CN113679685B - Preparation method of erythromycin cydocarbonate tablet - Google Patents
Preparation method of erythromycin cydocarbonate tablet Download PDFInfo
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
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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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/04—Antibacterial agents
Abstract
The application relates to the technical field of pharmaceutical preparations, in particular to a preparation method of erythromycin cydocarbonate tablets, which comprises the following steps: carrying out first mixing treatment on erythromycin cydocarbonate, a first filler and an adhesive solution, then carrying out drying treatment, and granulating to obtain initial mixed particles with the particle size of less than or equal to 0.8 mm; wherein the adhesive solution contains first carboxymethyl starch sodium with the mass fraction being more than or equal to 7 percent; and (3) carrying out second mixing treatment on the initial mixed particles, a second filler, second carboxymethyl starch sodium and a lubricant, and then tabletting to obtain the erythromycin cydocarbonate tablet. The erythromycin cydocarbonate tablet prepared by the preparation method has the characteristics of high stability and high dissolution speed of main drugs, so that the bioavailability of erythromycin cydocarbonate can be improved, and the tablet has a good application prospect.
Description
Technical Field
The application belongs to the technical field of pharmaceutical preparations, and particularly relates to a preparation method of a erythromycin cydocarbonate tablet.
Background
The chemical name of the cyclic ester erythromycin is (2R, 3S,4S,5R,6R,8R,9R,10R, 111R, 12S, 13R) -3- [ (2,6-dideoxy-3-C-methyl-3-O-methyl-alpha-L-nuclear-hexylpyranylcarbonyl) oxy ] -13-ethyl-9-hydroxy-2,4,6,8,10,12-hexamethyl-5- [ (3,4,6-trideoxy-3- (dimethylamino) -beta-D-wood-hexylpyranylcarbonyl) oxy ] -14-oxatetradecyl ring-6,9-oxy-1,9-dione ring 11,12-carbonate, the chemical structure is as follows:
erythromycin cydocarbonate was marketed in Poland in 1979 and then first in China in 2003 in the form of tablets, suspensions, gels and lotions. The medicine belongs to macrolide antibiotics, can be used for infection caused by sensitive bacteria, and has a wide antibacterial spectrum; it acts on the bacterial cell nuclear sugar body 50S subunit to inhibit the synthesis of bacterial protein; the erythromycin is introduced into the cyclocarbon-based semisynthetic derivative, so that the absorption is increased, the binding rate of serum protein is reduced, the antibacterial activity is improved, and the toxicity is reduced; the in vitro antibacterial activity of the erythromycin cydocarbonate on gram positive and negative bacteria and anaerobic bacteria is superior to that of erythromycin, roxithromycin and clarithromycin; the permeability of the erythromycin cydocarbonate in lung tissues is obviously higher than that of the erythromycin cydocarbonate, and the erythromycin cydocarbonate has higher concentration in the lung tissues, so that the erythromycin cydocarbonate has the advantage of treating respiratory bacterial infection; at present, the antibiotic is one of the best-sold antibiotic products in the medical market in China.
In order to further expand the clinical application of erythromycin cydocarbonate and better meet the requirements of the pharmaceutical industry on erythromycin cydocarbonate preparations, a erythromycin cydocarbonate preparation product with higher quality, better stability and better safety needs to be developed. Chinese patent CN10284657B discloses an enteric coated tablet containing erythromycin cydocarbonate which can dissolve and rapidly release an active ingredient when reaching the small intestine, and since the enteric coating does not dissolve in the stomach, gastric irritation is reduced; the main defects of the method are that the tablet is prepared by directly granulating through water, the viscosity of the carboxymethyl starch sodium is not fully induced, so that the mixing uniformity of the product is poor, the dissolution difference of the tablet is influenced, the bioavailability is finally influenced, and the sticking risk exists at the same time, so that the method is not beneficial to industrial production.
Disclosure of Invention
The application aims to provide a preparation method of erythromycin cydocarbonate tablets, and aims to solve the technical problem that dissolution stability of erythromycin cydocarbonate in existing erythromycin cydocarbonate tablets is influenced due to poor mixing uniformity of erythromycin cydocarbonate active ingredients.
In order to achieve the purpose of the application, the technical scheme adopted by the application is as follows:
the application provides a preparation method of a erythromycin cydocarbonate tablet, which comprises the following steps:
performing first mixing treatment on erythromycin cydocarbonate, a first filling agent and an adhesive solution, then performing drying treatment, and granulating to obtain initial mixed particles with the particle size of less than or equal to 0.8 mm; wherein the adhesive solution contains a first sodium carboxymethyl starch with the mass fraction of more than or equal to 7%;
and carrying out second mixing treatment on the initial mixed particles, a second filler, second carboxymethyl starch sodium and a lubricant, and then tabletting to obtain the erythromycin cydocarbonate tablet.
The application provides a preparation method of erythromycin cydocarbonate tablets, which comprises the steps of firstly mixing erythromycin cydocarbonate, a first filler and a binder solution of high-concentration carboxymethyl starch sodium (the mass fraction is more than or equal to 7 percent), then drying, and granulating to obtain initial mixed particles, wherein the carboxymethyl starch sodium at the concentration has strong inclusion effect, so that a high-viscosity erythromycin cydocarbonate raw material can be well wrapped, the initial mixed particles have strong fluidity, the sticking phenomenon is effectively improved, and the erythromycin cydocarbonate is uniformly mixed; the initial mixed particles with the subsequent particle size of less than or equal to 0.8mm can be uniformly tabletted with the second filler, the second carboxymethyl starch sodium and the lubricant, and the finally obtained erythromycin cydocarbonate tablet has the characteristics of high stability and high dissolution speed of the main drug, so that the bioavailability of erythromycin cydocarbonate can be improved, and the tablet has a good application prospect.
Drawings
In order to more clearly illustrate the technical solutions in the embodiments of the present application, the drawings needed to be used in the description of the embodiments are briefly introduced below, and it is obvious that the drawings in the following description are only some embodiments of the present application, and it is obvious for those skilled in the art to obtain other drawings based on these drawings without creative efforts.
FIG. 1 is a schematic diagram (5000 times) of a distribution diagram of a erythromycin cydocarbonate tablet under a Quanta400FEG thermal field emission scanning electron microscope according to example 1 of the present application;
FIG. 2 is a graph showing the dissolution profiles of example 1 of the present application and of the commercially available "Dawaku" formulation (reference formulation) and of comparative examples 1 to 3 in a phosphate buffer medium at pH6.8 for 0 to 120 minutes;
FIG. 3 is a graph showing the dissolution profiles of the erythromycin cydocarbonate tablet and the commercially available "dafenxin" (reference preparation) of example 1 of the present application transferred from an acidic medium to a medium of phosphate buffer at pH6.8 for 0 to 120 minutes.
Detailed Description
In order to make the technical problems, technical solutions and advantageous effects to be solved by the present application more clearly apparent, the present application is further described in detail below with reference to the embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the present application and are not intended to limit the present application.
In this application, the term "and/or" describes an association relationship of associated objects, meaning that there may be three relationships, e.g., a and/or B, which may mean: a is present alone, A and B are present simultaneously, and B is present alone. Wherein A and B can be singular or plural. The character "/" generally indicates that the former and latter associated objects are in an "or" relationship.
In the present application, "at least one" means one or more, "plural" means two or more. "at least one of the following" or similar expressions refer to any combination of these items, including any combination of the singular or plural items.
It should be understood that, in various embodiments of the present application, the sequence numbers of the above-mentioned processes do not mean the execution sequence, some or all of the steps may be executed in parallel or executed sequentially, and the execution sequence of each process should be determined by its function and inherent logic, and should not constitute any limitation to the implementation process of the embodiments of the present application.
The terminology used in the embodiments of the present application is for the purpose of describing particular embodiments only and is not intended to be limiting of the application. As used in the examples of this application and the appended claims, the singular forms "a", "an", and "the" are intended to include the plural forms as well, unless the context clearly indicates otherwise.
The weight of the related components mentioned in the description of the embodiments of the present application may not only refer to the specific content of each component, but also represent the proportional relationship of the weight among the components, and therefore, the content of the related components is scaled up or down within the scope disclosed in the description of the embodiments of the present application as long as it is scaled up or down according to the description of the embodiments of the present application. Specifically, the mass described in the specification of the examples of the present application may be a mass unit known in the chemical field such as μ g, mg, g, kg, etc.
The terms "first" and "second" are used for descriptive purposes only and are used for distinguishing purposes such as substances from one another, and are not to be construed as indicating or implying relative importance or implying any number of technical features indicated. For example, a first XX may also be referred to as a second XX, and similarly, a second XX may also be referred to as a first XX, without departing from the scope of embodiments of the present application. Thus, a feature defined as "first" or "second" may explicitly or implicitly include one or more of that feature.
The first aspect of the embodiments of the present application provides a preparation method of erythromycin cydocarbonate tablets, the preparation method including the following steps:
s01: carrying out first mixing treatment on erythromycin cydocarbonate, a first filler and an adhesive solution, then carrying out drying treatment, and granulating to obtain initial mixed particles with the particle size of less than or equal to 0.8 mm; wherein the adhesive solution contains first carboxymethyl starch sodium with the mass fraction being more than or equal to 7 percent;
s02: and (3) carrying out second mixing treatment on the initial mixed particles, a second filler, second carboxymethyl starch sodium and a lubricant, and then tabletting to obtain the erythromycin cydocarbonate tablet.
The embodiment of the application provides a preparation method of erythromycin cydocarbonate tablets, which comprises the steps of firstly mixing erythromycin cydocarbonate, a first filler and a binder solution of high-concentration carboxymethyl starch sodium (the mass fraction is more than or equal to 7%), then drying, and granulating to obtain initial mixed particles, wherein the carboxymethyl starch sodium at the concentration has strong inclusion effect, can well wrap a high-viscosity erythromycin cydocarbonate raw material, enables the initial mixed particles to have strong fluidity, effectively improves the sticking phenomenon, and enables the erythromycin cydocarbonate to be uniformly mixed; the obtained initial mixed particles with the particle size of less than or equal to 0.8mm can be uniformly mixed with a second filler, second carboxymethyl starch sodium and a lubricant for tabletting, and the finally obtained erythromycin cydocarbonate tablet has the characteristics of high stability and high dissolution speed of the main drug, so that the bioavailability of erythromycin cydocarbonate can be improved, and the tablet has a good application prospect.
In step S01, erythromycin cydocarbonate is the pharmaceutically active ingredient of erythromycin cydocarbonate tablets provided in the examples herein, and in some examples, D is selected 90 Erythromycin cydocarbonate less than or equal to 100 μm, preferably D 90 :2 to 100 μm, more preferably 20 to 50 μm. By selecting the erythromycin cydocarbonate with the granularity range, the in-vitro dissolution release degree of the erythromycin cydocarbonate tablet can be improved, and the bioavailability of the erythromycin cydocarbonate tablet is further improved.
Carboxymethyl starch sodium (CMS), which is the sodium salt of starch Carboxymethyl ether produced by reacting starch with chloroacetic acid under alkaline condition, is in the form of elliptical or spherical particles when examined under microscopic examination, and can be dispersed in water to form viscous colloidal solution with a volume of 300 times. In the embodiment of the application, the disintegration and dissolution of the erythromycin cydocarbonate tablet are influenced by the concentration of carboxymethyl starch sodium; when the concentration of the carboxymethyl starch sodium in the adhesive solution is higher than 7%, the inclusion effect is strong, and the high-viscosity erythromycin cydocarbonate raw material is wrapped in the granulation process to obtain particles with strong fluidity, so that the sticking phenomenon is effectively improved, the dissolution in an acid medium is improved, and the bioavailability is improved.
Therefore, the sodium carboxymethyl cellulose raw material of the embodiment of the application is divided into two parts (the first sodium carboxymethyl starch and the second sodium carboxymethyl starch) and added into the tabletting process, specifically, the first sodium carboxymethyl starch is prepared into a binder solution with the mass fraction of more than or equal to 7 percent, and the binder solution, the erythromycin cydocarbonate and the first filler are mixed in a slurry form and then dried and granulated to obtain initial mixed particles; and the second carboxymethyl starch sodium is mixed with the initial mixed particles, the second filler, the second carboxymethyl starch sodium and the lubricant in the form of particles and tabletted to obtain the final erythromycin cydocarbonate tablet. The sodium carboxymethyl cellulose can be used as an adhesive or a disintegrating agent, and after the sodium carboxymethyl cellulose is prepared into the erythromycin cydocarbonate tablet by the adhesive action, the erythromycin cydocarbonate raw material is released by the disintegrating action. The adhesive solution with the mass fraction of the first carboxymethyl starch sodium being more than or equal to 7 percent can also be used as a wetting agent to be granulated with the added erythromycin cydocarbonate by a wet method. In conclusion, the inclusion function and compressibility of the carboxymethyl starch sodium and good disintegration function are adopted, so that the hardness of the obtained erythromycin cydocarbonate tablet is increased, the friability is reduced, and the product quality is ensured.
In one embodiment, the binder solution with the first sodium carboxymethyl starch mass fraction being greater than or equal to 7% is a slurry of the first sodium carboxymethyl starch dispersed in water. According to the embodiment of the application, the flowability of the initial mixed particles is improved by adding the carboxymethyl starch sodium slurry for bonding through a wet granulation process, and the granulation process has good safety and is beneficial to industrial production.
Further, in the adhesive solution, the mass fraction of the first sodium carboxymethyl starch is 7-10%. The adhesive solution with the concentration can effectively reduce the excessive contact of the erythromycin cydocarbonate and water, and can ensure that the active ingredients of the erythromycin cydocarbonate are uniformly mixed, thereby improving the stability of the tablet.
In one embodiment, the temperature of the drying process is 40 ℃ to 70 ℃. The drying treatment is carried out within the temperature range, so that the drying efficiency can be ensured, and the stability of the obtained erythromycin cydocarbonate tablet can be improved. By the drying process, the moisture content in the granules can be reduced. Specifically, the drying temperature in the examples of the present application was 40 ℃, 45 ℃, 50 ℃, 55 ℃, 60 ℃, 65 ℃, 70 ℃.
In one embodiment, the initial mixed granules obtained after the drying process have a moisture content of 3.0% or less. The embodiment of the application leads the drying loss of the initial mixed particles through the drying treatmentThe heavy water content is less than or equal to 3.0 percent, and the impurity 10,11-anhydroerythromycin A (chemical formula is C) in the obtained erythromycin cydocarbonate tablet can be avoided 37 H 65 NO 12 Molecular weight 715.91) and the tendency of total impurities to grow too fast, thereby further improving the stability of the obtained erythromycin cydocarbonate tablet.
In one embodiment, the granulation process is a 0.8mm mesh screen to obtain the initial mixed granules. And (3) adopting a screen with the aperture of 0.8mm to carry out granulation, so that the diameter of the obtained initial mixed particles is less than or equal to 0.8mm, and obtaining the initial mixed particles with uniform particle size, thereby improving the compressibility of subsequent tabletting and the uniformity of the obtained erythromycin cydocarbonate tablet.
In step S02, the initial mixed granules obtained by wet granulation are mixed with the second filler, the second sodium starch glycolate and the lubricant and tabletted.
In one embodiment, the preparation method of the erythromycin cydocarbonate tablet of the embodiment of the application uses the following raw materials by weight:
wherein the weight ratio of the first filler to the second filler can be 3 (8-9).
Specifically, the weight of the erythromycin cydocarbonate can be 200 parts, 220 parts, 250 parts, 270 parts, 300 parts and the like; the first filler may be 15 parts and the second filler may be 40 parts, or the first filler may be 15 parts and the second filler may be 45 parts, or the first filler may be 18 parts and the second filler may be 48 parts, or the first filler may be 18 parts and the second filler may be 54 parts, etc.; the adhesive solution comprises 300 parts, 350 parts, 400 parts, 430 parts, 460 parts and the like, wherein the mass fraction of the first carboxymethyl starch sodium is 7-10%; the weight of the second sodium starch glycolate can be 20 parts, 25 parts, 30 parts, 35 parts, 40 parts and the like; the weight of the lubricant may be 14 parts, 22 parts, 28 parts, 30 parts, etc. According to the weight parts, the erythromycin cydocarbonate, the first filler and the adhesive solution are subjected to first mixing treatment, then drying treatment is carried out, and initial mixed particles with the particle size being less than or equal to 0.8mm are obtained through finishing. And then carrying out second mixing treatment on the obtained initial mixed particles, a second filler, second carboxymethyl starch sodium and a lubricant according to the weight parts, and tabletting to obtain the erythromycin cydocarbonate tablet. By adopting the raw materials in the proportion range, the prepared erythromycin cydocarbonate tablet has better comprehensive quality.
In one embodiment, the second mixing process includes: the initial mixed particles are mixed with the second filler, the second carboxymethyl starch sodium and 10-20 parts of lubricant, and then mixed with the rest 4-10 parts of lubricant. The lubricant is used as one of the excipients, can improve the fluidity of the materials, is beneficial to the subsequent tabletting treatment and promotes the realization of industrial scale-up production. And adding the lubricant twice can further improve the particle fluidity. Further, the lubricant is selected from at least one of magnesium stearate, stearic acid and talc, for example, 10 to 20 parts of talc and 4 to 10 parts of magnesium stearate can be selected, and specifically, the primary mixed granules are mixed with the second filler, the second sodium starch glycolate and 10 to 20 parts of talc, and then mixed with the remaining 4 to 10 parts of magnesium stearate.
In one embodiment, the first filler is selected from at least one of microcrystalline cellulose, lactose, sorbitol, and mannitol; the second filler is at least one selected from microcrystalline cellulose, lactose, sorbitol and mannitol. Wherein the weight ratio of the first filler to the second filler may be 3 (8-9). The embodiment of the application selects 60-80 parts of microcrystalline cellulose raw material by total weight, and the microcrystalline cellulose raw material is divided into a first microcrystalline cellulose and a second microcrystalline cellulose with the weight ratio of 3 (8-9). Specifically, in the embodiment of the application, firstly, a binder solution of erythromycin cydocarbonate, first microcrystalline cellulose and first sodium carboxymethyl starch is mixed and granulated to obtain an initial mixed granule, then, second microcrystalline cellulose, second sodium carboxymethyl starch and a lubricant are added for mixed tabletting, and dissolution of the tablet is improved through strong water absorption of microcrystalline cellulose, so that the bioavailability is further improved.
In some embodiments, other excipients, such as other binders, other disintegrants, colorants, co-solvents, and the like, may also be added. The other binder may be selected from at least one of pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose; the other disintegrant is at least one selected from pregelatinized starch, crospovidone, low-substituted hydroxypropyl cellulose, and carboxymethyl cellulose. Specifically, the other binder or the other disintegrant may be divided into two parts, and one part of the other binder or one part of the other disintegrant may be added in the first mixing process, and the remaining other binder or the remaining other disintegrant may be added in the second mixing process. Further, the colorant and/or co-solvent may be added during the first mixing process.
The embodiment of the application provides a erythromycin cydocarbonate tablet which is prepared by the preparation method of the erythromycin cydocarbonate tablet. Because the adhesive solution of the first carboxymethyl starch sodium with high viscosity (the mass fraction of the first carboxymethyl starch sodium is more than or equal to 7 percent based on 100 percent of the adhesive solution) is granulated in the preparation process of the preparation method, the adhesive solution of the gelatinous fluid can effectively reduce the excessive contact of the erythromycin cydocarbonate and water, improve the stability of the obtained erythromycin cydocarbonate tablet and reduce the occurrence of discoloration phenomenon. The wet granulation process can fully disperse the high-viscosity erythromycin cydocarbonate raw material, so that granules with good fluidity are prepared, the sticking phenomenon is effectively avoided, meanwhile, the degradation of the main drug in an acid medium is reduced, and the disintegration performance of the tablet is improved. Therefore, the erythromycin cydocarbonate tablet has the advantages of high stability, high main drug dissolution speed (the dissolution in buffer solutions with pH1.0, pH4.5 and pH6.8 can be improved), high bioavailability and good application prospect.
The following description will be given with reference to specific examples.
Example 1
A preparation method of erythromycin cydocarbonate tablets comprises the following specific steps:
the method comprises the following steps: 250g of erythromycin cydocarbonate (D) 90 About 5 mu m), mixing 15g of first microcrystalline cellulose in a wet granulator uniformly, adding 435g of carboxymethyl starch sodium slurry (the first carboxymethyl starch sodium is dispersed in water and has the solid content of 8.0 percent) to prepare a soft material, drying at the temperature of 60 ℃ until the moisture is less than or equal to 3.0 percent, and granulating by using a 0.8 mm-aperture screen to obtain initial mixed particles;
adding 40g of second microcrystalline cellulose, 20g of second carboxymethyl starch sodium and 15g of talcum powder into the initial mixed granules, mixing the mixture in a mixer, adding 7g of magnesium stearate, uniformly mixing, and tabletting to obtain the erythromycin cydocarbonate tablet.
In the above-prepared erythromycin cydocarbonate tablets, the raw materials and contents used per 1000 erythromycin cydocarbonate tablets are shown in table 1.
TABLE 1
Example 2
A preparation method of erythromycin cydocarbonate tablets comprises the following specific steps:
the method comprises the following steps: 250g of erythromycin cydocarbonate (D) 90 About 5 mu m), mixing 15g of first microcrystalline cellulose in a wet granulator uniformly, adding 430g of carboxymethyl starch sodium slurry (the first carboxymethyl starch sodium is dispersed in water and has solid content of 7.0 percent) to prepare a soft material, drying at the temperature of 60 ℃ until the moisture is less than or equal to 3.0 percent, and granulating by using a 0.8 mm-aperture screen to obtain initial mixed particles;
adding 45g of second microcrystalline cellulose, 20g of second carboxymethyl starch sodium and 15g of talcum powder into the initial mixed granules, mixing the mixture in a mixer, adding 7g of magnesium stearate, uniformly mixing, and tabletting to obtain the erythromycin cydocarbonate tablet.
In the above-prepared erythromycin cydocarbonate tablets, the raw materials and contents used per 1000 erythromycin cydocarbonate tablets are shown in table 2.
TABLE 2
Comparative example 1
A preparation method of erythromycin cydocarbonate tablets comprises the following specific steps:
the method comprises the following steps: 250g of erythromycin cydocarbonate (D) 90 About 20 mu m), mixing 15g of first microcrystalline cellulose in a wet granulator uniformly, adding 200g of purified water to prepare a soft material, drying at 60 ℃ until the water content is less than or equal to 3.0%, and finishing granules by using a 0.8 mm-aperture screen to obtain initial mixed granules;
step two: adding 55g of second microcrystalline cellulose, 40g of second carboxymethyl starch sodium and 15g of talcum powder into the initial mixed granules, mixing the mixture in a mixer, adding 7g of magnesium stearate, uniformly mixing, and tabletting to obtain the erythromycin cydocarbonate tablet.
Comparative example 2
A preparation method of erythromycin cydocarbonate tablets comprises the following specific steps:
the method comprises the following steps: 250g of erythromycin cydocarbonate (D) 90 About 20 mu m), mixing 15g of first microcrystalline cellulose in a wet granulator uniformly, adding 315g of carboxymethyl starch sodium slurry (the first carboxymethyl starch sodium is dispersed in water and has a solid content of 4.8%) to prepare a soft material, drying at 60 ℃ until the moisture is less than or equal to 3.0%, and finishing by using a 0.8 mm-aperture screen to obtain initial mixed particles;
step two: adding 40g of second microcrystalline cellulose, 40g of second carboxymethyl starch sodium and 15g of talcum powder into the initial mixed granules, mixing the granules in a mixer, adding 7g of magnesium stearate, uniformly mixing, and tabletting to obtain the erythromycin cydocarbonate tablets.
Comparative example 3
A preparation method of erythromycin cydocarbonate tablets comprises the following specific steps:
the method comprises the following steps: uniformly mixing 250g of erythromycin cydocarbonate (D90 is about 20 mu m) and 40g of first microcrystalline cellulose in a wet granulator, adding 364g of carboxymethyl starch sodium slurry (the first carboxymethyl starch sodium is dispersed in water and has the solid content of 6.6 percent) to prepare a soft material, drying at the temperature of 60 ℃ until the moisture is less than or equal to 3.0 percent, and granulating by using a 0.8 mm-pore sieve to obtain initial mixed particles;
step two: adding 26g of second microcrystalline cellulose, 20g of second carboxymethyl starch sodium and 15g of talcum powder into the initial granules, mixing the mixture in a mixer, adding 7g of magnesium stearate, uniformly mixing, and tabletting to obtain the erythromycin cydocarbonate tablet.
The raw materials and contents of erythromycin cydocarbonate tablets obtained in comparative examples 1 to 3 are shown in Table 3 for each 1000 erythromycin cydocarbonate tablets.
TABLE 3
Performance test
The erythromycin cydocarbonate tablets obtained in examples 1 to 2 and comparative examples 1 to 3 were subjected to dissolution curve test, and considering that the erythromycin cydocarbonate tablets were taken before meals to simulate the dissolution release rate of a product in an empty stomach state, a phosphate buffer solution (simulated intestinal fluid) with a pH of 6.8 was selected for dissolution curve examination, and dissolution was compared with a reference preparation (a commercially available original preparation "to develop new") under the condition of a paddle method of 100 rpm. Table 4 shows the dissolution profile data for reference formulation RLD, examples 1-2 and comparative examples 1-3 in phosphate buffer medium at pH6.8 for sampling time points of 5min, 10min, 15min, 30min, 45min, 90min and 120min, the graph being shown in FIG. 2.
TABLE 4
The results show that: the dissolution behavior of the product in a phosphate buffer medium with pH6.8 has good distinctiveness, examples 1-2 and comparative examples 1-3 achieve new dissolution behavior similar to that of a reference preparation sold in the market in a phosphate buffer medium with pH6.8, and the fitting risk of bioavailability is low. And after the first sodium carboxymethyl starch is prepared into the adhesive solution with the mass fraction of more than or equal to 7 percent, the dissolution of the first sodium carboxymethyl starch in a medium with pH of 6.8 is not slowed down, but the release of the medicament is accelerated to a certain extent in the early stage, and the bioavailability can be effectively improved. It is particularly noted that the products of comparative examples 1 to 3 all have different sticking phenomena in the tabletting process during the preparation process, while examples 1 to 2 have good smoothness of the tabletting process and no sticking phenomenon under the condition of smaller particle size and stronger adhesion of the raw material drug. The embodiment 1-2 well solves the sticking problem easily occurring in the process, and ensures the possibility of large-scale production of products.
To compare the dissolution behavior in acid of this example 1 and the commercial reference formulation, a comparative study was performed on the example 1 and the reference formulation using a dissolution method of ph1.2 medium (simulated gastric fluid) to ph6.8 medium. The specific dissolution method is to adopt a 50rpm paddle method to dissolve for one hour in a hydrochloric acid medium with pH1.2, then to replace a phosphate buffer medium with pH6.8, to adopt a paddle method to dissolve for two hours with 100rpm, and to observe the dissolution result. The elution amounts at the comparison end points in the hydrochloric acid medium, the cumulative elution amounts measured at pH6.8 in the media at 10min, 30min, 60min, 90min and 120min, are shown in Table 5 and FIG. 3.
TABLE 5
The results show that: the reference formulation on the market shows more active substance release and decomposition in the acid stage, compared with the tablet prepared in the example 1 of the present application, the accumulated dissolution amount in the acid is less, the decomposition of the active substance is avoided, and the active substance can reach the intestinal tract to be further absorbed.
The stability of the example 1 sample and reference formulation is compared between 0 days and 6 months (M) of acceleration in Table 6.
TABLE 6
According to the data of the substances related to the example 1 and the commercial reference preparation, the application example 1 effectively reduces the excessive contact of erythromycin cydocarbonate and water due to the use of high-concentration carboxymethyl starch sodium slurry, improves the stability of the obtained erythromycin cydocarbonate tablet, and reduces the occurrence of discoloration.
In conclusion, the erythromycin cydocarbonate tablets prepared in the examples have better stability.
The above description is only exemplary of the present application and should not be taken as limiting the present application, as any modification, equivalent replacement, or improvement made within the spirit and principle of the present application should be included in the protection scope of the present application.
Claims (8)
1. The preparation method of the erythromycin cydocarbonate tablet is characterized by comprising the following steps:
carrying out first mixing treatment on erythromycin cydocarbonate, a first filler and an adhesive solution, then carrying out drying treatment, and granulating to obtain initial mixed particles with the particle size of less than or equal to 0.8 mm; wherein the adhesive solution contains a first sodium carboxymethyl starch with the mass fraction of more than or equal to 7 percent;
performing second mixing treatment on the initial mixed particles, a second filler, second carboxymethyl starch sodium and a lubricant, and then tabletting to obtain a erythromycin cydocarbonate tablet;
wherein the first filler is selected from microcrystalline cellulose, the second filler is selected from microcrystalline cellulose, and the lubricant is selected from at least one of magnesium stearate, stearic acid and talc.
2. The method of claim 1, wherein the binder solution is a slurry of the first sodium starch glycolate dispersed in water.
3. The method of claim 2, wherein the first sodium starch glycolate is present in the binder solution in a mass fraction of 7% to 10%.
4. The method for preparing erythromycin cydocarbonate tablets according to claim 1, wherein the temperature of the drying treatment is 40 ℃ to 70 ℃.
5. The method of claim 4, wherein said initial mixed granules obtained after said drying process have a moisture content of 3.0% or less.
6. The method of preparing erythromycin cydocarbonate tablets according to claim 1, wherein the granulating to obtain initial mixed granules having a particle size of 0.8mm or less comprises: the primary mixed granules were obtained by granulating with a 0.8 mm-pore size sieve.
7. The process for preparing erythromycin cydocarbonate tablets according to any one of claims 1 to 6,
the weight of the erythromycin cydocarbonate is 200 to 300 parts
The total weight of the first filler and the second filler is 55 to 80 parts
The weight of the adhesive solution is 300 to 460 parts
The weight of the second sodium carboxymethyl starch is 20 to 40 parts
The weight of the lubricant is 14 to 30 parts
Wherein the weight ratio of the first filler to the second filler is 3 (8~9).
8. The method of preparing erythromycin cydocarbonate tablets according to claim 7, wherein the second mixing process comprises: mixing the initial mixed particles with the second filler, the second sodium carboxymethyl starch and 10 to 20 parts of the lubricant, and then mixing with the rest 4 to 10 parts of the lubricant.
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| CN102038700A (en) * | 2009-10-14 | 2011-05-04 | 海南澳美华制药有限公司 | Bitter-taste-masking erythromycin-cydocarbonate-containing oral composition |
| JP2012036140A (en) * | 2010-08-10 | 2012-02-23 | Kyoto Pharmaceutical Industries Ltd | Rapid disintegrating tablet with reduced bitterness |
| CN104688757A (en) * | 2013-12-09 | 2015-06-10 | 海南澳美华制药有限公司 | Dissolution rate increased erythromycin cydocarbonate oral composition |
| CN110548010A (en) * | 2019-04-02 | 2019-12-10 | 海南海神同洲制药有限公司 | preparation method of roxithromycin dispersible tablet |
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| CN102038700A (en) * | 2009-10-14 | 2011-05-04 | 海南澳美华制药有限公司 | Bitter-taste-masking erythromycin-cydocarbonate-containing oral composition |
| JP2012036140A (en) * | 2010-08-10 | 2012-02-23 | Kyoto Pharmaceutical Industries Ltd | Rapid disintegrating tablet with reduced bitterness |
| CN104688757A (en) * | 2013-12-09 | 2015-06-10 | 海南澳美华制药有限公司 | Dissolution rate increased erythromycin cydocarbonate oral composition |
| CN110548010A (en) * | 2019-04-02 | 2019-12-10 | 海南海神同洲制药有限公司 | preparation method of roxithromycin dispersible tablet |
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