CN109394718B - Amoxicillin dispersible tablet and preparation method thereof - Google Patents
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Abstract
The invention relates to an amoxicillin dispersible tablet and a preparation method thereof, belonging to the technical field of medicines. The amoxicillin dispersible tablet comprises a main drug amoxicillin which is distributed in a slow release part and a quick release part according to the weight ratio of 4: 6; the slow release part is formed by spraying a slow release coating liquid on a pill core at least containing microcrystalline cellulose as a filling material; the quick release part is prepared from a filling agent, a disintegrating agent and a lubricating agent. The amoxicillin dispersible tablet ensures complete dissolution and release within 4 hours, and the ratio of the amoxicillin in the sustained-release part to the amoxicillin in the quick-release part is 4:6, so that the dispersible tablet is ensured to be stable and complete in dissolution and release, finally the blood concentration in vivo is kept continuously higher than the MIC level for a long time, the antibacterial effect of amoxicillin is greatly ensured, the clinical curative effect is remarkably improved, the good steady-state reasonable blood concentration of the amoxicillin dispersible tablet in a human body is realized, and the safety of medication is also ensured.
Description
Technical Field
The invention relates to a medicinal preparation and a preparation method thereof, in particular to an amoxicillin dispersible tablet and a preparation method thereof, and belongs to the technical field of medicines.
Background
Amoxicillin (Amoxicillin) is an effective broad-spectrum beta-lactam antibiotic for oral administration, has an action mechanism of inhibiting the synthesis of bacterial cell walls, so that the cell membranes of the antibiotics are cracked and dissolved, and is mainly used for treating urinary system, respiratory system, biliary tract and other infections caused by sensitive bacteria clinically. Compared with the common amoxicillin dispersible tablets, the amoxicillin dispersible tablets have the characteristics of short disintegration time limit, quick drug dissolution, high bioavailability, less adverse reaction, convenient taking and the like, become the hot point of the current research, have products on the market, have wider clinical application, and are supplemented as the national basic drugs at present.
For example, Chinese patent 200810101332.3 discloses an amoxicillin dispersible tablet, which is composed of an amoxicillin raw drug and a medicinal carrier, wherein the medicinal carrier comprises a diluent, a disintegrating agent and a lubricant, and optionally comprises a sweetener and/or an aromatic; wherein the weight ratio of the amoxicillin technical material to the medicinal carrier is 3: 1; the diluent in the medicinal carrier is microcrystalline lactose, the disintegrant is crosslinked polyvinylpyrrolidone, and the lubricant is magnesium stearate; the pharmaceutical carrier comprises 82% of microcrystalline lactose, 15% of cross-linked polyvinylpyrrolidone and 3% of magnesium stearate by weight respectively; the microcrystalline lactose is a composite formed by premixing microcrystalline cellulose and spray-dried lactose. The production method adopts a powder direct compression technology.
Chinese patent 201110289124.2 discloses an amoxicillin dispersible tablet and a production method thereof, which is prepared by preparing amoxicillin, microcrystalline cellulose, crospovidone, low-substituted hydroxypropyl cellulose, croscarmellose sodium, magnesium stearate, silicon dioxide, saccharin sodium, vanillin, apricot essence and orange essence as raw and auxiliary materials into master batch particles, standby material particles and sub-material particles respectively according to different proportions, then mixing according to a certain proportion, crushing, sieving, magnetic sieving, drying, finishing, weighing, bonding and pressing into the amoxicillin dispersible tablet. The production method of the amoxicillin dispersible tablet is additionally provided with a magnetic screening procedure, and iron powder, fine iron paste and the like which are possibly generated in the processing processes of crushing, screening and the like of raw and auxiliary materials can be sucked out, so that the purity of the amoxicillin dispersible tablet is ensured.
Chinese patent 201410446830.7 discloses an amoxicillin dispersible tablet, its preparation method and use, which is prepared by a powder direct tabletting method, and dry powder tabletting is directly carried out without the steps of soft material preparation, granulation, drying and the like.
Pellets are a typical multiple unit type drug delivery system developed in recent years, and have the following advantages: the contact area between the oral preparation and the gastrointestinal mucosa is increased, so that the medicine is completely absorbed, and the bioavailability of the medicine is improved; ② can reduce or eliminate the irritation of the medicine to the gastrointestinal tract, etc. Extrusion spheronization is a common method for preparing large-dose drug pellets. When the pellet is prepared by an extrusion spheronization method, microcrystalline cellulose (MCC) is the most commonly used spheronization promoter, and the obtained pellet has high yield and good roundness. However, the literature reports that the micro-pill prepared by MCC is slow in disintegration and can delay the dissolution of the medicine.
The inventor discovers that the conventional amoxicillin dispersible tablet has the advantages of quick oral absorption, too early peak reaching time, too short half-life period and short time of the drug with short half-life period in vivo, namely the drug effect has short duration, the bacteriostatic effect of the drug in vivo is seriously influenced, and the drug resistance is easier to generate in the process of researching the amoxicillin dispersible tablet.
Disclosure of Invention
The invention develops a new amoxicillin dispersible tablet by research, and the amoxicillin is distributed in the slow release part and the quick release part, the dispersible tablet can lead the drug absorption peak to be stable, prolong the time of T > MIC, increase the curative effect and reduce the side effect.
After the amoxicillin dispersible tablet is administrated, a part of amoxicillin is quickly dissolved out, the blood concentration reaches above MIC, the amoxicillin dispersible tablet takes effect quickly, the later sustained-release part slowly releases to maintain the in-vivo drug concentration to be kept above MIC for a long time, thus realizing that the amoxicillin is effective in vivo for a long time, playing a better drug effect, and solving the defects of unstable blood concentration, short maintenance effective time and poor curative effect of patients in the use of the amoxicillin dispersible tablet in the prior art.
The technical problem to be solved by the invention is realized by the following technical scheme.
An amoxicillin dispersible tablet, wherein a main drug amoxicillin is distributed in a slow release part and a quick release part according to the weight ratio of 4: 6; the slow release part is formed by spraying a slow release coating liquid on a pill core at least containing microcrystalline cellulose as a filling material; the slow-release material in the slow-release coating liquid is processed cashew nut gum; the quick release part is prepared from a filling agent, a disintegrating agent and a lubricating agent; the filling agent is microcrystalline cellulose, the disintegrating agent is one or two of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, and the lubricating agent is one or two of magnesium stearate, talcum powder and superfine silica gel powder.
Further, the amoxicillin dispersible tablet is characterized in that the pill core is prepared from a main drug amoxicillin and a filling material by adopting an extrusion and spheronization method, wherein the filling material also contains one or two of starch and lactose; the slow release coating solution is prepared by dissolving the processed cashew nut gum, the plasticizer and the anti-sticking agent by using 85-95% ethanol solution. Wherein, the plasticizer is selected from one or two of polyethylene glycol 4000, triethyl citrate and benzyl benzoate, and the anti-sticking agent is selected from magnesium stearate or aerosil.
Further, in the amoxicillin dispersible tablet, the weight ratio of the microcrystalline cellulose to the treated cashew gum in the pill core filling material is 1: 1.02-1.08.
The processing method of the amoxicillin dispersible tablet comprises the following steps:
grinding cashew nut gum and sieving the ground cashew nut gum with a 20-mesh sieve; 95% of ethanol, sodium hydroxide and the sieved and crushed materials in a weight ratio of 5: 0.5: stirring for 5 hours to obtain reaction liquid; neutralizing the reaction solution with 732 type strong acid ion exchange resin until the pH is 7; filtering to remove resin, and concentrating the filtrate by reduced pressure distillation to obtain a viscous liquid; adding 95% ethanol, stirring until the mixture is dispersed and turbid, performing suction filtration, and performing spray drying on the filtrate to obtain the treated cashew gum.
According to the cashew nut gum processing method, the set conditions of the spray drying are as follows: the outlet temperature was 73 deg.C, the inlet temperature was 112 deg.C, and the feed rate was 10.5 mL/min.
Every 1000 tablets of the amoxicillin dispersible tablets are prepared from the following raw and auxiliary materials:
wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
Every 1000 tablets of the amoxicillin dispersible tablets are prepared from the following raw and auxiliary materials:
wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
Every 1000 tablets of the amoxicillin dispersible tablets are prepared from the following raw and auxiliary materials:
wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
A preparation method of the amoxicillin dispersible tablet comprises the following steps:
(1) preparing raw and auxiliary materials: sieving the raw materials and adjuvants respectively with 100 mesh sieve;
(2) preparing a pill core: uniformly mixing amoxicillin serving as a main drug in a prescription amount and a filling material, placing the mixture in a wet granulator, gradually adding purified water serving as a wetting agent in the prescription amount to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate, transferring the extruded strips into a rounding machine for rounding, taking out rounded pellet cores after rounding for 2.5min, drying, sieving the dried pellet cores, weighing an appropriate amount of pellet cores to determine the content of amoxicillin, converting the weight of the pellet cores required by a sustained-release part according to the ratio of the amoxicillin in a quick-release part and a sustained-release part, and weighing for later use;
(3) coating a slow release layer: slowly adding the slow-release material, the plasticizer and the anti-adhesion agent in the formula amount into 85-95% ethanol under stirring, and stirring until the materials are dissolved for later use; placing the weighed pill cores in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare drug-containing slow-release pellets;
(4) tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with amoxicillin, a filler, a disintegrating agent and a lubricant which are main drugs and are prescribed in the quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
The preparation method of the amoxicillin dispersible tablet comprises the step (2) of 0.8mm of aperture of the sieve plate, 80r/min of extrusion rotating speed and 820r/min of rotating speed of a spheronizer.
The preparation method of the amoxicillin dispersible tablet comprises the step (2) of taking out the round pill core and drying the round pill core at 40 ℃ under reduced pressure until the water content is less than 1%.
The preparation method of the amoxicillin dispersible tablet comprises the steps of (2) sieving the dried pill cores to remove fine powder and large particles, and sieving the pill cores with a 20-24-mesh sieve for later use.
The preparation method of the amoxicillin dispersible tablet comprises the following steps of (1) respectively setting the parameters of the fluidized bed in the step (3): the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
The amoxicillin dispersible tablet achieves the dissolution and release effect which is the combined effect of the effect of delaying the dissolution of the drug of the microcrystalline cellulose of the pill core filling material and the slow release effect of the treated cashew gum, ensures that the dispersible tablet is completely dissolved and released within 4 hours, ensures that the amoxicillin in the slow release part and the quick release part has a ratio of 4:6, ensures that the dispersible tablet is stably and completely dissolved and released, finally realizes that the blood concentration of the product in the body is kept continuously higher than the MIC level for a long time, greatly ensures the antibacterial effect of the amoxicillin, remarkably improves the clinical curative effect, simultaneously realizes the good steady-state reasonable blood concentration of the amoxicillin dispersible tablet in the human body, and also ensures the safety of the medication. In addition, the starch and the lactose in the pill core are used as a regulator, so that the yield of the pill core prepared in the step (2) can be improved, if the regulator is not added, the yield of the pill core is 80%, and if the regulator is added in an amount of 4-5%, the yield of the pill core is over 90%.
Drawings
FIG. 1 dissolution Release curves of comparative example A and comparative example B
FIG. 2 Effect of the ratio of Amoxicillin in the quick Release portion to the sustained Release portion on the dissolution Release behavior of the dispersible tablets
FIG. 3 Amoxicillin dispersible tablets dissolution release profile of examples 2-4
Detailed Description
The present invention will be described in further detail with reference to specific examples.
Example 1 Pre-treatment of cashew nut gum
Adding the cashew nut gum into a grinder for grinding, and sieving by using a 20-mesh vibrating screen; 95% ethanol solution, sodium hydroxide and the sieved and crushed materials in a weight ratio of 5: 0.5: 1 for 5 hours to obtain reaction liquid; neutralizing the reaction solution to pH 7 by using 732 type strong acid ion exchange resin which is treated by hydrochloric acid of 1mol/L in advance; filtering to remove resin, and concentrating the filtrate by reduced pressure distillation to obtain a viscous liquid; adding 95% ethanol, stirring until the mixture is dispersed and turbid, performing suction filtration, and performing spray drying on the filtrate to obtain refined cashew nut gum powder, wherein the outlet temperature of a spray dryer is set to be 73 ℃, the inlet temperature is set to be 112 ℃, and the feeding speed is set to be 10.5 mL/min.
Comparative test example 1 Effect of cashew nut gum treatment on Amoxicillin dispersible tablets before and after treatment
Different amoxicillin dispersible tablets were prepared with untreated cashew gum and the cashew gum treated according to the method of example 1 as slow release coating materials, respectively, to investigate the effect on amoxicillin dispersible tablets before and after cashew gum treatment.
Comparative example A preparation of Amoxicillin dispersible tablet from untreated cashew nut Gum
Prescription: each prepared into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing main drugs amoxicillin, microcrystalline cellulose and starch according to the prescription amount, putting the mixture into a wet granulator, gradually adding purified water of the prescription amount as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion rotating speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotating speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the pellets at 40 ℃ under reduced pressure until the moisture is less than 1%, sieving the dried pellet cores to remove fine powder and large particles, taking the pellet cores with 20-24 meshes, sieving the pellet cores with a proper amount to measure the amoxicillin content, converting the weight of the pellet cores required by 100g amoxicillin, and weighing for later use.
3. Coating a slow release layer: slowly adding the untreated cashew nut gum, polyethylene glycol 4000 and magnesium stearate into 95% ethanol under stirring, and stirring uniformly for later use. And (3) placing the pill cores containing 100g of amoxicillin serving as the main drug weighed in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare the drug-containing sustained-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with main drugs of amoxicillin, microcrystalline cellulose, sodium carboxymethyl starch and talcum powder in the prescription of a quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
Comparative example B preparation of Amoxicillin dispersible tablet from treated cashew nut gum
Prescription: each prepared into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing main drugs amoxicillin, microcrystalline cellulose and starch according to the prescription amount, putting the mixture into a wet granulator, gradually adding purified water of the prescription amount as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion rotating speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotating speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the pellets at 40 ℃ under reduced pressure until the moisture is less than 1%, sieving the dried pellet cores to remove fine powder and large particles, taking the pellet cores with 20-24 meshes, sieving the pellet cores with a proper amount to measure the amoxicillin content, converting the weight of the pellet cores required by 100g amoxicillin, and weighing for later use.
3. Coating a slow release layer: slowly adding the processed cashew nut gum, polyethylene glycol 4000 and magnesium stearate into 95% ethanol under stirring, and stirring until the cashew nut gum, the polyethylene glycol 4000 and the magnesium stearate are dissolved for later use. And (3) placing the weighed pill cores containing 100g of amoxicillin serving as the main drug in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare the drug-containing sustained-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with main drugs of amoxicillin, microcrystalline cellulose, sodium carboxymethyl starch and talcum powder in the prescription of a quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
The dissolution rate of the amoxicillin dispersible tablets is determined according to a second method of appendix XC of Chinese pharmacopoeia 2010 edition, 900mL of water with pH6.8 is used as a dissolution medium, the rotating speed is 75r/min, samples are taken at 40, 80, 120, 160, 200, 240, 280, 320, 360, 400, 440 and 480min, the dissolution rate of the amoxicillin dispersible tablets is determined according to a first supplement of Chinese pharmacopoeia 2010 edition, the cumulative dissolution percentage is calculated, and a dissolution release curve is drawn, as shown in Table 1 and figure 1.
TABLE 1 dissolution data for comparative example A and comparative example B
Untreated cashew gum cannot be completely dissolved in 85-95% ethanol, so that excellent coating liquid is difficult to prepare for coating, the prepared amoxicillin dispersible tablet is too slow to dissolve out, the amoxicillin dispersible tablet in comparative example A is dissolved out by 86.6% in 8 hours and is taken three times a day, when the amoxicillin dispersible tablet is taken for the second time, the drug taken for the first time is not completely dissolved out, and the dissolution behavior easily causes unstable blood concentration in vivo. In addition, the dissolution curve of the comparative example A is also poor, the dissolution is fast in the early stage, the slow release part is released too slowly, the phenomenon of burst release occurs, and meanwhile, the slow release can cause the blood concentration in vivo to be lower than MIC, so that the bacteriostatic and bactericidal effects cannot be ensured.
The cashew gum can be dissolved in 85-95% ethanol after being treated by the method of the embodiment 1, and the amoxicillin dispersible tablets are prepared according to the prescription and the method, so that the effect of stable and long-term continuous bacteriostasis through dissolution and release in vivo and in vitro can be realized, and the safety and the effectiveness of medication are also ensured.
Comparative test example 2 Effect of Amoxicillin with different ratios of quick release/sustained release on dissolution and release behavior of dispersible tablet
Different amoxicillin dispersible tablets are prepared according to the prescription in the following table according to 4 proportions of amoxicillin in the quick release part and the sustained release part, namely 4:6, 5:5, 6:4 and 7:3, respectively, so as to examine the influence of the different proportions of amoxicillin in the quick release part and the sustained release part on the dissolution and release behaviors of the dispersible tablets.
Prescription: each prepared into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing main medicines of amoxicillin, microcrystalline cellulose and starch according to the prescription amount, putting the mixture into a wet granulator, gradually adding purified water of the prescription amount as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion rotating speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotating speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the pellets at 40 ℃ under reduced pressure until the moisture is less than 1%, sieving the dried pellet cores to remove fine powder and large particles, taking the pellet cores through a 20-24-mesh sieve, weighing a proper amount of the pellet cores to measure the amoxicillin content, converting the weight of the pellet cores required by a sustained-release part according to the ratio of the amoxicillin in a quick-release part and a sustained-release part, and weighing for later.
3. Coating a slow release layer: slowly adding the processed cashew nut gum, polyethylene glycol 4000 and magnesium stearate into 95% ethanol under stirring, and stirring until the cashew nut gum, the polyethylene glycol 4000 and the magnesium stearate are dissolved for later use. And (3) placing the pill cores weighed in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to obtain the drug-containing slow-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with main drugs of amoxicillin, microcrystalline cellulose, sodium carboxymethyl starch and talcum powder in the prescription of a quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
The dissolution rate of the amoxicillin dispersible tablets is determined according to a second method of appendix XC of Chinese pharmacopoeia 2010 edition, 900mL of water with pH6.8 is used as a dissolution medium, the rotating speed is 75r/min, samples are taken at 20 min, 40min, 60 min, 80min, 100 min, 120 min, 140 min, 160 min, 180 min, 200 min, the dissolution rate of the amoxicillin dispersible tablets is determined according to a first supplement of Chinese pharmacopoeia 2010 edition, the cumulative dissolution percentage is calculated, and a dissolution release curve is drawn, as shown in Table 2 and figure 2.
TABLE 2 dissolution data of amoxicillin dispersible tablets with different ratios of quick-release/sustained-release raw materials
As shown in the results of the table 2 and the figure 2, when the ratio of the amoxicillin in the quick-release part to the sustained-release part is 6:4, the amoxicillin dispersible tablet has the most stable dissolution and release curve, and the cumulative dissolution percentage at 4h can reach 99.8%. In other proportion conditions of the quick release/slow release amoxicillin, the dispersible tablet is not stably dissolved, the final cumulative dissolution percentage is also low, and finally, the preferred ratio of the amoxicillin in the quick release part and the slow release part is 6: 4.
EXAMPLE 2 preparation of Amoxicillin dispersible tablets
Prescription: making into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing 120g of amoxicillin serving as a main drug, 32g of microcrystalline cellulose and 8g of starch, then placing the mixture in a wet granulator, gradually adding 40g of purified water serving as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotation speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the rounded pellet cores at 40 ℃ under reduced pressure until the moisture content is less than 1%, screening the dried pellet cores to remove fine powder and large particles, taking the pellet cores with 20-24 meshes, weighing a proper amount of the pellet cores to measure the amoxicillin content, converting the weight of the pellet cores required by 100g of amoxicillin serving as the main drug, and weighing the pellets.
3. Coating a slow release layer: adding 29g of processed cashew nut gum, 40003 g of polyethylene glycol and 6g of magnesium stearate into 95% ethanol slowly with stirring, and stirring until the materials are dissolved for later use. And (3) placing the weighed pill cores containing 100g of amoxicillin serving as the main drug in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare the drug-containing sustained-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with 150g of amoxicillin, 320g of microcrystalline cellulose, 26g of sodium carboxymethyl starch and 3g of talcum powder which are main medicines of a quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
EXAMPLE 3 preparation of Amoxicillin dispersible tablets
Prescription: making into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing 120g of amoxicillin serving as a main drug, 45g of microcrystalline cellulose and 7g of lactose, putting the mixture into a wet granulator, gradually adding 37g of purified water serving as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotation speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the rounded pellet cores at 40 ℃ under reduced pressure until the moisture is less than 1%, sieving the dried pellet cores to remove fine powder and large particles, taking the pellet cores of 20-24 meshes, weighing a proper amount of the pellet cores to measure the content of amoxicillin, converting the weight of the pellet cores required by 100g of amoxicillin serving as the main drug, and weighing the pellet cores.
3. Coating a slow release layer: slowly adding 38g of treated cashew gum, 9g of triethyl citrate and 12g of superfine silica gel powder into 95% ethanol under stirring, and stirring until the materials are dissolved for later use. And (3) placing the weighed pill cores containing 100g of amoxicillin serving as the main drug in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare the drug-containing sustained-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with 150g of amoxicillin, 350g of microcrystalline cellulose, 35g of croscarmellose sodium and 4g of aerosil serving as a main quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablets.
EXAMPLE 4 preparation of Amoxicillin dispersible tablets
Prescription: making into 1000 pieces
The preparation process comprises the following steps:
1. preparing raw and auxiliary materials: the raw and auxiliary materials in the prescription are respectively sieved by a 100-mesh sieve for later use.
2. Preparing a pill core: uniformly mixing 120g of amoxicillin serving as a main drug, 38g of microcrystalline cellulose and 8g of lactose, putting the mixture into a wet granulator, gradually adding 35g of purified water serving as a wetting agent to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate (the aperture is 0.8mm, the extrusion speed is 80r/min), transferring the extruded strips into a rounding machine for rounding at the rotation speed of 820r/min, taking out the rounded pellet cores after rounding for 2.5min, drying the rounded pellet cores at 40 ℃ under reduced pressure until the moisture is less than 1%, sieving the dried pellet cores to remove fine powder and large particles, taking the pellet cores with 20-24 meshes, weighing a proper amount of the pellet cores to measure the content of amoxicillin, converting the weight of the pellet cores required by 100g of amoxicillin serving as the main drug, and weighing the pellet cores.
3. Coating a slow release layer: adding 33g of treated cashew gum, 5g of benzyl benzoate and 10g of aerosil into 85% ethanol slowly with stirring, and stirring until the cashew gum is dissolved for later use. And (3) placing the weighed pill cores containing 100g of amoxicillin serving as the main drug in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare the drug-containing sustained-release pellets. The experimental parameters are respectively as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
4. Tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with 150g of amoxicillin, 330g of microcrystalline cellulose, 30g of cross-linked polyvinylpyrrolidone and 3g of magnesium stearate which are main medicines of a quick release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
TEST EXAMPLE 1 in vitro test of Amoxicillin dispersible tablets
The dissolution release of examples 2-4 was tested according to the dissolution test method for amoxicillin dispersible tablets in comparative test example 1, as shown in table 3 and fig. 3.
Table 3 amoxicillin dispersible tablets dissolution data of examples 2-4
The amoxicillin dispersible tablets in embodiments 2-4 of the invention have good dissolution effect, the cumulative dissolution percentage released for 4 hours reaches more than 99.5%, and the stable absorption of the amoxicillin dispersible tablets in vivo is effectively ensured.
TEST EXAMPLE 2 Amoxicillin dispersible tablet in vivo test
Pharmacokinetic experiments
Medicine preparation:
the sample of the invention: amoxicillin dispersible tablets prepared by methods of embodiments 2-4 of the invention
Comparative example 1 sample: patent CN200810101332.3 Amoxicillin dispersible tablet obtained in example 1
Comparative example 2 sample: amoxicillin dispersible tablet obtained in patent CN201110289124.2 specific embodiment
Comparative example 3 sample: patent CN201410446830.7 Amoxicillin dispersible tablet obtained in example 1
Commercial controls: amoxicillin dispersible tablet of Shanxi Tongda pharmaceutical industry Co., Ltd, batch No. 160901
The experimental method comprises the following steps:
an in vivo pharmacokinetic test is carried out by referring to a method of 'the pharmacokinetics and pharmacodynamics of amoxicillin/potassium clavulanate tablets in healthy human bodies' in an article published in 'Chinese clinical pharmacology journal' in 2006.
Subject selection: 10 male volunteers were selected, with average age (21.33 soil 1.12) years, height (175.09 soil 3.67) cm, and weight (68.32 soil 7.81) kg. Has no beta lactam antibiotics allergic history, and does not participate in the drug test within 4 months. In 72h before the test, carrying out comprehensive physical examination, and detecting that the blood and urine are normal, the blood biochemical indexes are normal, and the electrocardiogram is normal; during the test period, smoking and alcohol were prohibited.
The administration scheme is as follows: 10 healthy subjects are fasted for 12h before administration, and 500mg of amoxicillin dispersible tablets are respectively administered with 250mL of warm water on the current day of the experiment; 4h after administration, a unified standard meal is given; during the test period, a proper amount of drinking water is supplied; the test was started around 8 a.m.
Collecting a specimen: taking 3.5mL of blood from the upper limb elbow vein, standing for 5min, centrifuging at 3000r/min for 10min, separating serum, and storing the sample in a refrigerator at-40 ℃ for determination at 0.25, 0.50, 0.75, 1, 1.5, 2, 3, 4, 5, 6, 8 and 10h before and after administration.
In-vivo pharmacokinetic tests were performed on samples of examples 2 to 4, comparative examples 1 to 3, and commercially available products, respectively, and the samples were measured by a microbiological method, and the relationship between the amoxicillin blood concentration and the MIC of clinically isolated pathogenic bacteria in each sample was determined by treatment, as shown in table 4.
TABLE 4 relationship between amoxicillin blood concentration and MIC of clinically isolated pathogenic bacteria
The amoxicillin dispersible tablet of the invention starts to release a part of amoxicillin to reach the expected blood concentration, takes effect quickly, and then continuously and slowly releases the rest amoxicillin, so as to maintain the drug concentration to be kept above MIC for a long time, and the effect is sustained and effective. Amoxicillin is a time-dependent antibiotic, and can not inhibit the growth of bacteria when the concentration is lower than MIC, and can effectively kill bacteria when the concentration reaches MIC, and then the blood concentration is continuously increased, and the sterilization effect can not be increased. Thus T > MIC is a key parameter for predicting clinical efficacy of beta lactam antibiotics, and when T > MIC is 20% or less of the time between administrations, the mortality rate is 100%; when T is more than MIC and is increased to 35% -40% of the administration interval, the antibacterial effect is enhanced, and the viable count is obviously reduced; when the time of T > MIC in the administration interval reaches or exceeds 40-50%, the bacteriological curative effect reaches 90-100%, so that the treatment aim is to ensure that the T > MIC is more than or equal to 4O%.
According to the data from the experiments of examples 2-4 in Table 4, for Streptococcus pneumoniae, the plasma concentration of amoxicillin exceeds the MIC for about 5.1-5.3 hours, and if the administration is performed 3 times a day, the T > MIC accounts for 63.8% -66.3% of the 8-hour administration interval; for haemophilus influenzae, the time for the amoxicillin blood concentration to exceed MIC is about 4.0-4.2h, and accounts for 50.0% -52.5% of the administration interval of 8 h; for methicillin-sensitive staphylococcus aureus, the time for the amoxicillin blood concentration to exceed MIC is about 4.3-4.4h, and accounts for 55.0% -53.8% of the 8h dosing interval; for staphylococcus epidermidis, the time for the amoxicillin blood concentration to exceed MIC is about 5.0-5.1h, and accounts for 62.5% -63.8% of the administration interval of 8 h; for penicillin-resistant streptococcus pneumoniae, the time for the amoxicillin blood concentration to exceed MIC is about 3.2-3.3h, and accounts for 40.0% -41.3% of the administration interval of 8 h; for Moraxella catarrhalis and Streptococcus pyogenes, the time for amoxicillin plasma concentrations to exceed the MIC was over 8 hours, accounting for 100% of the 8 hour dosing interval.
As can be seen from the results in Table 4, the samples of examples 2 to 4 were effective against Streptococcus pneumoniae, Haemophilus influenzae, Moraxella catarrhalis, methicillin-sensitive Staphylococcus aureus, Staphylococcus epidermidis, Streptococcus pyogenes and enterococcus faecalis for a long time in which the T > MIC accounts for more than 50% of the 8h dosing interval, i.e., the samples remained effective in vivo for a long period of time until the next dosing. Compared with the samples of comparative examples 1-3 and the samples of the products sold on the market, the dosage intervals of T > MIC accounting for 8h are all more than 40 percent for only streptococcus pneumoniae and staphylococcus epidermidis, but the dosage intervals of T > MIC accounting for 8h accounting for other pathogens are all about 30 percent, namely the T > MIC cannot be continuously effective, the effect is not achieved when the next medicine taking is carried out, and the blood concentration in vivo is lower than the MIC. In addition, the invention also unexpectedly discovers that the product designed by the invention has the effect of lasting effectiveness on penicillin-resistant streptococcus pneumoniae, wherein T > MIC accounts for more than 40% of the administration interval of 8h, so that the invention also solves the problem of penicillin resistance.
The results show that the amoxicillin dispersible tablet of the invention has stable release, sustained and effective effect in vivo, and better drug effect compared with the comparative example and the market products.
Claims (8)
1. An amoxicillin dispersible tablet is characterized in that a main drug amoxicillin is distributed in a slow release part and a quick release part according to the weight ratio of 4: 6; the slow release part is formed by spraying a slow release coating liquid on a pill core at least containing microcrystalline cellulose as a filling material; the slow-release material in the slow-release coating liquid is processed cashew nut gum; the quick release part is prepared from a filling agent, a disintegrating agent and a lubricating agent; the filling agent is microcrystalline cellulose, the disintegrating agent is one or two of sodium carboxymethyl starch, cross-linked sodium carboxymethyl cellulose and cross-linked polyvinylpyrrolidone, and the lubricating agent is one or two of magnesium stearate, talcum powder and superfine silica gel powder; the processing method of the processed cashew nut gum comprises the following steps: grinding cashew nut gum and sieving the ground cashew nut gum with a 20-mesh sieve; 95% of ethanol, sodium hydroxide and sieved and crushed cashew nut gum according to the weight ratio of 5: 0.5: stirring for 5 hours to obtain reaction liquid; neutralizing the reaction solution with a 732 strong acid ion exchange resin to pH = 7; filtering to remove resin, and concentrating the filtrate by reduced pressure distillation to obtain a viscous liquid; adding 95% ethanol, stirring until the mixture is dispersed and turbid, performing suction filtration, and performing spray drying on the filtrate to obtain treated cashew nut gum; wherein the set conditions of the spray drying are as follows: the outlet temperature was 73 deg.C, the inlet temperature was 112 deg.C, and the feed rate was 10.5 mL/min.
2. The amoxicillin dispersible tablet of claim 1, wherein the pellet core is prepared from amoxicillin as a main drug and a filling material by an extrusion spheronization method, wherein the filling material further contains one or two of starch and lactose; the slow release coating solution is prepared by dissolving the processed cashew nut gum, the plasticizer and the anti-sticking agent by using 85-95% ethanol solution; wherein, the plasticizer is selected from one or two of polyethylene glycol 4000, triethyl citrate and benzyl benzoate, and the anti-sticking agent is selected from magnesium stearate or aerosil.
3. An amoxicillin dispersible tablet according to claim 1, characterized in that the weight ratio of microcrystalline cellulose to treated cashew gum in the pellet core filling material is 1: 1.02-1.08.
4. The amoxicillin dispersible tablets according to claim 1, characterized in that each 1000 tablets are prepared from the following raw and auxiliary materials: the sustained-release part comprises a pill core and sustained-release coating liquid, wherein the pill core is prepared from 120g of amoxicillin, 32g of microcrystalline cellulose, 8g of starch and 40g of purified water; the slow-release coating liquid is prepared from 29g of processed cashew nut gum, 40003 g of polyethylene glycol and 6g of magnesium stearate; the quick-release part is a wrapping layer and is prepared from 150g of amoxicillin, 320g of microcrystalline cellulose, 26g of sodium carboxymethyl starch and 3g of talcum powder; wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
5. The amoxicillin dispersible tablets according to claim 1, characterized in that each 1000 tablets are prepared from the following raw and auxiliary materials: the sustained-release part comprises a pill core and sustained-release coating liquid, wherein the pill core is prepared from 120g of amoxicillin, 45g of microcrystalline cellulose, 7g of lactose and 37g of purified water; the slow-release coating liquid is prepared from 38g of processed cashew gum, 9g of triethyl citrate and 12g of micro silica gel; the quick-release part is a wrapping layer and is prepared from 150g of amoxicillin, 350g of microcrystalline cellulose, 35g of crosslinked sodium carboxymethyl cellulose and 4g of superfine silica gel powder; wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
6. The amoxicillin dispersible tablets according to claim 1, characterized in that each 1000 tablets are prepared from the following raw and auxiliary materials: the sustained-release part comprises a pill core and sustained-release coating liquid, wherein the pill core is prepared from 120g of amoxicillin, 38g of microcrystalline cellulose, 8g of lactose and 35g of purified water; the slow-release coating liquid is prepared from 33g of processed cashew nut gum, 5g of benzyl benzoate and 10g of superfine silica gel powder; the quick-release part is a wrapping layer and is prepared from 150g of amoxicillin, 330g of microcrystalline cellulose, 30g of crosslinked polyvinylpyrrolidone and 3g of magnesium stearate; wherein, the dosage of the pill core of the sustained-release part needs to be converted according to the ratio of 4:6 of the amoxicillin in the sustained-release part and the quick-release part, namely the pill core containing 100g of amoxicillin as the main drug is needed.
7. A process for the preparation of amoxicillin dispersible tablets according to any one of claims 1 to 6, comprising the steps of:
(1) preparing raw and auxiliary materials: sieving the raw materials and adjuvants respectively with 100 mesh sieve;
(2) preparing a pill core: uniformly mixing amoxicillin serving as a main drug in a prescription amount and a filling material, placing the mixture in a wet granulator, gradually adding purified water serving as a wetting agent in the prescription amount to prepare a soft material, transferring the prepared soft material into an extruder, extruding the soft material into strips through an extrusion sieve plate, transferring the extruded strips into a rounding machine for rounding, taking out rounded pellet cores after rounding for 2.5min, drying, sieving the dried pellet cores, weighing an appropriate amount of pellet cores to determine the content of amoxicillin, converting the weight of the pellet cores required by a sustained-release part according to the ratio of the amoxicillin in a quick-release part and a sustained-release part, and weighing for later use;
(3) coating a slow release layer: slowly adding the slow-release material, the plasticizer and the anti-adhesion agent in the formula amount into 85-95% ethanol under stirring, and stirring until the materials are dissolved for later use; placing the weighed pill cores in the step (2) into a fluidized bed, starting the fluidized bed, setting the fluidized bed, and then starting liquid spraying and coating to prepare drug-containing slow-release pellets;
(4) tabletting: and (3) uniformly mixing the drug-containing sustained-release pellets prepared in the step (3) with amoxicillin, a filler, a disintegrating agent and a lubricant which are main drugs and are prescribed in the quick-release part, and tabletting by adopting a direct tabletting method to obtain the amoxicillin dispersible tablet.
8. A process for preparing amoxicillin dispersible tablets according to claim 7, wherein in step 2, the aperture of the sieve plate is 0.8mm, the extrusion speed is 80r/min, and the spheronizer speed is 820 r/min; step 2, taking out the round pill core, and drying the round pill core at 40 ℃ under reduced pressure until the water content is less than 1 percent; screening the dried pellet cores in the step 2 to remove fine powder and large particles, and screening the pellet cores with a 20-24-mesh screen for later use; in the step 3, the parameters of the fluidized bed are respectively set as follows: the diameter of the nozzle is 0.5mm, the air inlet temperature is 40-45 ℃, the material temperature is 30-35 ℃, and the atomization pressure is 0.15-0.20 MPa.
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