CN112137965A - Cefaclor particle pharmaceutical composition - Google Patents
Cefaclor particle pharmaceutical composition Download PDFInfo
- Publication number
- CN112137965A CN112137965A CN202010850150.7A CN202010850150A CN112137965A CN 112137965 A CN112137965 A CN 112137965A CN 202010850150 A CN202010850150 A CN 202010850150A CN 112137965 A CN112137965 A CN 112137965A
- Authority
- CN
- China
- Prior art keywords
- cefaclor
- sodium carboxymethyl
- hydroxypropyl methylcellulose
- carboxymethyl starch
- product
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1611—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
- A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
-
- 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 relates to a cefaclor granule pharmaceutical composition, and belongs to the technical field of pharmaceutical preparations. The technical scheme of the invention is as follows: a cefaclor granule composition contains cefaclor, corn starch, sucrose, sodium carboxymethyl starch, silicon dioxide and hydroxypropyl methylcellulose, wherein the dosage of the hydroxypropyl methylcellulose and the sodium carboxymethyl starch are not lower than 9% of the total weight of a unit dose product respectively, the mass ratio of the hydroxypropyl methylcellulose to the sodium carboxymethyl starch is 1:1, the mass ratio of the sum of the dosages of the hydroxypropyl methylcellulose and the sodium carboxymethyl starch to cefaclor (calculated in anhydrous state) is 18-24: 12-16, and the viscosity of the hydroxypropyl methylcellulose is less than 100 mPa.S (at 20 ℃). The invention provides a cefaclor particle pharmaceutical composition which has stable quality and is equivalent to the original biological research.
Description
Technical Field
The invention relates to a cefaclor granule pharmaceutical composition, and belongs to the technical field of pharmaceutical preparations.
Background
Cefaclor, developed by the Li Lai laboratory under the trade name Sechilau®（Ceclor®) Second-generation cephalosporins, which have a broad-spectrum antibacterial action in the same mechanism as other cephalosporins and achieve bactericidal action mainly by inhibiting cell wall synthesis, are marketed in countries such as the united states and japan, and are now sold in many countries including china, and their trade names are mainly Ceclor, hitachio, Distaclor, kefral, keflor, koffir, etc. At present, dry suspension, capsules, tablets, granules and other various formulations are sold in China, and the Selauh is produced by the Lilesu pharmaceutical company in 2 months in 2018®(Cefaclor dry suspension, specification: 0.125 g) is selected as a reference preparation for the evaluation of the pharmaceutical imitation consistency in China (twelfth batch of reference preparation catalog).
The cefaclor granules are unique dosage forms in China, can be taken after being dissolved in warm water when in use, are convenient for the old, children and patients with dysphagia to take, and have good compliance. Experiments show that the biological equivalence of cefaclor granules and a reference preparation has certain difficulty, so far, domestic cefaclor granule-free production enterprises only apply few enterprises to carry out biological equivalence tests through the evaluation of the consistency of the imitation drugs. The possible reasons for the analysis are as follows:
(1) most oral drugs are mainly absorbed in the small intestine, the absorption part of cefaclor is the upper part of the small intestine, the total length of the absorption part in the digestive tract is very short, and the absorption position and the absorption area of the drugs are limited.
(2) The stability of cefaclor in vivo is greatly influenced by the pH of the environment, and when the pH is more than 6.0, the cefaclor is rapidly degraded, which means that the cefaclor leaving the upper part of the small intestine is rapidly degraded, and particularly, when the cefaclor is taken after a meal, the absorption window of cefaclor left by the alkaline intestinal environment is narrower due to the sharp decrease of the pH of gastric juice, and the cefaclor is more difficult to be bioequivalent with a reference preparation.
(3) The physiological characteristics of human bodies are very complex, and the pharmaceutical composition may contain a plurality of different auxiliary materials or have personalized physicochemical characteristics of drugs, and may influence the gastrointestinal peristalsis rate. For example, the auxiliary materials such as xylitol, sorbitol and mannitol can not be well absorbed by gastrointestinal tracts, but can increase the intestinal osmotic pressure and change the water flux of the gastrointestinal tracts, thereby influencing the gastric emptying time and the intestinal transit time of the medicine; different preparation process parameters and preparation structures of the medicine possibly influence the dissolution of the medicine or the distribution of the medicine in the gastrointestinal tract after the dissolution. Differences in gastrointestinal transit time may affect the residence time of cefaclor at the site of absorption, thereby affecting drug absorption; in addition, food may also have an effect on the disintegration, dissolution, distribution and even absorption of a drug in the body, "such food effects may reduce the bioavailability of a particular drug below a therapeutically effective concentration range, rendering the drug less effective or ineffective". (FDA bioequivalence Standard/(American) robust residual (Lawrence, X.Y), (American) Libingo (Bing, V.L.) original works; Yaojinsi-New-translation-Beijing: Beijing university medical Press, 2017.1)
The precondition of the absorption of the medicine is the dissolution/release of the medicine, and the dissolution stability of the medicine have great significance on the bioavailability and the curative effect of the medicine. During the research, the cefaclor preparation has the problems of dissolution and dissolution stability.
Patent CN 103330685B discloses that a main drug is coated after a polyvinyl alcohol-polyethylene glycol graft copolymer is dissolved in ethanol, so that a cefaclor granule product with good stability and quick dissolution is obtained, the defect is that an ethanol solution is used, certain potential safety hazard is brought to industrial production, explosion-proof requirements need to be considered, the process requirement is complex, and meanwhile, as a process mode that a main drug coating is directly mixed with other auxiliary materials and then filled to obtain a cefaclor granule finished product is adopted, the granularity of the finished product is difficult to meet the granularity requirement of pharmacopeia granule general rules (the sum of the cefaclor granule product which cannot pass through a first sieve and can pass through a fifth sieve is not more than 15 percent) theoretically; patent CN 103623412B discloses a method for preparing cefaclor tablets by melting diethylene glycol monoethyl ether and colloidal silicon dioxide to form a solid dispersion, and then performing dry granulation and tabletting with other raw and auxiliary materials, which solves the incompatibility between the main drug and the lubricant, and effectively improves the dissolution rate of the product, and has the disadvantages that the granulation process needs to use a melting technology, the process is complex and the cost is high; patent application CN 108743547A discloses that the main drug is wrapped after polyethylene glycol with a specific proportion is dissolved in ethanol, a cefaclor granule product with good stability and fast dissolution is obtained, the production explosion-proof risk of using organic reagent ethanol exists as in patent CN 103330685B, the adopted decompression drying step increases the complexity of the process, prolongs the production time and is not beneficial to cost control.
According to the reference preparation published to the country®Quality analysis of cefaclor dry suspension (specification 0.125 g), stability sample under accelerated condition (40 ℃ +/-2 ℃/65% +/-5% RH) is prolonged along with investigation time, dissolution rate is reduced rapidly, and potential adverse effects such as reduction of bioavailability and drug effect exist, namely Hidilao®Storage temperatures below 20 ℃ are therefore also required; experiments show that the dissolution rate of cefaclor granules with different formulas in the storage process also has the stability problem.
Cefaclor granules are unique dosage forms in China, reference is not made to reference preparation formulas, in order to solve the problems, the formulas and processes need to be independently designed, the auxiliary material combinations and preparation processes adopted by the medicines have multiple kinds, the complexity of in-vivo medicine release and absorption environments and the cooperation and antagonism among the auxiliary materials exist, so that the formulas and processes which can meet the requirements (such as bioequivalence) are difficult to be easily obtained by the technical personnel in the field only by limited test times or brain storm type analysis and deduction, and the inventor needs to spend creative labor to find the proper combination with the required performance.
Disclosure of Invention
The purpose of the invention is as follows: provides a cefaclor granular composition and a preparation method thereof, the composition is bioequivalent to a reference preparation (cefaclor dry suspension), and the dissolution is stable in the storage process.
According to the auxiliary material manual (pharmaceutical auxiliary material manual/[ lnelo (Rowe, R.C.), [ Meissky (Sheskey, P.J.), [ Inflate (Weller, P.J.); Zhengjun folk-Nakayasu-Beijing: chemical industry Press, 2004.7), the usage concentration of hypromellose as a binder of the wet granulation tablet is 2%, and the usage concentration of the binder of the dry granulation tablet is 5%; the dosage of the sodium carboxymethyl starch in the tablet is 2-8%.
The inventor tests and finds that in the cefaclor granule composition, hypromellose and sodium carboxymethyl starch are used in an amount exceeding the conventional auxiliary materials, the prepared granule is bioequivalent to a reference preparation, and the dissolution rate in an aqueous medium is not obviously changed during the accelerated condition stability investigation.
The technical scheme of the invention is as follows:
a cefaclor granule composition contains cefaclor, corn starch, sucrose, sodium carboxymethyl starch, silicon dioxide and hydroxypropyl methylcellulose, wherein the dosage of the hydroxypropyl methylcellulose and the sodium carboxymethyl starch are not lower than 9% of the total weight of a unit dose product respectively, the mass ratio of the hydroxypropyl methylcellulose to the sodium carboxymethyl starch is 1:1, the mass ratio of the sum of the dosages of the hydroxypropyl methylcellulose and the sodium carboxymethyl starch to cefaclor (calculated in anhydrous state) is 18-24: 12-16, and the viscosity of the hydroxypropyl methylcellulose is less than 100 mPa.S (at 20 ℃).
The cefaclor is a monohydrate, the sucrose accounts for 30-65% of the total weight of a unit dosage product, the corn starch accounts for 10-20% of the total weight of the unit dosage product, and the sodium carboxymethyl starch is A type.
Preferably, the cefaclor granule composition comprises the sum of the dosages of hydroxypropyl methylcellulose and sodium carboxymethyl starch and cefaclor (calculated by anhydrous substance) in a ratio of 20:14, wherein the weight of sucrose accounts for 40-50% of the total weight of a unit dose product, the weight of corn starch accounts for 13-17% of the total weight of the unit dose product, and the dosage of silicon dioxide accounts for 3.5% of the total weight of the unit dose product.
The pharmaceutical composition of the present invention may also contain appropriate amounts of pH adjusting agents and/or coloring and/or flavoring agents.
The wetting agent of the cefaclor granule pharmaceutical composition is purified water or a purified water solution containing 10-30 wt% of ethanol, and is removed in the drying process.
The total weight of cefaclor granules in unit dose of the cefaclor granules is not more than 1.5g, and the specification of cefaclor (in anhydrous basis) is 125 mg.
The preparation method of the cefaclor granule composition comprises the following steps:
step 1, preparing a wetting agent; adding the purified water/ethanol and water into a container according to the prescription amount (when the ethanol and the purified water are wetting agents, the ethanol is added into the purified water and is uniformly stirred);
step 2, adding the cefaclor, the sucrose, the corn starch, the hydroxypropyl methylcellulose, the sodium carboxymethyl starch and the silicon dioxide in the prescription amount into a granulator, and uniformly mixing;
step 3, adding the material obtained in the step 1 into a granulator with the material in the step 2 in a guniting mode under stirring, quickly guniting, and continuously wet-mixing to prepare a soft material after guniting is finished;
the preferable guniting pressure in the step is more than 0.3Mpa and is finished within 1 minute.
Step 4, wetting the soft material prepared in the step 3 into granules by using a swing granulator or a quick granulating machine, wherein the mesh number of a screen is 18-24 meshes;
step 5, transferring the wet granules to a fluidized bed dryer for drying, wherein the temperature of the materials is controlled not to exceed 60 ℃ during drying;
step 6, using a screening machine to screen out particles which do not meet the requirements (the sum of the particles which can not pass through a 10-mesh standard sieve and the particles which can pass through an 80-mesh standard sieve after the particles are required to be screened out is not more than 15%);
step 7, mixing the particles obtained in the step 6 uniformly;
and 8, subpackaging the total mixed particles obtained in the step 7 according to requirements to obtain a finished product.
According to the preparation method, the flavoring agent, the pH regulator and/or the coloring agent can be added in the step 2, or can be dissolved/dispersed in the wetting agent in the step 1 and added along with the wetting agent in the step 3.
The proportion of the auxiliary materials is very critical, and the dosage of the auxiliary materials exceeding the requirement of the patent can cause incomplete dissolution of the medicine and can be degraded quickly after missing an absorption part in a body; or the dissolution rate of the medicine is changed after the medicine residues which are not completely dissolved out are wrapped by the food; it may also cause the permeability, distribution range and total absorption amount per unit time of the liquid medicine formed in vivo after the product is dissolved to be different from that of the reference preparation, thereby causing biological inequality in vivo.
The invention has the beneficial effects that:
provides a cefaclor granular composition and a preparation method thereof, and the obtained product and a reference preparation sold in the market are Hiclitochi®Bioequivalence, the dissolution stability of the in vitro dissolution behavior is superior to that of a reference preparation in a stability investigation test under an accelerated condition, the problem of bioequivalence of cefaclor granules is solved, and the in vitro dissolution behavior has positive significance for relieving medical insurance pressure and reducing the medication burden of patients; the product obtained by the method has better dissolution stability, and can better ensure the curative effect of the medicine in the whole life cycle of the product.
Detailed Description
The following examples are only preferred embodiments of the present invention, and are not intended to limit the scope of the present invention, but all changes that can be made by applying the principles of the present invention and without inventive work on the basis thereof shall fall within the scope of the present invention.
Example 1:
prescription:
the preparation method comprises the following steps:
step 1, adding the ethanol and the phosphoric acid with the prescription amount into the purified water with the prescription amount under stirring, and uniformly stirring to obtain the product.
And 2, adding the cefaclor, the sucrose, the corn starch, the hydroxypropyl methylcellulose, the sodium carboxymethyl starch, the silicon dioxide, the sucralose and the natural equivalent orange powder essence in the formula amount into a wet granulator, and uniformly mixing.
And 3, adding the material obtained in the step 1 into a granulator with the material in the step 2 in a guniting mode under stirring, and carrying out quick guniting (the guniting pressure is greater than 0.3Mpa and is finished within one minute), and after the guniting is finished, continuously carrying out wet mixing to prepare a soft material.
And 4, wetting the soft material prepared in the step 3 by using a swinging particle machine, wherein the mesh number of the screen is 20.
And 5, transferring the wet granules obtained in the step 4 into a fluidized bed dryer, setting the temperature of the materials to be 55 ℃ for drying, and stopping discharging when the moisture of the granules is less than or equal to 1.5%.
And 6, screening the particles by using a standard sieve, wherein the sum of the particles which cannot pass through a 10-mesh standard sieve and the particles which can pass through an 80-mesh standard sieve is not more than 15%.
And 7, mixing the particles obtained in the step 6 uniformly.
And 8, subpackaging by using a particle subpackaging machine. The finished product 64451 bags are obtained, and the yield is 92.07%.
Example 2:
prescription:
the preparation method comprises the following steps: steps 1 to 8 are the same as example 1, and a finished product 65065 bags with a yield of 92.95% is obtained.
Example 3:
prescription:
the preparation method comprises the following steps:
steps 1 to 8 are the same as example 1, and a finished product 64758 bag is obtained, wherein the yield is 92.51%.
Comparative example 1:
prescription:
the preparation method comprises the following steps:
the steps 1 to 8 are the same as the step 1, and a finished product of 49252 bags is obtained, wherein the yield is 70.36%.
The finished product rate is low, and the finished product particles are relatively small and fine by visual inspection.
Comparative example 2:
prescription:
the preparation method comprises the following steps:
steps 1 to 8 are the same as example 1, and a finished product 42369 bag is obtained, wherein the yield is 60.53%.
The soft material prepared in the step 3 is sticky, the swinging granulation is difficult, and the yield is low.
Comparative example 3:
prescription:
the preparation method comprises the following steps:
the steps 1 to 8 are the same as the step 1, and finished products of 47247 bags with the yield of 67.50 percent are obtained.
The finished product rate is low, and the finished product particles are relatively small and fine by visual inspection.
Comparative example 4:
prescription:
the preparation method comprises the following steps:
steps 1 to 8 are the same as example 1, and a finished product 58841 bag is obtained, wherein the yield is 84.06%.
Test example 1: in vitro dissolution test
The dissolution rates of the products prepared in examples 1 to 3 and comparative examples 1 to 4 in an aqueous medium were measured by reference to the dissolution rate measurement method of cefaclor granules recorded in the Chinese pharmacopoeia (2015 edition), and the data are recorded in Table 1.
The detection method comprises the following steps:
chromatographic conditions are as follows: a chromatographic column: shimadzu ODS-3V 4.6mm X250 mm 5 μm type chromatographic column or equivalent performance chromatographic column; mobile phase: buffer (780 ml water and 10ml triethylamine mixed, adding 1g pentane sodium sulfonate dissolved, using phosphoric acid to adjust pH value to 2.5 + -0.1) -methanol (70: 30); detection wavelength: 265 nm; flow rate: 1.5 ml/min; column temperature: 30 ℃; sample introduction amount: 20 μ l
Dissolution conditions: paddle method, 50 revolutions per minute; an aqueous medium; temperature: 37.0 ℃; volume: 900 ml; sampling quantity: 5ml of the solution; liquid supplement amount: 5ml of
Sampling time: 5min, 10min, 15min, 30min
The limit requirements are as follows:
the average elution amount in 15min is not less than 85% of the indicated amount.
Sample batch number:
self-made preparation: examples 1 to 3, comparative examples 1 to 4
Reference formulation: shi Lao®(batch Nos. C774622, C781745, C873035)
TABLE 1 summary of the results of dissolution in aqueous medium for the products of examples 1-3, comparative examples 1-4 and commercial reference formulations
The data in table 1 and the phenomena of the product production process show that:
(1) the average cumulative release amount of the products of examples 1-3 in an aqueous medium at 15min is more than 85 percent, which meets the requirement of the Hichloa selguhr of a reference preparation®The in vitro dissolution is similar to the requirement, most of the main drug is dissolved out in 30min, the whole dissolution process, the dissolution phenomenon and the dissolution amount are similar to those of a reference preparation, and no particles are agglomerated and stacked at the bottom of a dissolution cupOr form a flaky insoluble solid and the like. While the products of comparative examples 1-4 have slower dissolution, the dissolution phenomenon and the dissolution rate are different from those of the reference preparation Xidiao®The difference is large.
(2) The products of comparative examples 1-4 have powdery, flaky or agglomerated material residues after being dissolved out for 30min, and the dissolution data shows that more main medicines can not be dissolved out, which indicates that more main medicines can not be absorbed in human body, and the risk of biological inequality is very high.
(3) The products of comparative example 1 and comparative example 2 show that: when the ratio of the sum of the dosages of the sodium carboxymethyl starch and the hydroxypropyl methylcellulose to the main medicament is lower than or higher than the ratio (18-24: 12-16) required by the patent, the yield of the comparative example 1 particles with low dosages is lower, the visual observation particles are relatively smaller and thinner, and the early-stage dissolution is faster when the dissolution and release are carried out; the soft material prepared by the comparative example 2 with high dosage is sticky, granulation is difficult, the yield is low, the whole dissolving process is slow, agglomeration phenomenon exists, both the soft material and the granular material are not dissolved completely after being dissolved for 30min, and obvious deposit residue exists at the bottom of a cup.
(4) The in vitro dissolution of the products of comparative example 3 and comparative example 4 indicates that: when one of the carboxymethyl starch sodium or the hydroxypropyl methylcellulose exceeds the ratio required by the patent (the ratio of the carboxymethyl starch sodium to the hydroxypropyl methylcellulose is 1: 1), the yield of the particles in comparative example 3 with low dosage of the hydroxypropyl methylcellulose is lower, the visual observation particles are relatively smaller and finer, and the early-stage dissolution is faster; comparative example 3, in which the amount of the sodium carboxymethyl starch is low, is slow in the whole dissolution process, both of the sodium carboxymethyl starch and the sodium carboxymethyl starch are not completely dissolved after being dissolved for 30min, and obvious deposit residues are left at the bottom of a cup.
Test example 2 stability examination
Taking the products of examples 1-3, comparative examples 1-4 and Schizochralski respectively®(C873035) 100 bags are stored in a stability test box under the conditions of 40 +/-2 ℃/75 +/-5% RH, and samples are taken at the end of 3 rd month and 6 th month respectively to detect the dissolution of the aqueous medium and compare with the sample in 0 th month (the data of the cited test example 1).
The test method was the same as in test example 1, and the test data are shown in Table 2.
TABLE 2 summary of dissolution results from stability studies of the products of examples 1-3, comparative examples 1-4 and commercial reference formulations
As can be seen from the data in Table 2:
(1) under the acceleration condition (40 ℃ +/-2 ℃/75% +/-5% RH), the accumulative dissolution amount of the aqueous medium in the examples 1-3 has no obvious change in a drug stability investigation test for 6 months continuously, which indicates that the in vitro dissolution stability is good; reference preparation Xidiao®In vitro dissolution gradually decreases with prolonged stability time, potentially affecting in vivo bioequivalence.
(2) In the stability test of the products of examples 1-3 under accelerated conditions, the dissolution behavior has no obvious change, and the dissolution stability is superior to that of the commercial product Hichloa Schuelan®Has better dissolution stability, solves the potential risk of reduced dissolution of cefaclor granules during the storage of the medicament, and can deduce that the storage temperature of the product can adopt room temperature (about 25 ℃), which is more than the commercial reference preparation Xijilao®(storage below 20 ℃ is required) the storage temperature is less demanding.
(3) In the stability test of the products of comparative examples 1 to 4 under accelerated conditions, the incomplete dissolution is not improved, and the dissolution is reduced to different degrees, which reflects the characteristic of poor dissolution stability of cefaclor granules with different formulas to a certain extent.
Test example 3 in vivo bioequivalence examination
Evaluation of self-made cefaclor granules and cefaclor dry suspensions (Hidilo) by means of a two-cycle, random, cross-over experimental design®Specification 0.125 g) was applied to bioequivalence studies in healthy adult subjects in fasting and postprandial states. Analysis software was used to collect the processed data during the experiment.
Volunteers: male and female subjects of 18-55 years (including 18 years and 55 years) are divided into 2 groups according to a random method, wherein one group takes the reference preparation firstly, and then takes the test preparation after 3 days of elution; the other group was administered in the reverse order.
Test formulations: cefaclor granules (products of example 1, example 2 and example 3), size 0.125 g; orally taking 0.125g (one bag) at a time, and taking 240mL of warm water; single administration.
Reference formulation: cefaclor dry suspension (batch No. C873035), trade name: hechilao, specification 0.125 g; orally taking 0.125g (one bag) at a time, and taking 240mL of warm water; single administration.
The detection method comprises the following steps: and carrying out quantitative analysis on cefaclor by using a UPLC-MS/MS method.
Mass spectrum conditions: AB SCIEX Triple Quad 4500 Triple quadrupole mass spectrometer, Analyst workstation; the ion source was ESI, in positive ion mode, MRM, gas curtain gas (CUR) 35psi, collision gas (CAD) 7psi, ionization voltage (IS) 5500v, ion source Temperature (TEM) 550 ℃, spray gas (GS 1) 55psi, assisted heating gas (GS 2) 55 psi.
Chromatographic conditions are as follows: ultra-high performance liquid chromatograph (Exion LC)TMAC): comprises a quaternary pump system, an automatic sample injector and a column incubator; a chromatographic column: agilent SB-Aq column (2.1X 100mm, 1.8 micron); protection of the column: phenomenex securityGuardTM ULTRA, AJO-9000 (LOT: 062416); mobile phase: a phase of 0.2% formic acid solution, B phase of methanol, A-B (60:40) isocratic elution; needle washing: needle wash 3s (50% methanol water); operating time: 3.0 min; flow rate: 0.25 mL/min; column temperature: 30 ℃; sample introduction amount: 3 muL.
Fasting administration study:
fasting is carried out for 12 h before the test, drinking water can be carried out after 2h of taking the medicine, and the meal is unified after 4 h. The subject can avoid strenuous exercise after taking the medicine and can not lie in bed for a long time. The light diet was unified during the experiment. Before and after taking the medicine: the elbow venous blood is extracted for 4.0ml at 0min, 5min, 15min, 30min, 45min, 1.00h, 1.25h, 1.50h, 1.75h, 2.00h, 2.50h, 3.00h, 3.50h, 4.00h, 5.00h, 6.00h and 8.00 h.
Post-prandial dosing study:
volunteers took high fat meal for dosing. After the medicine is taken for 2 hours, water can be drunk, and the meal can be unified after 4 hours. The subject can avoid strenuous exercise after taking the medicine and can not lie in bed for a long time. The light diet was unified during the experiment. Before and after taking the medicine: : 4.0ml of elbow venous blood is extracted at 0h, 15min, 30min, 1h15min, 1h30min, 1h45min, 2h15min, 2h30min, 2h45min, 3h, 3.5h, 4h, 4.5h, 5h, 6h, 8h and 10 h.
The data for cefaclor concentration in blood, area under the curve, etc. are reported in tables 3-5, respectively.
Table 3 bioequivalence test data (n = 12) for the test formulation (product of example 1) and the reference formulation (C873035)
Table 4 bioequivalence test data (n = 24) for the test formulation (product of example 2) and the reference formulation (C873035)
Table 5 bioequivalence test data (n = 12) for the test formulation (product of example 3) and the reference formulation (C873035)
As can be seen from tables 3 to 5:
(1) the products of examples 1, 2 and 3 and cefaclor dry suspension (schichlo's disease) whether in fasting or postprandial conditions®0.125 g) AUC0-t, AUC0- ∞, Cmax all satisfy the pharmacopoeia requirement that the 90% confidence interval of the geometric mean ratio should fall within the accepted range of 80.00% -125.00% "(national pharmacopoeia committee 9011 pharmaceutical formulation human bioavailability and bioequivalence test guidelines (the four part 2015 edition of the chinese pharmacopoeia) [ M]Chinese medical science and technology press, 2015: 356-362.), which are bioequivalent.
(2) Example 1 and example 3 the 90% confidence intervals for the geometric mean ratios of AUC0-t and AUC0- ∞ in both fasting and postprandial conditions of the products are slightly less than in example 2; when the test is carried out after meal administration, the lower limit of the confidence interval of the Cmax of the example 1 and the upper limit of the confidence interval of the Cmax of the example 3 are closer to the boundary of the acceptable limit relative to the product of the example 2, so the implementation effect of the product of the example 2 is better than that of the products of the examples 1 and 3; the change in the amount of the auxiliary materials in combination with examples 1 to 3 indicates that: in the prescription, the dosage of the auxiliary materials is different, so that the concentration of cefaclor passing through an absorption part in vivo can be influenced, and the combination and proportion of the auxiliary materials selected in the patent can enable cefaclor particles and cefaclor dry suspension (reference preparation) to be in vivo bioequivalence.
(3) The ratio of the sum of the dosages of the carboxymethyl starch sodium and the hydroxypropyl methylcellulose to the dosage of the main drug is lower, the Cmax of the postprandial bioequivalence test in example 1 (18: 16) is lower and is close to the lower limit of the qualified standard, the Cmax of the postprandial bioequivalence test in example 3 (24: 12) is higher and is close to the upper limit of the qualified standard, and when the dosage of the product in example 2 (20: 14) is moderate, the corresponding Cmax data is closer to the median of the qualified range, and the phenomenon that the dosage ratio is positively correlated with the Cmax of the postprandial bioequivalence.
(4) In vivo research data in tables 3-5 indicate that when the dose ratio is at the endpoints (example 1 and example 3), the postprandial Cmax data is close to the lower and upper qualified limits, respectively, and it can be inferred from combination of (3) that the dose ratio of the sum of the amounts of carboxymethyl starch sodium and hypromellose and the dose of the main drug, which exceeds the requirement of the present patent, cannot satisfy the requirement of postprandial equivalence.
In conclusion, the pharmaceutical composition with a specific proportion disclosed by the patent meets the fasting and postprandial bioequivalence requirements of a reference preparation, the adopted common preparation method of the granules has the advantages of simple process, low cost and good economic value, and the product shows the characteristic that the dissolution stability is superior to that of the reference preparation in stability investigation, thereby being more beneficial to the stable curative effect of the product in the life cycle.
Claims (5)
1. The cefaclor granule composition contains cefaclor, corn starch, sucrose, sodium carboxymethyl starch, silicon dioxide and hydroxypropyl methylcellulose, and is characterized in that in a unit dose of the composition, the dosage of the hydroxypropyl methylcellulose and the dosage of the sodium carboxymethyl starch are not lower than 9% of the total weight of a unit dose of the product respectively, the mass ratio of the hydroxypropyl methylcellulose to the sodium carboxymethyl starch is 1:1, and the mass ratio of the sum of the dosages of the hydroxypropyl methylcellulose and the sodium carboxymethyl starch to the anhydrous cefaclor is 18-24: 12-16.
2. The cefaclor granule composition as claimed in claim 1, wherein sucrose accounts for 30-65% of the total weight of the unit dose product, and corn starch accounts for 10-20% of the total weight of the unit dose product.
3. The cefaclor granule composition as claimed in claim 1, wherein the mass ratio of the sum of the dosages of hypromellose and sodium carboxymethyl starch to anhydrous cefaclor is 20:14, the weight of sucrose accounts for 40-50% of the total weight of the unit dose product, the weight of corn starch accounts for 13-17% of the total weight of the unit dose product, and the dosage of silicon dioxide accounts for 3.5% of the total weight of the unit dose product.
4. A process for the preparation of a cefaclor granular composition as claimed in claim 1, characterized by comprising the steps of:
step 1, preparing a wetting agent; adding the purified water/ethanol and water in the prescription amount into a container to obtain the product;
step 2, adding the cefaclor, the sucrose, the corn starch, the hydroxypropyl methylcellulose, the sodium carboxymethyl starch and the silicon dioxide in the prescription amount into a granulator, and uniformly mixing;
step 3, adding the material obtained in the step 1 into a granulator with the material in the step 2 in a guniting mode under stirring, quickly guniting, and continuously wet-mixing to prepare a soft material after guniting is finished;
step 4, wetting the soft material prepared in the step 3 into granules by using a swing granulator or a quick granulating machine, wherein the mesh number of a screen is 18-24 meshes;
step 5, transferring the wet granules to a fluidized bed dryer for drying, wherein the temperature of the materials is controlled not to exceed 60 ℃ during drying;
step 6, using a screening machine to screen out particles which do not meet the requirements, wherein the sum of the particles which can not pass through a 10-mesh standard sieve and the particles which can pass through an 80-mesh standard sieve is not more than 15 percent after the particles are screened;
step 7, mixing the particles obtained in the step 6 uniformly;
and 8, subpackaging the total mixed particles obtained in the step 7 to obtain a finished product.
5. Process for the preparation of a granular composition of cefaclor as claimed in claim 4, wherein the spraying pressure of step 3 is greater than 0.3MPa, and is completed within 1 minute.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010850150.7A CN112137965A (en) | 2020-08-21 | 2020-08-21 | Cefaclor particle pharmaceutical composition |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202010850150.7A CN112137965A (en) | 2020-08-21 | 2020-08-21 | Cefaclor particle pharmaceutical composition |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN112137965A true CN112137965A (en) | 2020-12-29 |
Family
ID=73888056
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202010850150.7A Pending CN112137965A (en) | 2020-08-21 | 2020-08-21 | Cefaclor particle pharmaceutical composition |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN112137965A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113995727A (en) * | 2021-11-08 | 2022-02-01 | 山东鲁抗医药股份有限公司 | Type 5 phosphodiesterase inhibitor tablet and preparation method thereof |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101816635A (en) * | 2010-05-17 | 2010-09-01 | 广东恒健制药有限公司 | Cephalosporin suspension granule and preparation method thereof |
| CN101912373A (en) * | 2010-08-24 | 2010-12-15 | 北京京丰制药有限公司 | Stable cefeclor dispersible tablet and preparation method thereof |
| CN102579455A (en) * | 2012-03-19 | 2012-07-18 | 迪沙药业集团有限公司 | Stable cefaclor chewing composition |
| CN103349646A (en) * | 2013-05-24 | 2013-10-16 | 海口市制药厂有限公司 | Medicinal composition containing cefaclor particles, and preparation method and application thereof |
| CN108743547A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of content of cefaclor granules and preparation method thereof |
-
2020
- 2020-08-21 CN CN202010850150.7A patent/CN112137965A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101816635A (en) * | 2010-05-17 | 2010-09-01 | 广东恒健制药有限公司 | Cephalosporin suspension granule and preparation method thereof |
| CN101912373A (en) * | 2010-08-24 | 2010-12-15 | 北京京丰制药有限公司 | Stable cefeclor dispersible tablet and preparation method thereof |
| CN102579455A (en) * | 2012-03-19 | 2012-07-18 | 迪沙药业集团有限公司 | Stable cefaclor chewing composition |
| CN103349646A (en) * | 2013-05-24 | 2013-10-16 | 海口市制药厂有限公司 | Medicinal composition containing cefaclor particles, and preparation method and application thereof |
| CN108743547A (en) * | 2018-06-28 | 2018-11-06 | 苏州中联化学制药有限公司 | A kind of content of cefaclor granules and preparation method thereof |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113995727A (en) * | 2021-11-08 | 2022-02-01 | 山东鲁抗医药股份有限公司 | Type 5 phosphodiesterase inhibitor tablet and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP6151727B2 (en) | Ulipristal acetate ester tablets | |
| KR101710935B1 (en) | Solid dosage forms of bendamustine | |
| WO2014104671A1 (en) | Pharmaceutical composition with improved stability, containing temozolomide, and preparation method therefor | |
| CN102988296A (en) | Celecoxib solid dispersion and preparation method thereof | |
| CN100488515C (en) | Ground erythromycin enteric micropill and its preparation method | |
| CN103054826A (en) | Orally disintegrating tablet of memantine hydrochloride sustained-release pellets and preparation method thereof | |
| CN109662949A (en) | A kind of fludrocortisone acetate oral disnitegration tablet and preparation method thereof | |
| CN102600132A (en) | Oral preparation containing amisulpride | |
| US20240148693A1 (en) | Composition, preparation method therefor, and use thereof | |
| WO2016029496A1 (en) | Methosulide tablet and preparation method therefor | |
| CN112137965A (en) | Cefaclor particle pharmaceutical composition | |
| CN103263395A (en) | Telmisartan tablet preparation and preparation method thereof | |
| CN105343028A (en) | Medicine composition with norfloxacin and method for preparing medicine composition | |
| CN112426408A (en) | Melatonin composition and preparation process thereof | |
| CN106860404A (en) | A kind of sildenafil citrate taste masking resin complexes and its application | |
| CN101642461B (en) | Drug composition of iguratimod and glucosamine, preparation method and drug application thereof | |
| CN107412198A (en) | Duloxetine hydrochloride enteric slow release granule and preparation method thereof | |
| CN115124532B (en) | Rhein and matrine eutectic crystal, preparation method, composition and application thereof | |
| CN115124420B (en) | Rhein and matrine eutectic hydrate, preparation method, composition and application thereof | |
| WO2004087126A1 (en) | Pharmaceutical composition containing platinum complex as active substance and method of manufacturing thereof | |
| CN101491493A (en) | Ferulic acid piperazine slow-release medicine preparation | |
| CN104224728B (en) | A kind of Esomeprazole enteric pellet and preparation method thereof | |
| CN103007286A (en) | Solid medicine composition of tolvaptan | |
| US20090264476A1 (en) | CB-1 receptor modulator formulations | |
| CN105902564A (en) | Pharmaceutical composition for treating hypertension and preparation method thereof |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| TA01 | Transfer of patent application right | ||
| TA01 | Transfer of patent application right |
Effective date of registration: 20210910 Address after: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant after: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Address before: No.1 Qingdao South Road, Weihai Economic and Technological Development Zone, Shandong Province Applicant before: DISHA PHARMACEUTICAL GROUP Co.,Ltd. Applicant before: Dijia Pharmaceutical Group Co.,Ltd. |
|
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20201229 |