610184636.5 patent improves dissolution rate and instability of dissolution rate by adding superfine silica powder; 201410515777.1 patent adopts talcum powder and stearic acid added in specific proportion, and the prepared tablet has good quality controllability; 201810219934.2 patent adds low substituted hydroxypropyl cellulose, surfactant and crospovidone in the prescription to solve the problem of unsatisfactory dissolution rate.
However, the above technologies do not solve the problem that the impurity E is obviously increased in the storage process of the prepared levofloxacin hydrochloride oral preparation.
Disclosure of Invention
The purpose of the invention is as follows: provides a levofloxacin hydrochloride composition with stable quality, and solves the defect of rising of impurity E in the storage process.
Experiments show that in the prescription of the levofloxacin hydrochloride composition, the citric acid and the sodium acetate are reasonably compatible, so that the dissolution rate can be improved, and the degradation can be effectively avoided.
The technical scheme of the invention is as follows:
a levofloxacin hydrochloride composition comprises levofloxacin hydrochloride, aerosil, citric acid and sodium acetate, wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.6-2.6.
When the content of sodium acetate is lower than the ratio range, the dissolution rate of the prepared composition is reduced along with the reduction of the content of sodium acetate; when the content of sodium acetate is higher than the above ratio range, the degradation impurity E tends to increase during the storage of the prepared composition.
Preferably, each 1000 tablets of the levofloxacin hydrochloride composition contain 100g of levofloxacin hydrochloride, 10-14g of citric acid, a proper amount of sodium acetate, 60-80g of aerosil, 60-120g of microcrystalline cellulose, 8-15g of crospovidone and 1-2g of magnesium stearate. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.8-2.2.
Preferably, each 1000 tablets of the levofloxacin hydrochloride composition contain 100g of levofloxacin hydrochloride, 12g of citric acid, a proper amount of sodium acetate, 66-75g of aerosil, 80-100g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate. The mass ratio of the citric acid to the sodium acetate is 1: 2-2.17.
Preferably, each 1000 tablets of the levofloxacin hydrochloride composition contain 100g of levofloxacin hydrochloride, 12g of citric acid, 25g of sodium acetate, 70g of aerosil, 90g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate. The mass ratio of the citric acid to the sodium acetate is 1: 2.08.
The preparation method of the levofloxacin hydrochloride composition comprises the following steps:
in the first step, raw levofloxacin hydrochloride is sieved by a 100-mesh sieve, and auxiliary materials are sieved by a 80-mesh sieve.
And secondly, weighing raw and auxiliary materials according to the prescription amount.
And step three, uniformly mixing levofloxacin hydrochloride in a prescription amount with citric acid, sodium acetate, superfine silica gel powder, microcrystalline cellulose and crospovidone in a prescription amount.
And fourthly, placing the granules obtained in the third step into a fluidized bed, spraying softened water for granulation, drying at 60 ℃ and finishing the granules.
Fifthly, adding magnesium stearate with the prescription amount into the granules obtained in the fourth step, and tabletting.
Has the advantages that: according to the technical scheme of the invention, by means of the synergistic effect of citric acid and sodium acetate, the dissolution rate is improved, the pharmaceutical preparation is stabilized, and a safe and reliable pharmaceutical preparation is provided for clinic.
Example 1 levofloxacin hydrochloride 100g, citric acid 10g, sodium acetate 26g, aerosil 60g, microcrystalline cellulose 60g, crospovidone 8g, magnesium stearate 1 g. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 2.6. 1000 tablets are prepared according to the preparation method of the technical scheme of the specification.
Example 2 levofloxacin hydrochloride 100g, citric acid 14g, sodium acetate 22.4g, aerosil 80g, microcrystalline cellulose 120g, crospovidone 15g, magnesium stearate 2 g. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.6. 1000 tablets are prepared according to the preparation method of the technical scheme of the specification.
Example 3 levofloxacin hydrochloride 100g, citric acid 12g, sodium acetate 25g, aerosil 70g, microcrystalline cellulose 90g, crospovidone 10g, magnesium stearate 1.5 g. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 2.08. 1000 tablets are prepared according to the preparation method of the technical scheme of the specification.
Comparative example 1.
100g of levofloxacin hydrochloride, 12g of citric acid, 14.4g of sodium acetate, 70g of aerosil, 90g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.2. 1000 tablets are prepared by the preparation method according to the technical scheme of the specification.
Comparative example 2.
100g of levofloxacin hydrochloride, 12g of citric acid, 36g of sodium acetate, 70g of aerosil, 90g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate. Wherein the mass ratio of the citric acid to the sodium acetate is 1: 3. 1000 tablets are prepared by the preparation method according to the technical scheme of the specification.
Comparative example 3.
100g of levofloxacin hydrochloride, 120g of aerosil, 90g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate.
Description of the drawings: the prescription is free of citric acid and sodium acetate. 1000 tablets are prepared by the preparation method according to the technical scheme of the specification.
Test example 1 dissolution rates and contents of related substances (including impurity E) of the products of examples 1 to 3 and comparative examples 1 to 3 were measured according to pharmacopoeia specifications, respectively, and the data are shown in table 1.
And (3) dissolution rate determination: according to the determination method of dissolution rate and release rate of Chinese pharmacopoeia (first method of general rule 0931), 900ml of hydrochloric acid solution (9 → 1000 ml) is used as dissolution medium, the rotation speed is 100 rpm, and the dissolution rate is measured at 45 minutes. The absorbance was measured at a wavelength of 294nm by ultraviolet-visible spectrophotometry (general rule 0401), and the amount of elution was calculated for each tablet. The limit is 80% of the indicated amount.
And (3) related substance determination: according to Chinese pharmacopoeia, adopting a C18 chromatographic column, dissolving ammonium acetate sodium perchlorate solution (4.0 g of sodium acetate and 7.0g of sodium perchlorate in 1300ml of water, adjusting the pH value to 2.2 by using phosphoric acid), taking acetonitrile (85: 15) as a mobile phase A, taking acetonitrile as a mobile phase B, and carrying out gradient elution; the flow rate is 1 ml/min; the column temperature is 40 ℃; the detection wavelengths are 294nm and 238 nm; the injection volume is 10. mu.L. The limit of the impurity E is 0.3 percent and the total limit of related substances is 0.7 percent according to the self-comparison method.
TABLE 10 days dissolution and impurity E test summary
Table 1 the data illustrates: the dissolution rates of the products in examples 1 to 3, the contents of related substances and impurities E are in a qualified range, and the dissolution rate of the product in comparative example 3 is in an unqualified range, which shows that the reasonable addition of citric acid and sodium acetate in the technical scheme of the invention has a positive effect of correspondingly improving the dissolution rate.
Test example 2 stability test
100 tablets of the products of examples 1-3 and comparative examples 1-3 were taken, respectively packaged by aluminum-plastic, placed in a constant temperature and humidity cabinet, placed at 40 ℃ +/-2 ℃ and relative humidity of 75% +/-5% for 6 months, taken out at the end of 3 months and 6 months, respectively examined for dissolution and impurity E content, and the data are recorded in tables 2 and 3.
TABLE 2 summary of dissolution at end of 3 rd month and impurity E test
Table 2 the data illustrates: at the end of 3 rd month of the accelerated test, the dissolution rates of the products in examples 1-3, related substances and impurity E are in a qualified range, while the dissolution rates of the products in comparative example 1 and comparative example 3 are in an unqualified range, which shows that the dissolution rate is in a descending trend after the dosage of sodium acetate is less than 1.6 times of that of citric acid. The content of the impurity E in the comparison examples 2 and 3 is obviously increased, which indicates that sodium acetate and citric acid are not added, and the impurity E has an obvious increasing trend when the dosage of the sodium acetate exceeds 2.6 times of that of the citric acid.
TABLE 3 summary of dissolution at end of month 6 and impurity E measurements
Table 3 the data illustrates: at the end of 6 th month of the accelerated test, the dissolution rates, related substances and the content of the impurity E of the products of the examples 1 to 3 are stable and in a qualified range.
The dissolution rate of the products of the comparative examples 1 to 3 is in a unqualified range, which shows that the dissolution rate is in a descending trend after the dosage of the sodium acetate is 1.6 times lower than that of the citric acid. The content of the impurity E in the comparison examples 2 and 3 is obviously increased, which shows that the content of the impurity E is obviously increased after the sodium acetate and the citric acid are added, and the impurity E has an obvious increasing trend when the dosage of the sodium acetate exceeds 2.6 times of that of the citric acid.
Claims (5)
1. The levofloxacin hydrochloride composition is characterized by comprising levofloxacin hydrochloride, superfine silica gel powder, citric acid and sodium acetate, wherein the mass ratio of the citric acid to the sodium acetate is 1: 1.6-2.6.
2. The levofloxacin hydrochloride composition according to claim 1, wherein each 1000 tablets comprise 100g of levofloxacin hydrochloride, 10-14g of citric acid, a proper amount of sodium acetate, 60-80g of aerosil, 60-120g of microcrystalline cellulose, 8-15g of crospovidone and 1-2g of magnesium stearate, wherein the mass ratio of citric acid to sodium acetate is 1: 1.8-2.2.
3. The levofloxacin hydrochloride composition according to claim 1, wherein each 1000 tablets comprise 100g of levofloxacin hydrochloride, 12g of citric acid, a proper amount of sodium acetate, 66-75g of aerosil, 80-100g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate, wherein the mass ratio of the citric acid to the sodium acetate is 1: 2-2.17.
4. The levofloxacin hydrochloride composition according to claim 1, wherein each 1000 tablets comprise 100g of levofloxacin hydrochloride, 12g of citric acid, 25g of sodium acetate, 70g of aerosil, 90g of microcrystalline cellulose, 10g of crospovidone and 1.5g of magnesium stearate, wherein the mass ratio of the citric acid to the sodium acetate is 1: 2.08.
5. A process for preparing a levofloxacin hydrochloride composition according to claim 1, comprising the steps of:
firstly, sieving the levofloxacin hydrochloride raw material by a 100-mesh sieve, and sieving the auxiliary material by a 80-mesh sieve;
secondly, weighing raw and auxiliary materials according to the prescription amount;
thirdly, uniformly mixing the levofloxacin hydrochloride with the prescription amount and other auxiliary materials with the prescription amount;
fourthly, placing the granules obtained in the third step into a fluidized bed, spraying softened water for granulation, drying at 60 ℃ and finishing granules;
fifthly, adding magnesium stearate with the prescription amount into the granules obtained in the fourth step, and tabletting.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011122897.7A CN112190558A (en) | 2020-10-20 | 2020-10-20 | Levofloxacin composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202011122897.7A CN112190558A (en) | 2020-10-20 | 2020-10-20 | Levofloxacin composition |
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| Publication Number | Publication Date |
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| CN112190558A true CN112190558A (en) | 2021-01-08 |
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| Application Number | Title | Priority Date | Filing Date |
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| CN202011122897.7A Pending CN112190558A (en) | 2020-10-20 | 2020-10-20 | Levofloxacin composition |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115381791A (en) * | 2022-09-21 | 2022-11-25 | 迪沙药业集团有限公司 | Flunarizine hydrochloride pharmaceutical composition |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101461777A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable levofloxacin hydrochloride eye drops without bacteriostatic agent and preparation method thereof |
| CN102949334A (en) * | 2011-08-19 | 2013-03-06 | 苏州太湖美药业有限公司 | Levofloxacin hydrochloride gel-type eye-drops |
| CN103520124A (en) * | 2013-09-29 | 2014-01-22 | 南京正宽医药科技有限公司 | Levofloxacin hydrochloride tablet and preparation method thereof |
-
2020
- 2020-10-20 CN CN202011122897.7A patent/CN112190558A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101461777A (en) * | 2009-01-06 | 2009-06-24 | 河北科技大学 | Disposable levofloxacin hydrochloride eye drops without bacteriostatic agent and preparation method thereof |
| CN102949334A (en) * | 2011-08-19 | 2013-03-06 | 苏州太湖美药业有限公司 | Levofloxacin hydrochloride gel-type eye-drops |
| CN103520124A (en) * | 2013-09-29 | 2014-01-22 | 南京正宽医药科技有限公司 | Levofloxacin hydrochloride tablet and preparation method thereof |
Non-Patent Citations (1)
| Title |
|---|
| 倪华丽等: "盐酸左氧氟沙星氯化钠注射液生产过程质量控制", 《齐鲁药事》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115381791A (en) * | 2022-09-21 | 2022-11-25 | 迪沙药业集团有限公司 | Flunarizine hydrochloride pharmaceutical composition |
| CN115381791B (en) * | 2022-09-21 | 2023-06-16 | 迪沙药业集团有限公司 | Flunarizine hydrochloride pharmaceutical composition |
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| TA01 | Transfer of patent application right |
Effective date of registration: 20210902 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Dijia Pharmaceutical Group Co.,Ltd. |
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Application publication date: 20210108 |
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