CN111658616B - Cefprozil dry suspension and preparation method thereof - Google Patents
Cefprozil dry suspension and preparation method thereof Download PDFInfo
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- CN111658616B CN111658616B CN202010439911.XA CN202010439911A CN111658616B CN 111658616 B CN111658616 B CN 111658616B CN 202010439911 A CN202010439911 A CN 202010439911A CN 111658616 B CN111658616 B CN 111658616B
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
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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
- A61K31/54—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame
- A61K31/542—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one sulfur as the ring hetero atoms, e.g. sulthiame ortho- or peri-condensed with heterocyclic ring systems
- A61K31/545—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine
- A61K31/546—Compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins, cefaclor, or cephalexine containing further heterocyclic rings, e.g. cephalothin
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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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
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Abstract
The invention discloses a cefprozil dry suspension and a preparation method thereof. According to the scheme of the invention, citric acid-sodium citrate is added into the auxiliary materials, so that the increase of the impurity Z can be effectively inhibited, and the stability of the cefprozil dry suspension is improved.
Description
Technical Field
The invention relates to the technical field of medicine preparation, and particularly relates to a cefprozil dry suspension and a preparation method thereof.
Background
Cefprozil is the second generation oral cephalosporin approved by FDA in the United states at the end of 1991, has remarkable broad-spectrum antibacterial effect, and the bactericidal mechanism of the cefprozil is to block the synthesis of bacterial cell walls. In vitro tests show that the cefprozil has obvious effects on staphylococcus aureus (including beta-lactamase-producing strains), streptococcus pneumoniae and streptococcus pyogenes in gram-positive aerobic bacteria, and has inhibitory effects on enterococcus durans, listeria monocytogenes, staphylococcus epidermidis, staphylococcus saprophyticus, warneei staphylococcus, streptococcus agalactiae, streptococcus C, D, F, G groups and viridans streptococcus; is ineffective to methicillin-resistant staphylococcus and enterococcus faecalis; highly sensitive to haemophilus influenzae (including beta-lactamase-producing strains), moraxella catarrhalis (including beta-lactamase-producing strains), gram-negative aerobic bacteria; can inhibit the proliferation of Diversus Citrobacter, Escherichia coli, Klebsiella pneumoniae, Neisseria gonorrhoeae (including beta-lactamase producing strains), Proteus mirabilis, Salmonella, Shigella and Vibrio.
Besides the characteristics of wide antibacterial spectrum and the like, cefprozil also has good safety, the adverse reaction is lower than the incidence rate of the traditional cephalosporin, and the nephrotoxicity is greatly reduced than that of the previous generation, so cefprozil is the first oral cephalosporin antibiotic approved by the FDA in the United states and can be used for treating otitis media and nasosinusitis in children, the bioavailability is high, the oral absorption is good, and about 95 percent of dosage can be absorbed. The half-life period is longer and is about 1.3 hours (1.6-2.1 hours for children), so the medicine taking scheme is simple, and the treatment cost of patients can be saved.
Regarding cefprozil, the most current dosage forms at home and abroad are tablets, granules and dry suspensions, domestic experiments prove that the tablets and suspensions orally taken on an empty stomach have bioequivalence, and the dry suspensions are welcomed by pharmaceutical workers and patients at home and abroad due to the advantages of easy dissolution, taste correction, easy taking, stability, convenient carrying, convenient taking by children and the like. The Chinese patent application document CN104688743A discloses a cefprozil dry suspension and a preparation method thereof, the dry suspension is prepared by a diluent, a cosolvent, a suspending agent, a lubricant, a wetting agent (1 wt% citric acid aqueous solution), microcrystalline cellulose and sodium carboxymethylcellulose, and the like, and the preparation method specifically comprises the following steps: (1) pre-mixing the diluent, the microcrystalline cellulose and the sodium carboxymethylcellulose in a wet granulating machine; (2) then adding a cosolvent and a wetting agent for wet granulation; (3) drying and granulating, and marking as a material A; (4) and (3) mixing the cefprozil, the suspending agent and the lubricant with the material A in an equivalent progressive manner, uniformly mixing, and subpackaging to obtain the cefprozil dry suspension. The product has low impurity content, high dissolution rate, good stability, uniform dispersion of main drug, simple preparation process, no need of special equipment, and suitability for industrial mass production. However, it still has the following drawbacks: first, it has not been studied for a long time on the stability of the formulation, which patent only demonstrates stability within 10 days, which does not demonstrate that the impurity content does not increase within the shelf life; secondly, 1 wt% citric acid aqueous solution is used as a wetting agent, which may affect the pH value of the suspension, thereby causing the increase of impurities; finally, in the preparation process, the auxiliary materials need to be increased in number and mixed for multiple times, the preparation process is complicated, and the cost and quality control risk can be increased in the large-scale production process.
In addition, the inventor finds that the cefprozil raw material and the dry suspension have a characteristic unknown impurity Z which is not reported in the literature, and the impurity Z has a growing trend in the storage process, so that the quality of the preparation is influenced. The structure of the impurity Z was confirmed by a Liquid chromatography-High Resolution Tandem Mass spectrometer (LC-HR-MS/MS), and the specific structure of the impurity Z in the test sample was confirmed as follows:
in the analysis of the mechanism of impurity Z generation, the inventors speculate that it is cyclopropene ethyl ester, which is easily generated and tends to grow under high temperature and high humidity conditions, and affects the safety of the drug. In the prior art, no literature reports on the research on the impurity and an effective method for inhibiting the growth of the impurity.
Disclosure of Invention
The present invention is directed to solving at least one of the problems of the prior art. Therefore, the cefprozil dry suspension provided by the invention can effectively inhibit the increase of the impurity Z.
The invention also provides a preparation method of the dry suspension.
According to the cefprozil dry suspension provided by the embodiment of the first aspect of the invention, the preparation raw materials of the cefprozil dry suspension comprise cefprozil and auxiliary materials, the auxiliary materials comprise acidity adjusting and stabilizing agents, and the acidity adjusting and stabilizing agents comprise citric acid and sodium citrate.
According to some embodiments of the invention, the mass ratio of citric acid to sodium citrate is (1-6): (1-8); more preferably (2-3) to (4-6); further preferably 1: 2. By adjusting the mass ratio of citric acid to sodium citrate, the buffer capacity is ensured, the generation of unknown impurity Z is obviously reduced, and the safety of the medicine is improved.
According to some embodiments of the invention, the citric acid comprises 0.1-3% by mass of the dry suspension; preferably 0.6 to 0.9%.
According to some embodiments of the invention, the sodium citrate is present in an amount of no more than 2.55% by mass of the dry suspension; preferably, the sodium citrate accounts for 1.2-1.8% of the mass of the dry suspension.
According to some embodiments of the invention, the cefprozil accounts for 6-6.5% of the mass of the dry suspension; preferably 6.2-6.3%; more preferably 6.25%.
According to some embodiments of the invention, the adjuvant further comprises a shaping and flavoring agent; preferably, the excipient and flavoring agent is selected from sucrose, and can also be other conventional flavoring agents.
According to some embodiments of the invention, the excipient and flavoring agent accounts for 74.7-85% of the mass of the dry suspension; preferably 78.6-83.75%; more preferably 81.45 to 82.35%.
According to some embodiments of the invention, the adjuvant further comprises a suspending agent; preferably, the suspending agent is selected from microcrystalline cellulose-sodium carboxymethyl cellulose, and other conventional suspending agents can be used.
According to some embodiments of the invention, the suspending agent accounts for 8-10% of the mass of the dry suspension; preferably 8.5-9.5%; more preferably 9.2%.
According to some embodiments of the invention, the adjuvant further comprises a fragrance; preferably, the flavour is selected from sweet orange flavour, but also other flavours of conventional taste.
According to some embodiments of the invention, the flavor comprises 0.1-1% by mass of the dry suspension; preferably 0.1-0.5%; more preferably 0.4%.
According to some embodiments of the invention, the adjunct further comprises a wetting agent; preferably, the wetting agent can be ethanol solutions or purified water of varying concentrations.
The dry suspension provided by the embodiment of the invention at least has the following beneficial effects: according to the scheme of the invention, citric acid-sodium citrate is added into the auxiliary materials, so that the increase of the impurity Z can be effectively inhibited, and the stability of the cefprozil dry suspension is improved.
A method of making an embodiment according to the second aspect of the invention comprises the steps of:
s1, granulating: mixing cefprozil with citric acid and sodium citrate, adding a wetting agent to prepare a soft material, and preparing the soft material into wet granules;
s2, drying: and (5) drying the wet granules prepared in the step (S1).
According to some embodiments of the invention, the drying operation in step S2 is to dry the wet granulation to a moisture content of no more than 1.5%.
According to some embodiments of the invention, the method of preparation further comprises the step of adding a flavoring agent during granulation, the flavoring agent being pulverized prior to addition.
According to some embodiments of the invention, the preparation method further comprises a step of adding a perfume after drying, and the particles obtained after drying are mixed with the perfume.
The preparation method provided by the embodiment of the invention has at least the following beneficial effects: the scheme of the invention has simple preparation process, few operation steps, guaranteed quality control and obviously reduced production cost.
Additional aspects and advantages of the invention will be set forth in part in the description which follows and, in part, will be obvious from the description, or may be learned by practice of the invention.
Detailed Description
In order to explain the technical content, the objects and the effects of the present invention in detail, the following description will be given with reference to the embodiments. The test methods used in the examples are all conventional methods unless otherwise specified; the materials, reagents and the like used are commercially available reagents and materials unless otherwise specified.
The embodiment of the invention is as follows: the cefprozil dry suspension and the preparation method thereof are characterized in that the total amount of each prescription in the following examples 1-4 is consistent, the dosage of citric acid and sodium citrate in each prescription is different, the corresponding variable quantity is complemented by cane sugar, and the dosage of raw and auxiliary materials in each prescription is shown in table 1:
TABLE 1 formulation compositions of examples 1-4
The preparation method of the cefprozil dry suspension comprises the following steps:
(1) pulverizing sucrose, and sieving with 60 mesh sieve.
(2) Weighing cefprozil raw material, cane sugar, citric acid, sodium citrate, microcrystalline cellulose-sodium carboxymethylcellulose and other auxiliary materials in sequence according to the formula amount, mixing for 3 minutes in a wet granulation machine, adding wetting agent (water) to prepare soft materials, and adding the prepared soft materials into rotary granulation machine-made particles.
(3) And (3) placing the finished wet granules into a multifunctional granulating and coating machine for boiling drying until the moisture is less than or equal to 1.5%, stopping drying, and sieving with a 20-mesh sieve for finishing the granules.
(4) Adding sweet orange powder essence into the dry granules, mixing in a hopper of a mixer for 10min, and packaging the total mixed granules.
Comparative example
In this example, 1000 bags of 11 comparative samples were prepared by using the preparation method and the preparation raw material of example 2, and the numbers of the comparative samples were comparative examples 1 to 11. The comparative examples 1 to 11 are different from the example 2 only in that the amounts of citric acid and sodium citrate and/or the mass ratio of the citric acid to the sodium citrate in the formula are different, the remaining amounts are similar, and the change caused by the poor mass is compensated by adjusting the sucrose content, specifically, the specific amounts of citric acid and sodium citrate are shown in table 2:
TABLE 2 formulation compositions for comparative examples 1 to 10
Example of detection
In this example, 1000 bags of 11 comparative samples were prepared by using the preparation method and the preparation raw material of example 2, and the numbers of the comparative samples were comparative examples 1 to 11. The comparative examples 1-11 are different from the example 2 only in the dosage of citric acid and sodium citrate in the adhesive formula and/or the mass ratio of the citric acid and the sodium citrate.
Detection of impurity Z
Taking the preparations prepared in the examples 1 to 4 and the comparative examples 1 to 11, lofting the stability, and checking the method: high performance liquid chromatography (0512 in the four general regulations of the 2015 edition of Chinese pharmacopoeia) is adopted according to the standard of second spore propylene particles of the 2015 edition of Chinese pharmacopoeia.
The measured hetero Z content is shown in Table 3:
TABLE 3 impurity Z content (%)
As can be seen from the results in Table 3, the formulations of examples 2-4 can better achieve the expected technical effect, the impurity Z is significantly reduced, the growth is slower in the accelerated test, and the quality of the formulations is more stable; example 1 and comparative examples 1-10 are also reduced to some extent relative to the conventional method (i.e., comparative example 11).
Determination of the acidity of a suspension
Taking the stability lofting samples of the examples 1-4 and the comparative examples 1-11, and determining the method: taking a proper amount of the total mixed particles, adding new boiling cold water to prepare a suspension containing 35mg of cefprozil in each 1ml, and measuring the acidity by the method, wherein the results are shown in a table 4:
TABLE 4 pH of suspension
As can be seen from the results in Table 4, the formulations of examples 1-4 are more stable in acidity and have a smaller pH drift range.
It is to be understood that the invention disclosed is not limited to the particular methodology, protocols, and materials described, as these may vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to limit the scope of the present invention which will be limited only by the appended claims.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or directly or indirectly applied to the related technical field are included in the scope of the present invention.
Claims (8)
1. The cefprozil dry suspension is prepared from raw materials including cefprozil and auxiliary materials, wherein the auxiliary materials include acidity regulation and stabilizer, and the cefprozil dry suspension is characterized in that: the acidity regulating and stabilizing agent comprises citric acid and sodium citrate; the citric acid accounts for 0.6-0.9% of the mass of the dry suspension; the sodium citrate accounts for 1.2-1.8% of the mass of the dry suspension; the mass ratio of the citric acid to the sodium citrate is 1: 2; the cefprozil accounts for 6-6.5% of the mass of the dry suspension; the auxiliary materials also comprise excipient and correctant; the excipient and the flavoring agent account for 74.7-85% of the mass of the dry suspension; the auxiliary materials also comprise a suspending agent; the suspending agent is selected from microcrystalline cellulose-sodium carboxymethylcellulose, and accounts for 8-10% of the mass of the dry suspension.
2. Cefprozil dry suspension according to claim 1, characterized in that: the cefprozil accounts for 6.2-6.3% of the mass of the dry suspension.
3. Cefprozil dry suspension according to claim 1, characterized in that: the cefprozil accounts for 6.25% of the mass of the dry suspension.
4. Cefprozil dry suspension according to claim 1, characterized in that: the excipient and the flavoring agent are selected from sucrose.
5. Cefprozil dry suspension according to claim 4, characterized in that: the excipient and the flavoring agent account for 78.6-83.75% of the mass of the dry suspension.
6. Cefprozil dry suspension according to claim 5, characterized in that: the excipient and the flavoring agent account for 81.45-82.35% of the mass of the dry suspension.
7. Cefprozil dry suspension according to claim 1, characterized in that: the auxiliary materials also comprise a wetting agent.
8. A preparation method of cefprozil dry suspension is characterized by comprising the following steps: the cefprozil dry suspension is prepared from cefprozil and auxiliary materials, wherein the auxiliary materials comprise acidity adjusting and stabilizing agents, excipient and flavoring agents, suspending agents and wetting agents, and the acidity adjusting and stabilizing agents comprise citric acid and sodium citrate; the suspending agent is selected from microcrystalline cellulose-sodium carboxymethyl cellulose; the cefprozil accounts for 6-6.5% of the mass of the dry suspension; the excipient and the flavoring agent account for 74.7-85% of the mass of the dry suspension; the citric acid accounts for 0.6-0.9% of the mass of the dry suspension; the sodium citrate accounts for 1.2-1.8% of the mass of the dry suspension; the mass ratio of the citric acid to the sodium citrate is 1: 2; the suspending agent accounts for 8-10% of the mass of the dry suspension;
the preparation method comprises the following steps:
s1, granulating: mixing cefprozil with citric acid and sodium citrate, adding a wetting agent to prepare a soft material, and preparing the soft material into wet granules;
s2, drying: and (5) drying the wet granules prepared in the step (S1).
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011360A (en) * | 2007-02-05 | 2007-08-08 | 深圳致君制药有限公司 | Recipe composition of dry turbid agent and its preparation process |
| CN101953789A (en) * | 2010-06-17 | 2011-01-26 | 王丽燕 | Dry suspension containing cefprozil liposome and preparation method thereof |
| EP2528593A2 (en) * | 2010-01-29 | 2012-12-05 | Mahmut Bilgic | Effervescent formulations comprising cefprozil as active agent |
| CN104688743A (en) * | 2015-03-30 | 2015-06-10 | 华北制药河北华民药业有限责任公司 | Cefprozil suspension and preparation method thereof |
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- 2020-05-22 CN CN202010439911.XA patent/CN111658616B/en active Active
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101011360A (en) * | 2007-02-05 | 2007-08-08 | 深圳致君制药有限公司 | Recipe composition of dry turbid agent and its preparation process |
| EP2528593A2 (en) * | 2010-01-29 | 2012-12-05 | Mahmut Bilgic | Effervescent formulations comprising cefprozil as active agent |
| CN101953789A (en) * | 2010-06-17 | 2011-01-26 | 王丽燕 | Dry suspension containing cefprozil liposome and preparation method thereof |
| CN104688743A (en) * | 2015-03-30 | 2015-06-10 | 华北制药河北华民药业有限责任公司 | Cefprozil suspension and preparation method thereof |
Non-Patent Citations (2)
| Title |
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| 头孢丙烯干混悬剂的处方筛选和实验研究;陈增修等;《淮海医药》;20140720;第32卷(第4期);第395-396页第1.2-3部分，表3 * |
| 头孢丙烯干混悬剂的处方筛选实验;赵琳琳等;《黑龙江科技信息》;20080215(第05期);第2.1-3部分 * |
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