CN113952313A - Cefuroxime axetil capsule and preparation method thereof - Google Patents
Cefuroxime axetil capsule and preparation method thereof Download PDFInfo
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- CN113952313A CN113952313A CN202110989826.5A CN202110989826A CN113952313A CN 113952313 A CN113952313 A CN 113952313A CN 202110989826 A CN202110989826 A CN 202110989826A CN 113952313 A CN113952313 A CN 113952313A
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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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
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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
Abstract
The invention discloses a cefuroxime axetil capsule and a preparation method thereof, wherein the preparation method comprises the following steps: (1) pretreatment of raw materials: sieving solubilizer, glidant and lubricant with 60-100 mesh sieve; sieving cefuroxime axetil and the filler with a 60-100 mesh sieve for later use; (2) premixing: mixing the solubilizer, the glidant and the lubricant, and sieving the mixture through a 60-100-mesh sieve to obtain a mixture A; (3) mixing: uniformly mixing cefuroxime axetil and the mixture A, and then adding a filler and a disintegrating agent for uniform mixing to obtain intermediate powder; (4) and (3) filling capsules: filling the intermediate powder into the capsule shell according to the loading requirement, and then packaging to obtain the cefuroxime axetil capsule. The cefuroxime axetil and the auxiliary materials are uniformly mixed, and the capsule is directly filled by adopting a full-powder process without a granulation process. The stability of cefuroxime axetil is improved, and the bioavailability is improved; the production period is shortened, and the cost is reduced.
Description
Technical Field
The invention relates to the technical field of pharmaceutical preparations, in particular to a cefuroxime axetil capsule and a preparation method thereof.
Background
Cefuroxime axetil (cefuroxime axetil) is a second generation cephalosporin antibiotic. After being absorbed by gastrointestinal tract, the cefuroxime sodium can be rapidly hydrolyzed into cefuroxime under the action of esterase to play an antibacterial role. The activity against gram-positive cocci is similar to or slightly inferior to that of the first generation cephalosporins, but the beta lactamases produced by staphylococci and gram-negative bacilli appear to be rather stable. In addition to methicillin-resistant staphylococci, enterococci and Listeria, other positive cocci (including anaerobic cocci) are sensitive to this product.
At present, the domestic cefuroxime axetil preparation formulations mainly comprise tablets, capsules, dry suspensions and the like. The production process of the cefuroxime axetil capsules and tablets in China is generally divided into two types: one is to perform tabletting or fill capsules after wet granulation; the other is tabletting or filling by dry granulation.
Chinese patent application CN201210584846.5 discloses a cefuroxime axetil capsule which is in a non-gel state when meeting water and a preparation method thereof, wherein the capsule comprises the following raw materials and auxiliary materials in percentage by weight: 55-70% of cefuroxime axetil; 1-3% of sodium dodecyl sulfate; 1-3% of an anti-gel auxiliary agent; 15 to 30 percent of disintegrating agent; 5-20% of a filler; the anti-gel auxiliary agent is stearic acid and/or talcum powder, and a dry granulation method is adopted.
Chinese patent application CN201310022373.4 discloses a cefuroxime axetil capsule, which is prepared by mixing drug-loaded pellets containing cefuroxime axetil with talcum powder, and then loading the mixture into a capsule shell; the medicine-carrying pellets are prepared by the following method: weighing cefuroxime axetil and disintegrant, dissolving or dispersing in acetone, spraying the formed solution or suspension onto lactose pellets in a fluidized bed, coating, and drying to obtain the drug-loaded pellets.
Chinese patent application CN202010799275.1 discloses a stable cefuroxime axetil pharmaceutical preparation composition and a preparation method thereof. The composition comprises the following components: cefuroxime axetil, ethyl cellulose, povidone, microcrystalline cellulose, croscarmellose calcium, colloidal silicon dioxide, and sodium stearyl fumarate. The preparation method comprises the following steps: firstly, dissolving and drying the active ingredient cefuroxime axetil, ethyl cellulose and povidone in an organic solvent to prepare a microcapsule intermediate, and then mixing and filling the microcapsule intermediate with other auxiliary materials to prepare the cefuroxime axetil tablet or capsule.
Chinese patent application CN201310285771.5 discloses a cefuroxime axetil pharmaceutical composition, which is a capsule. The preparation method mainly comprises the steps of mixing cefuroxime axetil with superfine silica gel powder, carboxymethyl starch sodium and lauryl sodium sulfate, then carrying out dry granulation (wherein the disintegrant carboxymethyl starch sodium is added in an internal and external mode), and then filling the granules into capsules.
However, cefuroxime axetil is sensitive to external conditions such as humidity and heat, so that the problems of overproof drug degradation product content, unqualified drug content uniformity and the like often occur in the research and production processes, and the product quality and clinical application are affected, so that the cefuroxime axetil preparation still has an improved space in the aspects of stability, bioavailability and the like. In addition, most of cefuroxime axetil medicines are amorphous powder, and the absorption of the medicine in vivo can be adversely affected if the cefuroxime axetil is transformed into a certain crystal form in the processes of dry granulation and tablet pressing.
Disclosure of Invention
In view of the above, the invention provides a cefuroxime axetil capsule and a preparation method thereof, wherein cefuroxime axetil and auxiliary materials are uniformly mixed, and the capsule is directly filled by a full-powder process without a granulation process. The stability of cefuroxime axetil is improved, and the bioavailability is improved; the production period is shortened, and the cost is reduced.
In order to achieve the purpose, the invention adopts the following technical scheme:
a preparation method of cefuroxime axetil capsules comprises the following steps:
(1) pretreatment of raw materials: sieving solubilizer, glidant and lubricant with 60-100 mesh sieve; sieving cefuroxime axetil and the filler with a 60-100 mesh sieve for later use;
(2) premixing: mixing the solubilizer, the glidant and the lubricant, and sieving the mixture through a 60-100-mesh sieve to obtain a mixture A;
(3) mixing: uniformly mixing cefuroxime axetil and the mixture A, and then adding a filler and a disintegrating agent for uniform mixing to obtain intermediate powder;
(4) and (3) filling capsules: filling the intermediate powder into the capsule shell according to the loading requirement, and then packaging to obtain the cefuroxime axetil capsule.
Adopt above-mentioned technical scheme's beneficial effect: the invention mixes the main drug and the auxiliary materials evenly, and directly carries out capsule filling without granulating. The invention changes the traditional granulation method into the direct full-powder filling capsule production method, which is a breakthrough progress of the technology, avoids the dissolution rate reduction caused by the crystallization of amorphous powder in the granulation process, and breaks through the technical obstacle that the capsule can be filled only by granulating the superfine powder of large-size medicines.
Preferably, the cefuroxime axetil capsule comprises 62.80-74.11% of cefuroxime axetil, 6.67-26.17% of a filler, 4.18-22.25% of a disintegrant, 0.44-0.84% of a solubilizer, 0.46-3.56% of a glidant and 0.0-1.67% of a lubricant by mass percent.
Adopt above-mentioned technical scheme's beneficial effect:
preferably, the cefuroxime axetil is an amorphous ultrafine powder with a particle size of less than 30 μm.
Preferably, the filler is selected from any one or a mixture of more of microcrystalline cellulose, starch, calcium hydrogen phosphate, lactose, mannitol and beta-cyclodextrin.
Preferably, the microcrystalline cellulose is any one or a mixture of more of microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH301, microcrystalline cellulose PH302 and microcrystalline cellulose PH 115; the lactose is any one or mixture of lactose SuperTab11SD, lactose SuperTab14SD, lactose SuperTab30GR, lactose SuperTab21AN and lactose SuperTab22 AN.
Preferably, the disintegrant is selected from one or more of croscarmellose sodium, low substituted hydroxypropyl cellulose, croscarmellose calcium, sodium starch glycolate and crospovidone.
Preferably, the solubilizer is selected from any one of poloxamer and sodium lauryl sulfate.
Preferably, the lubricant is selected from any one of talc, magnesium stearate, hydrogenated vegetable oil, and stearic acid.
Preferably, the glidant is selected from any one of aerosil (colloidal silicon dioxide) and talcum powder.
The invention also provides the cefuroxime axetil capsule prepared by the preparation method.
The cefuroxime axetil raw material powder is amorphous (noncrystal) ultrafine powder with the particle size of less than 30 microns (mum), and each capsule contains 0.125g and 0.25g of raw material medicine (calculated according to cefuroxime), and the main medicine content of each capsule is larger. After the cefuroxime axetil capsule shell is dissolved, the content is very easy to form a colloidal mass and is very difficult to disperse so that the medicine is dissolved out, particularly the overlapped part of the capsule bottom and the capsule cover in the middle section of the capsule shell is very easy to gel into the mass. After the cefuroxime axetil capsule shell prepared by the formula and the method is dissolved, the small lumps of the content can be rapidly dispersed without gelation, the dissolution rate is greatly improved, the production period is shortened, and the production efficiency is improved.
The domestic existing production processes of cefuroxime axetil capsules are generally divided into two types: one is to fill the capsule after wet granulation; the other is capsule filling after dry granulation.
Firstly, because cefuroxime axetil is sensitive to external conditions such as humidity, heat and the like, the problems of overproof content of drug degradation products, unqualified uniformity of drug content and the like often occur in dry granulation or wet granulation, and the product quality and clinical application are influenced; the capsule prepared by directly filling the whole powder avoids the extrusion of dry granulation and the introduction of liquid medium in the wet granulation process, reduces the unstable factors of the product and improves the quality of the product.
Secondly, most of cefuroxime axetil medicines are amorphous powder, and adverse effects can be caused on the absorption of the medicines in vivo if the cefuroxime axetil is transformed into a certain crystal form in the processes of dry granulation and wet granulation; the capsule prepared by directly filling the whole powder avoids the adverse factors of dissolution reduction caused by crystal transformation of the cefuroxime axetil.
Thirdly, after granulation, the density of the particles is increased, and the dispersion and the slow gelation of the particles are serious when the dissolution is carried out, so that the dissolution rate is low, the capsule prepared by directly filling the whole powder has good dispersibility and hydrophilicity during the dissolution, the gelation phenomenon is avoided, and the dissolution rate is greatly improved.
And fourthly, the granulating process needs the processes of mixing, granulating, finishing, mixing, filling and packaging, while the direct full-powder filling technology needs the processes of mixing, filling and packaging, so that the three steps of granulating, finishing and mixing are omitted, labor and time are saved, energy is saved, consumption is reduced, and the production cost is reduced.
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1(1000 granules)
Prepared according to the formulation of Table 1
Table 1 example 1 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 66.85％ |
| Lactose SuperTab11SD | 15 | 6.67％ |
| Sodium starch glycolate | 50 | 22.25％ |
| Sodium dodecyl sulfate | 1 | 0.44％ |
| Silica gel micropowder | 8 | 3.56％ |
| Magnesium stearate | 0.5 | 0.22％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil and lactose with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding carboxymethyl starch sodium and lactose, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 2(1000 granules)
Prepared according to the formulation of Table 2
Table 2 example 2 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 66.85％ |
| Beta-cyclodextrin | 15 | 6.67％ |
| Sodium starch glycolate | 50 | 22.25％ |
| Sodium dodecyl sulfate | 1 | 0.44％ |
| Silica gel micropowder | 8 | 3.56％ |
| Magnesium stearate | 0.5 | 0.22％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil and beta-cyclodextrin through 60 meshes; standby;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding carboxymethyl starch sodium and beta-cyclodextrin, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 3(1000 granules)
Prepared according to the formulation of Table 3
Table 3 example 3 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 71.29％ |
| Microcrystalline cellulose PH301 | 28 | 13.29％ |
| Lactose SuperTab11SD | 15 | 7.12％ |
| Croscarmellose sodium | 10 | 4.74％ |
| Sodium dodecyl sulfate | 1 | 0.47％ |
| Silica gel micropowder | 6 | 2.85％ |
| Magnesium stearate | 0.5 | 0.24％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil, lactose and microcrystalline cellulose with a 60-mesh sieve; standby;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding microcrystalline cellulose, lactose and croscarmellose sodium, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 4(1000 granules)
Prepared according to the formulation of Table 4
Table 4 example 4 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 74.11％ |
| Microcrystalline cellulose PH115 | 13.5 | 6.66％ |
| Lactose SuperTab14SD | 20 | 9.86％ |
| Croscarmellose sodium | 8 | 3.95％ |
| Sodium starch glycolate | 4 | 1.97％ |
| Sodium dodecyl sulfate | 1 | 0.49％ |
| Silica gel micropowder | 6 | 2.96％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil, lactose and microcrystalline cellulose with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and sodium carboxymethyl starch, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding microcrystalline cellulose, lactose and croscarmellose sodium, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 5(1000 granules)
Prepared according to the formulation of Table 5
Table 5 example 5 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 62.80％ |
| Lactose SuperTab11SD | 45 | 18.81％ |
| Beta-cyclodextrin | 20 | 8.36％ |
| Sodium starch glycolate | 10 | 4.18％ |
| Sodium dodecyl sulfate | 2 | 0.84％ |
| Silica gel micropowder | 8 | 3.34％ |
| Hydrogenated vegetable oil | 4 | 1.67％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and hydrogenated vegetable oil with 80 mesh sieve; sieving cefuroxime axetil, lactose and beta-cyclodextrin with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and sodium carboxymethyl starch, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding lactose and beta-cyclodextrin, mixing for 15 minutes, adding hydrogenated vegetable oil, and mixing for 5 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 6(1000 granules)
Prepared according to the formulation of Table 6
Table 6 example 6 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 150.25 | 69.00％ |
| Calcium hydrogen phosphate | 30 | 13.78％ |
| Beta-cyclodextrin | 20 | 9.18％ |
| Cross-linked polyvidone | 15 | 6.89％ |
| Sodium dodecyl sulfate | 1 | 0.46％ |
| Silica gel micropowder | 1 | 0.46％ |
| Stearic acid | 0.5 | 0.23％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and stearic acid with 80 mesh sieve; sieving cefuroxime axetil with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and stearic acid, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding calcium hydrogen phosphate, beta-cyclodextrin and crospovidone, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 7(1000 granules)
Prepared according to the formulation of Table 7
Table 7 example 7 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 300.5 | 66.85％ |
| Lactose SuperTab11SD | 30 | 6.67％ |
| Carboxymethyl starchSodium salt | 100 | 22.25％ |
| Sodium dodecyl sulfate | 2 | 0.44％ |
| Silica gel micropowder | 16 | 3.56％ |
| Magnesium stearate | 1 | 0.22％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil and lactose with 60 mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding carboxymethyl starch sodium and lactose, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 8(1000 granules)
Prepared according to the formulation of Table 8
Table 8 example 8 formulation
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil and beta-cyclodextrin with a 60-mesh sieve; standby;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding carboxymethyl starch sodium and beta-cyclodextrin, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 9(1000 granules)
Prepared according to the formulation of Table 9
Table 9 example 9 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 300.5 | 71.29％ |
| Microcrystalline cellulose PH301 | 56 | 13.29％ |
| Lactose SuperTab11SD | 30 | 7.12％ |
| Croscarmellose sodium | 20 | 4.74％ |
| Sodium dodecyl sulfate | 2 | 0.47％ |
| Silica gel micropowder | 12 | 2.85％ |
| Magnesium stearate | 1 | 0.24％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil, lactose and microcrystalline cellulose with a 60-mesh sieve; standby;
2. premixing: weighing sodium dodecyl sulfate, silica gel micropowder and magnesium stearate, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding microcrystalline cellulose, lactose and croscarmellose sodium, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 10(1000 granules)
Prepared according to the formulation of Table 10
Table 10 example 10 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 300.5 | 74.11％ |
| Microcrystalline cellulose PH115 | 27 | 6.66％ |
| Lactose SuperTab14SD | 40 | 9.86％ |
| Croscarmellose sodium | 16 | 3.95％ |
| Sodium starch glycolate | 8 | 1.97％ |
| Sodium dodecyl sulfate | 2 | 0.49％ |
| Silica gel micropowder | 12 | 2.96％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and magnesium stearate with 80 mesh sieve; sieving cefuroxime axetil, lactose and microcrystalline cellulose with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and sodium carboxymethyl starch, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding microcrystalline cellulose, lactose and croscarmellose sodium, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 11(1000 granules)
Prepared according to the formulation of Table 11
Table 11 example 11 formulation
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and hydrogenated vegetable oil with 80 mesh sieve; sieving cefuroxime axetil, lactose and beta-cyclodextrin with a 60-mesh sieve for later use;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and sodium carboxymethyl starch, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding lactose and beta-cyclodextrin, mixing for 15 minutes, adding hydrogenated vegetable oil, and mixing for 5 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Example 12(1000 granules)
Prepared according to the formulation of Table 12
Table 12 example 12 formulation
| Raw materials | Weight (g) | Mass percent |
| Cefuroxime axetil | 300.5 | 69.00％ |
| Calcium hydrogen phosphate | 60 | 13.78％ |
| Beta-cyclodextrin | 40 | 9.18％ |
| Cross-linked polyvidone | 30 | 6.89％ |
| Sodium dodecyl sulfate | 2 | 0.46％ |
| Silica gel micropowder | 2 | 0.46％ |
| Stearic acid | 1 | 0.23％ |
The preparation method comprises the following steps:
1. material pretreatment: sieving sodium dodecyl sulfate, silica gel micropowder and stearic acid with 80 mesh sieve; sieving cefuroxime axetil with a 60-mesh sieve; standby;
2. premixing: weighing sodium dodecyl sulfate, micro silica gel powder and stearic acid, mixing for 5 minutes, sieving with a 60-mesh sieve, and sieving for three times to obtain a mixture A;
3. mixing: adding cefuroxime axetil into the mixture A, mixing for 5 minutes, adding calcium hydrogen phosphate, beta-cyclodextrin and crospovidone, and mixing for 20 minutes to obtain intermediate powder;
4. and (3) filling capsules: filling the capsules according to the filling requirement, and then packaging.
Each 6 cefuroxime axetil capsules prepared in examples 1 to 12 of the present invention were measured by a dissolution and release rate measuring method (second method of 0931, general rule) in the fourth part of 2020 edition, China pharmacopoeia. Respectively taking pH1.2 hydrochloric acid, pH4.5 acetate buffer solution, pH6.8 phosphate buffer solution and pH7.0 purified water as dissolution media, wherein the dissolution conditions are as follows: 900ml of dissolution medium, the rotation speed is 50 revolutions per minute, the temperature is 37 ℃, the sampling is carried out according to the method at 5 th, 10 th, 15 th, 20 th, 30 th, 45 th and 60 th min respectively, 5ml of dissolution medium is sampled every time, and the dissolution medium with the same temperature and the same volume is supplemented in a dissolution cup in time. Filtering the dissolution liquid at each time point, precisely taking a proper amount of the subsequent filtrate, and respectively quantitatively diluting with dissolution medium to obtain a solution containing about 15 μ g of cefuroxime in each 1ml as a test solution; another suitable amount of cefuroxime axetil control is precisely weighed, dissolved in a suitable amount of ethanol (1 ml of ethanol is added to every 5mg of cefuroxime axetil), and then quantitatively diluted with a dissolution medium to prepare a solution containing about 15 μ g of cefuroxime in every 1ml as a control solution.
The test solution and the reference solution are respectively taken, the absorbance is respectively measured at 278nm by an ultraviolet-visible spectrophotometry (the general rule 0401 of the Chinese pharmacopoeia 2020 edition), the dissolution amount and the cumulative dissolution percentage of each particle at different time are calculated, and the results are shown in the following tables 13-16.
TABLE 13 elution amount data under medium conditions of pH1.2
TABLE 14 elution data for acetate buffer medium at pH4.5
TABLE 15 elution data under pH6.8 phosphate buffer Medium conditions
TABLE 16 elution data under conditions of purified aqueous medium at pH7.0
Note 1: the similarity factor f2 is calculated as follows:
2: the average dissolution rate of the sample within 15 minutes is more than 85 percent, and f2 factors of the composition sample and the original preparation are considered to be more than 50, and f2 calculation is not carried out.
As can be seen from tables 1 to 4, the dissolution curves of the cefuroxime axetil capsules prepared in examples 1 to 12 are substantially the same as those of the original preparation, i.e., the dissolution behaviors are demonstrated to be the same, the process is scientific and feasible, the product quality is stable and the reproducibility is good, i.e., the cefuroxime axetil capsules prepared in examples 1 to 12 are substantially the same as those of the original preparation.
And (3) accelerated test: the cefuroxime axetil capsules prepared in examples 1 to 12 were subjected to an accelerated test, specifically, the following method:
related substances are as follows: measuring by high performance liquid chromatography (China pharmacopoeia 0512 of 2020 edition). Taking the fine powder of the content of the product, precisely weighing a proper amount (about 50mg equivalent to cefuroxime), putting the fine powder into a 100ml measuring flask, adding 10ml of methanol, strongly shaking to dissolve the fine powder, then diluting the fine powder to a scale by using a mobile phase, shaking uniformly, filtering, and taking the subsequent filtrate as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with a mobile phase, and shaking up to obtain a control solution. According to the chromatographic conditions under the content determination item, 20 mul of the control solution is injected into a liquid chromatograph, the detection sensitivity is adjusted, the peak height of the chromatographic peak of any main component in the two main components is 25 percent of the full-scale range, 20 mul of each of the sample solution and the control solution are immediately and precisely measured, the sample solution and the control solution are respectively injected into the liquid chromatograph, and the chromatogram is recorded until the retention time of the peak of the cefuroxime axetil A isomer is 3.5 times. If an impurity peak exists in a chromatogram of the test solution, the area sum of two E isomer peaks is not more than 1.5 times (1.5%) of the sum of two main peak areas of a control solution, the area sum of a delta 3-isomer peak is not more than 2 times (2.0%) of the sum of two main peak areas of the control solution, and the area sum of other single impurity peaks is not more than 1.0% of the sum of two main peak areas of the control solution; the sum of the areas of the peaks of the respective impurities must not be more than 4.5 times (4.5%) the sum of the areas of the two main peaks of the control solution. Any peak in the chromatogram of the test solution that is 0.05 times less than the sum of the areas of the major peaks in the control solution is negligible.
Moisture content: taking appropriate amount of the product content, and measuring according to water content determination method (first method 1 of 0832 in 2020 edition of Chinese pharmacopoeia) to obtain a product with water content of 6.0% or less.
Dissolution rate: taking the product, and determining according to dissolution rate and release rate determination method (second method of 0931 in the 2020 edition of Chinese pharmacopoeia). Taking 900ml of 0.1mol/L hydrochloric acid solution as a dissolution medium, operating at a rotation speed of 50 revolutions per minute, taking 5ml of dissolution liquid respectively at 15 minutes and 45 minutes according to the method, and supplementing the dissolution medium with the same temperature and volume in a dissolution cup in time. Taking the dissolution liquid at 15 minutes and 45 minutes, filtering, precisely taking appropriate amount of each of the subsequent filtrates, and quantitatively diluting with dissolution medium to obtain solution containing cefuroxime 15 μ g per 1ml as test solution (1) and (2); taking another appropriate amount of cefuroxime axetil as a control, precisely weighing, dissolving with appropriate amount of ethanol (1 ml ethanol is added to every 5mg of cefuroxime axetil), and quantitatively diluting with dissolution medium to obtain a solution containing 15 μ g of cefuroxime in every 1ml as a control solution; taking the test solution and the reference solution, respectively measuring absorbance at 278nm wavelength according to ultraviolet-visible spectrophotometry (in "Chinese pharmacopoeia" 2020 edition of general rules 0401), and calculating the dissolution amount of each granule at different time. Limitation: at 15 minutes, 60% of the indicated amount; at 45 minutes, 75% of the indicated amount should be in accordance with the specification.
Polymer (b): measuring by high performance liquid chromatography (China pharmacopoeia 0512 of 2020 edition). Description of the drawings: no polymer inspection is performed under the inspection item in the quality standard of cefuroxime axetil capsules in the second part of the '2020 edition of Chinese pharmacopoeia', but in order to ensure the medicine quality and meet the requirement of evaluation of the consistency of the imitation drugs, the inspection of the polymer in the stability inspection is increased.
Chromatographic conditions and system suitability test: polystyrene copolymer is used as a filling agent; methanol-water (95:5) as mobile phase, flow rate: 1.0 ml/min; the column temperature is 35 ℃; the detection wavelength was 278 nm. Precisely weighing a proper amount of cefuroxime axetil reference substance (about equivalent to 25mg of cefuroxime), putting the cefuroxime axetil reference substance into a 25ml measuring flask, adding a proper amount of methanol for dissolving and diluting to a scale, shaking up, and preparing a solution containing about 1.0mg of cefuroxime in every 1ml as a system applicability solution 1; precisely measuring 1ml of the solution, placing the solution into a 100ml measuring flask, diluting the solution to a scale with methanol, and shaking the solution uniformly to obtain a system suitability solution 2. And (3) respectively injecting 10 mu l of each of the two solutions into a liquid chromatograph, repeatedly injecting the sample for 6 times, and recording a chromatogram. The relative standard deviation of the main peak areas of the system suitability solution 1 and the system suitability solution 2 respectively must not be more than 2.0%.
The determination method comprises the following steps: taking 10 tablets of the product, precisely weighing, grinding, uniformly mixing, precisely weighing a proper amount (about equivalent to 25mg of cefuroxime), placing in a 25ml measuring flask, adding a proper amount of methanol, strongly shaking to dissolve, diluting the methanol to a scale, uniformly shaking, filtering, and taking a subsequent filtrate as a test solution; precisely measuring 1ml of the test solution, placing the test solution in a 100ml measuring flask, diluting the test solution to a scale with methanol, and shaking up to obtain a control solution. And precisely sucking 10 mu l of each of the control solution and the test solution, injecting into a liquid chromatograph, and recording the chromatogram. The content of each impurity was calculated according to the self-control method. If the test solution shows impurity peaks, the peak area of the impurity 1 should not be more than 1.0 times (1.0%) of the main peak area of the control solution, the peak area of the impurity 2 should not be more than 0.5 times (0.5%) of the main peak area of the control solution, the peak area of other single impurity should not be more than 0.5 times (0.5%) of the main peak area of the control solution, and the peak area of each impurity should not be more than 2.0 times (2.0%) of the main peak area of the control solution. Any peaks in the chromatogram of the test solution that are smaller than the area of the major peak and 0.01 times the control solution are negligible.
Content determination: measuring by high performance liquid chromatography (China pharmacopoeia 0512 of 2020 edition). Is used newly.
Test solution: taking the contents with different contents, grinding, mixing uniformly, precisely weighing a proper amount (about equivalent to 0.125g of cefuroxime), putting the mixture into a 100ml measuring flask, adding 25ml of methanol, shaking strongly to dissolve, diluting the mixture to a scale by using a mobile phase, shaking uniformly, filtering, precisely measuring 5ml of a subsequent filtrate, putting the subsequent filtrate into a 25ml measuring flask, diluting the subsequent filtrate to the scale by using the mobile phase, and shaking uniformly.
Control solution: taking a proper amount of cefuroxime axetil reference substance, precisely weighing, adding a proper amount of methanol for dissolving, and quantitatively diluting with a mobile phase to prepare a solution containing about 0.25mg of cefuroxime in each 1 ml.
System applicability solution (1): taking a proper amount of cefuroxime axetil reference substance, adding a mobile phase for dissolving and diluting to prepare a solution containing 0.2mg per 1ml, heating in a water bath at 60 ℃ for at least 1h, and cooling to obtain a solution containing the delta 3-isomer of cefuroxime axetil.
System applicability solution (2): taking a proper amount of cefuroxime axetil reference substance, adding a mobile phase for dissolving and diluting to prepare a solution containing about 0.2mg in each 1ml, and irradiating for 24h by ultraviolet light to obtain a solution containing two E isomers of cefuroxime axetil.
Chromatographic conditions are as follows: octadecylsilane chemically bonded silica is used as a filling agent; 0.2mol/L ammonium dihydrogen phosphate solution-methanol (62:38) is used as a mobile phase; the detection wavelength is 278 nm; the injection volume was 20. mu.l.
System applicability requirements: system suitability solution chromatograms are generated for the cefuroxime axetil A, B isomer, the Δ 3-isomer and the two E isomers at relative retention times of about 1.0, 0.9, 1.2 and 1.7 and 2.1, respectively. The separation between the peaks of the A, B isomers of cefuroxime axetil and the peaks of the A and delta 3 isomers of cefuroxime axetil should meet the requirements.
The determination method comprises the following steps: precisely measuring the test solution and the reference solution, respectively injecting into a liquid chromatograph, and recording the chromatogram. The content of C16H16N4O8S in the test sample was calculated by the external standard method based on the area of the two main peaks of cefuroxime axetil.
The cefuroxime axetil capsules prepared in examples 1 to 12 were placed at 40 ℃. + -. 2 ℃ and 75%. + -. 5% relative humidity for 6 months, and samples were taken at 1 month, 2 months, 3 months and 6 months during the test period, and the appearance, content, moisture, dissolution rate, related substances, polymers, content and other items were determined, and the results are shown in Table 17.
TABLE 17 data of results of accelerated testing of cefuroxime axetil capsules
As can be seen from Table 17, the cefuroxime axetil capsules prepared in examples 1 to 12 have no significant change in moisture, dissolution rate, related substances, polymers and contents after accelerated for 6 months, which indicates that the cefuroxime axetil capsules prepared by the preparation methods of cefuroxime axetil capsules of examples 1 to 12 have good quality stability.
The embodiments in the present description are described in a progressive manner, each embodiment focuses on differences from other embodiments, and the same and similar parts among the embodiments are referred to each other. The device disclosed by the embodiment corresponds to the method disclosed by the embodiment, so that the description is simple, and the relevant points can be referred to the method part for description.
The previous description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the present invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
1. A preparation method of cefuroxime axetil capsules is characterized by comprising the following steps:
(1) pretreatment of raw materials: sieving solubilizer, glidant and lubricant with 60-100 mesh sieve; sieving cefuroxime axetil and the filler with a 60-100 mesh sieve for later use;
(2) premixing: mixing the solubilizer, the glidant and the lubricant, and sieving the mixture through a 60-100-mesh sieve to obtain a mixture A;
(3) mixing: uniformly mixing cefuroxime axetil and the mixture A, and then adding a filler and a disintegrating agent for uniform mixing to obtain intermediate powder;
(4) and (3) filling capsules: filling the intermediate powder into the capsule shell according to the loading requirement, and then packaging to obtain the cefuroxime axetil capsule.
2. The preparation method according to claim 1, wherein the cefuroxime axetil capsule comprises 62.80-74.11% by mass of cefuroxime axetil, 6.67-26.17% by mass of a filler, 4.18-22.25% by mass of a disintegrant, 0.44-0.84% by mass of a solubilizer, 0.46-3.56% by mass of a glidant, and 0.0-1.67% by mass of a lubricant.
3. The method according to claim 1, wherein the cefuroxime axetil is an amorphous ultrafine powder having a particle size of less than 30 μm.
4. The preparation method according to claim 1, wherein the filler is selected from any one or a mixture of microcrystalline cellulose, starch, calcium hydrogen phosphate, lactose, mannitol and beta-cyclodextrin.
5. The preparation method according to claim 4, wherein the microcrystalline cellulose is any one or a mixture of microcrystalline cellulose PH101, microcrystalline cellulose PH102, microcrystalline cellulose PH301, microcrystalline cellulose PH302 and microcrystalline cellulose PH 115; the lactose is any one or mixture of lactose SuperTab11SD, lactose SuperTab14SD, lactose SuperTab30GR, lactose SuperTab21AN and lactose SuperTab22 AN.
6. The preparation method according to claim 1, wherein the disintegrating agent is selected from one or more of croscarmellose sodium, low substituted hydroxypropyl cellulose, croscarmellose calcium, carboxymethyl starch sodium, and crospovidone.
7. The preparation method according to claim 1, wherein the solubilizer is selected from any one of poloxamer and sodium lauryl sulfate.
8. The method according to claim 1, wherein the lubricant is selected from any one of talc, magnesium stearate, hydrogenated vegetable oil, and stearic acid.
9. The preparation method according to claim 1, wherein the glidant is selected from any one of aerosil and talcum powder.
10. Cefuroxime axetil capsule prepared by the process according to any one of claims 1 to 9.
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