CN113456599A - Preparation method of cefpodoxime proxetil tablets and cefpodoxime proxetil tablets prepared by same - Google Patents
Preparation method of cefpodoxime proxetil tablets and cefpodoxime proxetil tablets prepared by same Download PDFInfo
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- 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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- 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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- A61K9/2004—Excipients; Inactive ingredients
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Abstract
The invention provides a cefpodoxime proxetil tablet which contains 30-70 w/w% of cefpodoxime proxetil superfine powder, 5-20 w/w% of disintegrating agent, 0.1-2.0 w/w% of gel inhibitor and 3-8 w/w% of coating powder. The invention also provides a preparation method of the cefpodoxime proxetil tablet, and the cefpodoxime proxetil tablet has high stability, high dissolution rate and good operability.
Description
Technical Field
The invention relates to the technical field of veterinary drug preparations, in particular to a cefpodoxime proxetil tablet preparation method and a cefpodoxime proxetil tablet prepared by the same.
Background
Cefpodoxime Proxetil is a third-generation semi-synthetic cephalosporin antibiotic, has high sensitivity to various gram-positive bacteria and gram-negative bacteria, and has the characteristics of broad spectrum, high efficiency, long half-life period and the like. Cefpodoxime proxetil is a prodrug, is metabolized into cefpodoxime as an active ingredient under the action of digestive tract system enzyme after oral administration, is absorbed and enters a blood circulation system to play a systemic antibacterial role, and is widely applied to treatment of respiratory tract, urinary tract, gynecological infectious diseases, suppurative otitis media and the like.
The cefpodoxime proxetil preparation is available in the forms of granule, coated tablet, dispersible tablet, capsule, dry suspension, etc. At present, cefpodoxime proxetil tablets applied to canine infectious diseases exist abroad, and no preparation products approved to be applied to animals such as canines exist at home. At present, the domestic cefpodoxime proxetil preparation mainly comprises three types: the first granule is prepared by adding adjuvants such as correctant and lubricant, and granulating by dry method or wet method. In the second tablet form, the raw and auxiliary materials are granulated and then added with auxiliary materials such as flavoring agent and the like for tabletting. The third is dry suspension type, and is prepared by a physical mixing method, a spray drying method and a solid dispersion method. Each dosage form aims at different audiences, and no product exists in the field of veterinary use at home.
The cefpodoxime proxetil tablets are applied to animals such as dogs and the like, and have the following difficulties: firstly, the stability is poor, cefpodoxime proxetil is third-generation cephalosporin, is sensitive to water, high humidity and illumination, and is easy to degrade in the preparation and storage processes; secondly, the solubility is poor, cefpodoxime proxetil is a BCS IV drug, the solubility and the permeability are poor, gel or gel-like substances are easily formed when the cefpodoxime proxetil meets water, the disintegration speed and the dissolution speed are reduced, the absorption in the gastrointestinal tract is reduced, and the bioavailability is low; thirdly, the palatability is poor, the cefpodoxime proxetil is bitter in taste, the palatability is poor, and the animal use difficulty is high; fourthly, the working procedures are more, and the operability of the production process is poor. Because the problems of stability, solubility, palatability and the like of cefpodoxime proxetil need to be solved, operations such as taste masking, coating and the like need to be added, and the process requirement is higher.
CN105963269B discloses a cefpodoxime proxetil flavored chewable tablet, which is prepared by granulating, coating granules, granulating again, adding beef essence, and tabletting, and improves palatability, dissolution and stability. The process route of CN108815130A is similar to that of the above patent, and adopts a particle coating and re-tabletting method. However, the particle coating has high requirement on the particle size uniformity of the particles, the particle coating needs to be carried out after the particles are sized, large particles and fine powder need to be repeatedly treated, and the process operability is poor. Meanwhile, after the particles are coated, the dissolving-out speed of the cefpodoxime proxetil is slower than that before the coating.
CN103479589B and CN108261404A disclose cefpodoxime proxetil tablets, which are prepared into finished products by dry granulation and tabletting, and the dry granulation produces more fine powder, and needs to granulate for many times, which is not beneficial to industrial production, and the stability is slightly poor because of no coating process.
How to prepare cefpodoxime proxetil tablets with high stability, high dissolution, good palatability and strong production process operability is an urgent need in production.
Disclosure of Invention
In order to overcome the defects of the prior art, the invention provides a cefpodoxime proxetil tablet which has high stability, high dissolution and good palatability; also provides a preparation method thereof.
In a first aspect of the present invention, there is provided a method for preparing cefpodoxime proxetil tablets, which is characterized in that the method comprises the following steps: step (1), micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving disintegrating agent and filler with 40 mesh sieve; step (2), uniformly mixing the cefpodoxime proxetil superfine powder pretreated in the step (1), a filling agent and a disintegrating agent, preparing a soft material by using an adhesive aqueous solution, sieving the soft material by using a 16-24-mesh sieve for granulation, drying the soft material at 40-50 ℃, and finishing the particles by using a 16-24-mesh sieve; and (3) granulating in the step (2), adding a gel inhibitor, a lubricant and a flavoring agent, uniformly mixing, and tabletting.
The cefpodoxime proxetil tablet prepared by the preparation method has high dissolution rate: by micronization technology and addition of proper gel inhibitor, the product of the invention can be dissolved rapidly (more than 85% in 30 min) in dissolution media with pH1.5, pH3.0, pH4.0 and pH6.8; and the palatability is good: the essence which is easily accepted by dogs is added to improve the bitter taste of cefpodoxime proxetil; meanwhile, the preparation method has simple and convenient operation of the technical process and is suitable for industrial production.
Different from the existing cefpodoxime proxetil tablet which is directly granulated and tabletted, the method remarkably improves the dissolution rate of the product by carrying out superfine grinding on the raw materials and adding a gel inhibitor; meanwhile, the original granule coating process is changed, and the tablet core coating technology after tabletting is adopted. The process is simple, the requirement on equipment is low, the large-scale production is facilitated, the coating layer is isolated from certain water humidity and illumination, and the stability of the product is improved. The invention not only optimizes the prescription, but also innovates the process, and solves the problems of low dissolution rate, poor stability, high requirement on preparation equipment and complex process of the cefpodoxime proxetil. The cefpodoxime proxetil tablet prepared by the invention has high dissolution rate, good stability and palatability, and is easy for large-scale production.
As an embodiment of the invention, the concentration of the adhesive in the step (4) of the method for preparing cefpodoxime proxetil tablets is 3-8 w/w%.
The concentration of the adhesive is selected from 3 w/w%, 4 w/w%, 5 w/w%, 6 w/w%, 7 w/w%, 8 w/w%.
As an implementation mode of the invention, the method for preparing the cefpodoxime proxetil tablets further comprises the step (4), wherein the tablet pressed in the step (3) is coated by a coating powder aqueous solution with the concentration of 10-15 w/w%, and the tablet is dried to obtain the cefpodoxime proxetil tablets.
The concentration of the coating powder aqueous solution is selected from 10 w/w%, 11 w/w%, 12 w/w%, 13 w/w%, 14 w/w% and 15 w/w%.
By adding the tablet core coating technology, the finished product has stable properties and content after being stored for 6 months under the accelerated condition, and related substances are not obviously increased and have good stability.
In the method for preparing cefpodoxime proxetil tablets, the disintegrant is one selected from sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, crospovidone and sodium carboxymethyl starch; the gel inhibitor is selected from one of sodium dodecyl sulfate and polyethylene glycol 6000; the coating powder is one of Opadry and Uttch; the filler is selected from one or more of lactose, microcrystalline cellulose, maltodextrin and pre-crosslinked starch; the adhesive is selected from one of hydroxypropyl cellulose, crospovidone and hypromellose; the lubricant is one of magnesium stearate, superfine silica gel powder and talcum powder; the flavoring agent is one of artificial chicken essence, artificial beef essence and artificial pork essence.
In a preferred embodiment of the present invention, in the method for preparing cefpodoxime proxetil tablets, the gel inhibitor is sodium lauryl sulfate, the coating powder is opadry, the filler is lactose, the binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate.
Another aspect of the present invention is to provide cefpodoxime proxetil tablets prepared by the method.
The cefpodoxime proxetil tablet prepared by the preparation method has high dissolution rate and good palatability.
The cefpodoxime proxetil tablet comprises 30-70 w/w% of cefpodoxime proxetil superfine powder, 5-20 w/w% of disintegrating agent, 5-25 w/w% of filling agent, 2-5 w/w% of adhesive, 0.1-2.0 w/w% of gel inhibitor, 0.3-1.0 w/w% of lubricant, 0.5-10 w/w% of flavoring agent and 3-8 w/w% of coating powder.
The content of the cefpodoxime proxetil superfine powder is selected from 30 w/w%, 35 w/w%, 40 w/w%, 45 w/w%, 50 w/w%, 55 w/w%, 60 w/w%, 65 w/w% and 70 w/w%.
The content of the disintegrant is selected from 5 w/w%, 6 w/w%, 7 w/w%, 8 w/w%, 9 w/w%, 10 w/w%, 11 w/w%, 12 w/w%, 13 w/w%, 14 w/w%, 15 w/w%, 16 w/w%, 17 w/w%, 18 w/w%, 19 w/w%, 20 w/w%.
The filler content is selected from 5 w/w%, 6 w/w%, 7 w/w%, 8 w/w%, 9 w/w%, 10 w/w%, 11 w/w%, 12 w/w%, 13 w/w%, 14 w/w%, 15 w/w%, 16 w/w%, 17 w/w%, 18 w/w%, 19 w/w%, 20 w/w%, 21 w/w%, 22 w/w%, 23 w/w%, 24 w/w%, 25 w/w%.
The binder content is selected from 2 w/w%, 2.5 w/w%, 3 w/w%, 3.5 w/w%, 4 w/w%, 4.5 w/w%, 5 w/w%.
The gel inhibitor content is selected from 0.1 w/w%, 0.2 w/w%, 0.3 w/w%, 0.4 w/w%, 0.5 w/w%, 0.6 w/w%, 0.7 w/w%, 0.8 w/w%, 0.9 w/w%, 1.0 w/w%, 1.1 w/w%, 1.2 w/w%, 1.3 w/w%, 1.4 w/w%, 1.5 w/w%, 1.6 w/w%, 1.7 w/w%, 1.8 w/w%, 1.9 w/w%, 2.0 w/w%.
The content of the lubricant is selected from 0.3 w/w%, 0.4 w/w%, 0.5 w/w%, 0.6 w/w%, 0.7 w/w%, 0.8 w/w%, 0.9 w/w%, 1.0 w/w%.
The content of the flavoring agent is selected from 0.5 w/w%, 0.6 w/w%, 0.7 w/w%, 0.8 w/w%, 0.9 w/w%, 1.0 w/w%, 2 w/w%, 3 w/w%, 4 w/w%, 5 w/w%, 6 w/w%, 7 w/w%, 8 w/w%, 9 w/w% and 10 w/w%.
The content of the coating powder is selected from 3 w/w%, 4 w/w%, 5 w/w%, 6 w/w%, 7 w/w% and 8 w/w%.
The cefpodoxime proxetil tablet has the characteristics of high stability, high dissolution, good palatability and strong operability of a preparation production process. The dissolution rate is improved mainly by a micronization technology and the addition of a gel inhibitor, and taste modification and stability are realized by wet granulation, tabletting and coating.
In a preferred embodiment of the present invention, in the cefpodoxime proxetil tablet, the disintegrant is selected from one of sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, hydroxypropyl cellulose, crospovidone, and sodium carboxymethyl starch; the gel inhibitor is selected from one of sodium dodecyl sulfate and polyethylene glycol 6000; the coating powder is one of Opadry and Uttch.
In a more preferred embodiment of the present invention, in the cefpodoxime proxetil tablet, the gel inhibitor is sodium dodecyl sulfate, and the coating powder is opadry.
As a preferred embodiment of the present invention, in the cefpodoxime proxetil tablet, the filler is selected from one or more of lactose, microcrystalline cellulose, maltodextrin and pre-crosslinked starch; the adhesive is selected from one of hydroxypropyl cellulose, crospovidone and hypromellose; the lubricant is one of magnesium stearate, superfine silica gel powder and talcum powder; the flavoring agent is one of artificial chicken essence, artificial beef essence and artificial pork essence.
In a more preferred embodiment of the present invention, in the cefpodoxime proxetil tablet, the filler is lactose, the binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate.
Detailed Description
The invention will be further described with reference to specific embodiments, and the advantages and features of the invention will become apparent as the description proceeds. These examples are illustrative only and do not limit the scope of the present invention in any way. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention, and that such changes and modifications may be made without departing from the spirit and scope of the invention.
The artificial beef flavor used in the embodiment of the invention is food grade, is purchased from Chenxi flavor and spice Limited company in Shenzhen city, the rest raw and auxiliary materials are pharmaceutical grade, cefpodoxime proxetil is purchased from Shandong Rui Yingpion pharmacy Limited company, hydroxypropyl cellulose is purchased from Asia Xiilan (China) investment Limited company, carboxymethyl cellulose calcium is purchased from Anhui Shanhe pharmaceutical auxiliary material Gmby, Opadry coating powder is purchased from Shanghai Kalerkang coating technology Limited company, and the rest is purchased from Jiuzhan pharmaceutical preparation Gmby company in Hunan south China. The experimental methods described in the present invention are all conventional methods unless otherwise specified.
Preparation of example 1
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Calcium carboxymethylcellulose | Disintegrating agent | 15％ |
| Lactose | Filler | 13％ |
| Hydroxypropyl cellulose | Adhesive agent | 2％ |
| Sodium dodecyl sulfate | Gel inhibitor | 0.5％ |
| Magnesium stearate | Lubricant agent | 0.5％ |
| Artificial beef essence | Flavouring agent | 5％ |
| Opadry | Coating powder | 4％ |
The preparation method comprises the following steps:
(1) micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving carboxymethyl cellulose calcium and lactose with 40 mesh sieve;
(2) uniformly mixing the pretreated cefpodoxime proxetil, carboxymethylcellulose calcium and lactose, preparing a soft material by using a hydroxypropyl cellulose aqueous solution with the concentration of 5%, and sieving by using a 24-mesh sieve for granulation. Drying at 40-50 deg.C, and grading with 24 mesh sieve.
(3) Adding sodium dodecyl sulfate, magnesium stearate, and artificial beef essence, mixing, and tabletting.
(4) Coating with 10% Opadry water solution, and drying to obtain cefpodoxime proxetil tablet.
Preparation of example 2
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Calcium carboxymethylcellulose | Disintegrating agent | 10％ |
| Lactose | Filler | 16％ |
| Hydroxypropyl cellulose | Adhesive agent | 2％ |
| Sodium dodecyl sulfate | Gel inhibitor | 1.5％ |
| Magnesium stearate | Lubricant agent | 0.5％ |
| Artificial beef essence | Flavouring agent | 5％ |
| Opadry | Coating powder | 5％ |
The preparation method comprises the following steps:
(1) micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving carboxymethyl cellulose calcium and lactose with 40 mesh sieve;
(2) uniformly mixing the pretreated cefpodoxime proxetil, carboxymethylcellulose calcium and lactose, preparing a soft material by using a hydroxypropyl cellulose aqueous solution with the concentration of 3%, and sieving by using a 24-mesh sieve for granulation. Drying at 40-50 deg.C, and grading with 24 mesh sieve.
(3) Adding sodium dodecyl sulfate, magnesium stearate, and artificial beef essence, mixing, and tabletting.
(4) Coating with 10% Opadry water solution, and drying to obtain cefpodoxime proxetil tablet.
Preparation of example 3
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Calcium carboxymethylcellulose | Disintegrating agent | 20％ |
| Lactose | Filler | 10％ |
| Hydroxypropyl cellulose | Adhesive agent | 2％ |
| Sodium dodecyl sulfate | Gel inhibitor | 1％ |
| Magnesium stearate | Lubricant agent | 0.5％ |
| Artificial beef essence | Flavouring agent | 3％ |
| Opadry | Coating powder | 3.5％ |
The preparation method comprises the following steps:
(1) micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving carboxymethyl cellulose calcium and lactose with 40 mesh sieve;
(2) uniformly mixing the pretreated cefpodoxime proxetil, carboxymethyl cellulose calcium and lactose, preparing a soft material by using a hydroxypropyl cellulose aqueous solution with the concentration of 8%, and sieving by using a 24-mesh sieve for granulation. Drying at 40-50 deg.C, and grading with 24 mesh sieve.
(3) Adding sodium dodecyl sulfate, magnesium stearate, and artificial beef essence, mixing, and tabletting.
(4) Coating with 10% Opadry water solution, and drying to obtain cefpodoxime proxetil tablet.
Preparation of example 4
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Calcium carboxymethylcellulose | Disintegrating agent | 15％ |
| Lactose | Filler | 16.5％ |
| Hydroxypropyl cellulose | Adhesive agent | 3％ |
| Sodium dodecyl sulfate | Gel inhibitor | 0.5％ |
| Magnesium stearate | Lubricant agent | 0.5％ |
| Artificial beef essence | Flavouring agent | 0.5％ |
| Opadry | Coating powder | 4％ |
The preparation method comprises the following steps:
(1) micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving carboxymethyl cellulose calcium and lactose with 40 mesh sieve;
(2) uniformly mixing the pretreated cefpodoxime proxetil, carboxymethylcellulose calcium and lactose, preparing a soft material by using a hydroxypropyl cellulose aqueous solution with the concentration of 5%, and sieving by using a 24-mesh sieve for granulation. Drying at 40-50 deg.C, and grading with 24 mesh sieve.
(3) Adding sodium dodecyl sulfate, magnesium stearate, and artificial beef essence, mixing, and tabletting.
(4) Coating with 10% Opadry water solution, and drying to obtain cefpodoxime proxetil tablet.
Comparative example 5
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Cross-linked polyvidone | Disintegrating agent | 15％ |
| Microcrystalline cellulose | Filler | 15％ |
| Polyvinylpyrrolidone | Adhesive agent | 1％ |
| Artificial beef essence | Flavouring agent | 4％ |
| Opadry | Coating powder | 5％ |
The preparation method comprises the following steps:
(1) respectively sieving cefpodoxime proxetil, crospovidone and microcrystalline cellulose with a 80-mesh sieve for later use;
(2) uniformly mixing the pretreated cefpodoxime proxetil, the crospovidone and the microcrystalline cellulose, preparing a soft material by using a polyvinylpyrrolidone aqueous solution with the concentration of 5%, and granulating by sieving through a 24-mesh sieve. Drying at 40-50 deg.C, sieving with 24-mesh or 40-mesh sieve, grading, and removing coarse and fine particles.
(3) Coating the sieved granules with Opadry water solution with the concentration of 10%, and drying to obtain coated granules.
(4) And (3) uniformly mixing the coated particles with the artificial beef flavor, and tabletting to obtain the cefpodoxime proxetil tablets.
Comparative example 6
| Composition (I) | Function of | Content (wt.) |
| Cefpodoxime proxetil | Active ingredient | 60％ |
| Sodium carboxymethylcellulose | Disintegrating agent | 15％ |
| Microcrystalline cellulose | Filler | 18％ |
| Polyethylene glycol 200 | Wetting agent | 1％ |
| Artificial beef essence | Flavouring agent | 4％ |
| Magnesium stearate | Coating powder | 2％ |
The preparation method comprises the following steps:
(1) sieving the raw materials and the auxiliary materials with a 80-mesh sieve respectively for later use;
(2) uniformly mixing the pretreated cefpodoxime proxetil, microcrystalline cellulose, polyethylene glycol 200, a half of sodium carboxymethylcellulose and a half of magnesium stearate, and putting the mixture into a dry-method granulator to be sieved by a 24-mesh sieve for granulation. Drying at 40-50 deg.C, sieving with 24-mesh or 40-mesh sieve, grading, and removing coarse and fine particles.
(3) And adding the screened particles into the artificial beef flavor and the rest sodium carboxymethylcellulose and magnesium stearate, uniformly mixing, and tabletting to obtain the cefpodoxime proxetil tablets.
Example 7 comparative experiment:
in order to verify the advantages, especially high dissolution rate and high stability, of the cefpodoxime proxetil tablet prepared by the invention, the following samples are selected for carrying out a comparative test, and the comparative test comprises the following steps: examples 1-6.
(1) Dissolution test:
experimental methods and conditions: according to the determination method of dissolution and release of the glycine-sodium chloride-hydrochloric acid solution (pH3.0) in 2015 edition of Chinese pharmacopoeia, 54.5g of glycine and 42.6g of sodium chloride are taken and placed in a 1000ml measuring flask, 500ml of water is added for dissolution, 14.2ml of hydrochloric acid is slowly added, the mixture is cooled, diluted to the scale with water and shaken up to be used as stock solution. Taking 50ml stock solution, adding water to 900ml (adjusting pH to 3.0 + -0.1 with 10mol/L sodium hydroxide solution if necessary), and rotating at 75 rpm as dissolution medium. Taking a proper amount of the solution after 5, 10, 15, 30, 45 and 60 minutes, filtering, precisely taking a proper amount of subsequent filtrate, quantitatively diluting the solution with a dissolution medium to prepare a solution containing about 11 mu g of cefpodoxime in each 1ml, and measuring the absorbance at the wavelength of 259nm by an ultraviolet-visible spectrophotometry; and precisely weighing a proper amount of cefpodoxime proxetil reference substance, adding a proper amount of methanol for dissolving, quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mu g of cefpodoxime in each 1ml, and measuring by the same method. The amount of elution was calculated for each tablet. The results are shown in Table 1.
TABLE 1 dissolution test results (pH3.0) for each sample
As can be seen from Table 1, the samples prepared in examples 1 to 4 were rapidly dissolved in a medium with a pH of 3.0, and the dissolution rates in 30min were all up to 85% or more; the samples prepared in examples 5 and 6 were prepared by sieving the raw material with a 80-mesh sieve, controlling the particle size to 150 μm, which is larger than that achieved by micronization, and the dissolution was slow, requiring 45min to 85% or more, since no gel inhibitor was added, and the dissolution was further slow since the sample prepared in example 5 was further subjected to particle coating. The cefpodoxime proxetil tablets prepared in examples 1 to 4 have high dissolution rate and can release active ingredients more quickly.
(2) Dissolution test at different pH:
dissolution media with pH1.5, pH4.0 and pH6.8 were prepared according to the guidelines of dissolution test technique for common oral solid preparations, and the dissolution rates of examples 1-6 were determined in the same manner as described above. The method comprises the following specific steps: the volume of the dissolution medium is 900ml, the rotating speed is 75 revolutions per minute, when 5, 10, 15, 30, 45 and 60 minutes pass, a proper amount of solution is taken, filtration is carried out, a proper amount of subsequent filtrate is precisely taken, the dissolution medium is quantitatively diluted to prepare a solution containing about 11 mu g of cefpodoxime in each 1ml, and the absorbance is respectively measured at the wavelength of 262nm, 255nm and 253nm by an ultraviolet-visible spectrophotometry; and precisely weighing a proper amount of cefpodoxime proxetil reference substance, adding a proper amount of methanol for dissolving, quantitatively diluting with a dissolution medium to prepare a solution containing about 11 mu g of cefpodoxime in each 1ml, and measuring by the same method. The amount of elution was calculated for each tablet. The results are shown in tables 2 to 4.
TABLE 2 dissolution test results (pH1.5) for each sample
| Sample (I) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| 0min | 0 | 0 | 0 | 0 | 0 | 0 |
| 5min | 92.3 | 91.4 | 96.1 | 93.0 | 88.7 | 92.5 |
| 10min | 95.2 | 94.5 | 99.0 | 96.5 | 93.4 | 95.2 |
| 15min | 96.4 | 97.3 | 99.3 | 97.1 | 95.6 | 97.7 |
| 30min | 96.1 | 97.9 | 99.9 | 96.9 | 97.3 | 99.1 |
| 45min | 96.6 | 96.9 | 99.2 | 95.9 | 97.6 | 98.4 |
TABLE 3 dissolution test results (pH4.0) for each sample
| Sample (I) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| 0min | 0 | 0 | 0 | 0 | 0 | 0 |
| 5min | 45.5 | 47.7 | 45.3 | 46.0 | 35.5 | 46.2 |
| 10min | 65.1 | 68.1 | 64.9 | 65.6 | 59.3 | 62.2 |
| 15min | 78.0 | 80.8 | 77.5 | 78.6 | 71.4 | 72.4 |
| 30min | 88.4 | 90.8 | 87.2 | 89.6 | 80.1 | 83.5 |
| 45min | 92.6 | 93.3 | 91.8 | 93.0 | 86.6 | 89.2 |
| 60min | 96.4 | 96.9 | 93.9 | 95.5 | 92.4 | 92.9 |
TABLE 4 dissolution test results (pH6.8) for each sample
| Sample (I) | Example 1 | Example 2 | Example 3 | Example 4 | Example 5 | Example 6 |
| 0min | 0 | 0 | 0 | 0 | 0 | 0 |
| 5min | 40.2 | 38.1 | 42.8 | 39.5 | 28.7 | 39.4 |
| 10min | 61.4 | 65.6 | 61.3 | 63.8 | 58.4 | 65.9 |
| 15min | 75.2 | 78.9 | 75.0 | 76.4 | 70.3 | 73.6 |
| 30min | 86.8 | 87.9 | 85.1 | 86.2 | 78.2 | 80.8 |
| 45min | 92.3 | 92.9 | 90.5 | 92.9 | 86.5 | 88.1 |
| 60min | 95.3 | 96.9 | 93.5 | 95.9 | 91.3 | 93.2 |
Tables 1 to 4 are combined to show that the cefpodoxime proxetil tablets prepared in examples 1 to 4 are rapidly dissolved out in various media and can rapidly release active ingredients.
(3) Test for influencing factor
Experimental methods and conditions: the samples of examples 1, 5 and 6 were put in a flat weighing bottle, and subjected to an influence test according to the relevant regulation of "Chinese veterinary pharmacopoeia" 2015 edition, and properties, contents and related substances were examined under the conditions of high temperature 40 ℃. + -. 2 ℃, high humidity 75% RH. + -. 5% RH and strong light 4500 lx. + -. 500lx for 10 days. The results are shown in tables 5 to 7.
TABLE 5 Properties, contents and related substances of the samples of example 1 under the conditions of the influencing factors
TABLE 6 Properties, contents and related substances of example 5 samples under the conditions of influencing factors
TABLE 7 Properties, contents and related substances of the samples of example 6 under the conditions of the influencing factors
As can be seen from tables 5 to 7, the samples of examples 1 and 5 were kept at a high temperature of 40 ℃ C. + -. 2 ℃ C., a high humidity of 75% RH. + -. 5% RH and a high light of 4500 lx. + -. 500lx for 10 days, and the properties, contents and related substances were stable without significant changes. Example 1 is slightly better than example 5; the sample in the embodiment 6 has a color change phenomenon under illumination, and the content change is slightly large under high-temperature and high-humidity conditions, which indicates that the sample is sensitive to illumination and has certain influence on high temperature and high humidity; the stability of the prepared sample can be ensured by the tablet core coating technology.
(4) Accelerated stability test
Experimental methods and conditions: in order to predict the stability of the samples during storage, the samples of example 1 were packaged in double aluminum packages, and accelerated stability tests were performed according to the relevant regulations of the "chinese veterinary pharmacopoeia" 2015 edition, and the properties, contents and related substances accelerated for 1, 2, 3 and 6 months were examined under the conditions of 40 ℃ ± 2 ℃/75% RH ± 5% RH. The results are shown in Table 8.
TABLE 8 sample Properties, contents and related substances under accelerated conditions
As can be seen from table 8, the sample of example 1 has good stability under accelerated conditions, the content of the sample decreases by 2.4% in an accelerated test for 6 months, the total impurities increase by 0.52%, and the impurities C + B-II + D-I increase by 0.46%, and no significant change is observed according to the guidelines of the drug stability test of the chinese pharmacopoeia 2015 edition. The cefpodoxime proxetil tablet prepared in the example 1 is shown to completely isolate the cefpodoxime proxetil from direct contact with outside light and moisture after coating, the stability is better, the product of the invention has stable property and content after being stored for 6 months under the acceleration condition, and related substances are not obviously increased.
The three types of comparison experiment results show that the cefpodoxime proxetil tablet prepared by the invention has the characteristics of high stability and high dissolution, and provides convenience and quality assurance for clinical medication of animals.
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents, improvements and the like that fall within the spirit and principle of the present invention are intended to be included therein.
Claims (8)
1. A method for preparing cefpodoxime proxetil tablets, which comprises the following steps:
step (1), micronizing cefpodoxime proxetil to particle size below 70 μm, and respectively sieving disintegrating agent and filler with 40 mesh sieve;
step (2), uniformly mixing the cefpodoxime proxetil superfine powder pretreated in the step (1), a filling agent and a disintegrating agent, preparing a soft material by using an adhesive aqueous solution, sieving the soft material by using a 16-24-mesh sieve for granulation, drying the soft material at 40-50 ℃, and finishing the particles by using a 16-24-mesh sieve;
and (3) after the granules are sized in the step (2), adding a gel inhibitor, a lubricant and a flavoring agent, uniformly mixing, and tabletting.
2. The method according to claim 1, wherein the concentration of the binder in the step (4) is 3-8 w/w%.
3. The method according to claim 1, further comprising a step (4) of coating the tablet compressed in the step (3) with an aqueous coating powder solution with a concentration of 10-15 w/w% and drying to obtain the cefpodoxime proxetil tablet.
4. The method according to claim 3, wherein the disintegrant is selected from one of sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, crospovidone, sodium carboxymethyl starch; the gel inhibitor is selected from one of sodium dodecyl sulfate and polyethylene glycol 6000; the coating powder is one of Opadry and Uttch; the filler is selected from one or more of lactose, microcrystalline cellulose, maltodextrin and pre-crosslinked starch; the adhesive is selected from one of hydroxypropyl cellulose, crospovidone and hypromellose; the lubricant is one of magnesium stearate, superfine silica gel powder and talcum powder; the flavoring agent is one of artificial chicken essence, artificial beef essence and artificial pork essence; preferably, the gel inhibitor is sodium lauryl sulfate, the coating powder is opadry, the filler is lactose, the binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate.
5. Cefpodoxime proxetil tablets prepared by the process according to claims 1 to 4.
6. The cefpodoxime proxetil tablet according to claim 5, wherein the cefpodoxime proxetil tablet comprises 30-70 w/w% of cefpodoxime proxetil superfine powder, 5-20 w/w% of disintegrating agent, 5-25 w/w% of filling agent, 2-5 w/w% of adhesive, 0.1-2.0 w/w% of gel inhibitor, 0.3-1.0 w/w% of lubricant, 0.5-10 w/w% of flavoring agent and 3-8 w/w% of coating powder.
7. The cefpodoxime proxetil tablet according to claim 6 wherein the disintegrant is selected from one of sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropylcellulose, crospovidone, sodium starch glycolate; the gel inhibitor is selected from one of sodium dodecyl sulfate and polyethylene glycol 6000; the coating powder is one of Opadry and Uttch; preferably, the gel inhibitor is sodium lauryl sulfate and the coating powder is opadry.
8. The cefpodoxime proxetil tablet according to claim 6 wherein the filler is selected from one or more of lactose, microcrystalline cellulose, maltodextrin, and pregelatinized starch; the adhesive is selected from one of hydroxypropyl cellulose, crospovidone and hypromellose; the lubricant is one of magnesium stearate, superfine silica gel powder and talcum powder; the flavoring agent is one of artificial chicken essence, artificial beef essence and artificial pork essence; preferably, the filler is lactose, the binder is hydroxypropyl cellulose, and the lubricant is magnesium stearate.
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| CN115813868A (en) * | 2022-12-06 | 2023-03-21 | 江西省保灵动物保健品有限公司 | High-dissolution cefpodoxime proxetil tablet and preparation method thereof |
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