CN105726477A

CN105726477A - Pediatric domperidone suspension and preparation method thereof

Info

Publication number: CN105726477A
Application number: CN201610115136.6A
Authority: CN
Inventors: 乔敏; 袁武杰
Original assignee: SHANDONG SIBANGDE PHARMACEUTICAL CO Ltd
Current assignee: Laiyang State Bbd Pharmaceutical Co Ltd; SHANDONG SIBANGDE PHARMACEUTICAL CO Ltd
Priority date: 2016-03-01
Filing date: 2016-03-01
Publication date: 2016-07-06
Anticipated expiration: 2036-03-01
Also published as: CN105726477B

Abstract

The invention discloses a pediatric domperidone suspension and a preparation method thereof. The suspension comprises domperidone, an antibacterial agent, a corrective, a suspending agent, a masking agent and a diluent, wherein the suspending agent and the masking agent both are montmorillonite, the average particle size of the montmorillonite is 8 to 27 [mu]m, and the dosage of the montmorillonite is 0.22% to 4.34% (w/w) of the total amount of the formula. According to the invention, the suspension is prepared by processes of preparing the domperidone with montmorillonite hydrogels, hydrogel microparticles with a rapid diffusion controlled drug release mechanism, a drug-containing suspension and the like, so that the problems of low drug dissolution rate, bitterness and the like are successfully solved to greatly improve the medication compliance and provide a good effect for functional dyspepsia of children.

Description

Pediatric domperidone suspension and preparation method thereof

Technical Field

The invention relates to a gastrointestinal prokinetic drug, in particular to a pediatric domperidone suspension and a preparation method thereof, belonging to the technical field of medicines.

Background

Domperidone was the first peripheral dopamine receptor blocker, and increased lower esophageal sphincter pressure and improved gastric emptying by increasing gastric emptying and promoting antro-duodenal coordination. Upper gastrointestinal motility disorders play a critical role in the pathogenesis of functional upper abdominal discomfort.

Anorexia caused by infantile stomach power deficiency is also called infantile functional dyspepsia, and is a symptom mainly comprising anorexia or anorexia for a long time caused by the deficiency of stomach power, and the anorexia or the anorexia is developed all the year round. Anorexia has influence on growth and development, nutrition status, and intelligence development of children. Long-term anorexia can lead to malnutritional anemia, rickets, hypoimmunity, recurrent respiratory tract infection and the like. In recent years, with the change of society and the action of various factors such as schools, families and environments, the incidence rate of functional dyspepsia of children is on a remarkable rising trend, the health level, the learning performance and the life quality of children patients are seriously affected, and great psychological stress and mental burden are brought to parents. Therefore, the search for an economical and effective medicine for the functional dyspepsia with the dyskinesia type is of great significance to researchers in the primary pediatrics aspect.

Chinese patent document CN103893130A discloses a domperidone microparticle, a domperidone preparation and a preparation method thereof, wherein the preparation method comprises the following steps: dispersing domperidone and a dispersion aid in a solvent, and adding acid to dissolve to obtain a solution I; adding alkali liquor into the solution I under the stirring condition to obtain a mixture containing domperidone particles; separating the domperidone particles. The defects of the patents are that the pH value is adjusted by adding the sodium hydroxide aqueous solution in the preparation method, so that certain influence is generated on the stability of the medicine, and related substances are easily generated in the content of the medicine in the period of validity.

Chinese patent document CN1850080 discloses an oral dispersion type domperidone controlled release gel and a preparation method thereof, the formula of which is: domperidone and polyvinylpyrrolidone, and one or more of carbomer, hydroxypropyl methylcellulose, methylcellulose and hydroxypropyl cellulose, and the preparation method comprises the following steps: swelling the substrate; dissolving domperidone and polyvinylpyrrolidone in ethanol, and drying; regulating pH value with triethanolamine. The defects of the patents are that more auxiliary materials are selected, and triethanolamine is selected to adjust the pH value, wherein the triethanolamine is mainly selected as an external auxiliary material in the medicine, is less used in oral medicine, and related substances are added, so that the safety problem of the medicine is solved.

Chinese patent document CN102113997A discloses a domperidone suspension and a preparation method thereof; the patent consists of the following components per 1000mL of suspension: 1g of domperidone, 6-8 g of sodium carboxymethylcellulose, 8-12 g of microcrystalline cellulose, 0.3-0.7 mL of polysorbate, 80-120 g of sorbitol, 1.5-2.0 g of methyl paraben, 0.1-0.3 g of propyl paraben, 0.1-0.4 g of saccharin sodium and the balance of water. The defects of the above patents are that the number of selected auxiliary materials is large, and the use amount of suspension auxiliary materials is large, so that the release of the medicine is influenced.

Experiments prove that no matter the amount of domperidone in the prescription, uncomfortable and unsmooth feeling can be left in the oral cavity, and regurgitation can occur when children take tablets and suspensions every time, so that the children are difficult to take the medicine. The development of a novel domperidone preparation, in particular to a pediatric domperidone suspension prepared by taking montmorillonite as a taste masking agent, solves the clinical problem which is urgently needed by children at present. By adopting a conventional prescription and a conventional preparation process, the technical problems of the dissolution rate and the bitter feeling of the medicine are difficult to solve, and the preparation process is difficult to ensure that the medicine has lower production cost and is convenient for children and patients under dysphagia or special environment to take according to the domestic existing auxiliary materials and production conditions, and the taste correction and the taste masking of the existing oral medicine are urgent problems to be solved in pediatric medicine; to date, pediatric domperidone suspensions prepared with montmorillonite as taste masking agent have not been reported.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a pediatric domperidone suspension and a preparation method thereof, and the problems of low drug dissolution, drug bitterness and the like are successfully solved through innovative adjuvant selection, optimized adjuvant proportion and an innovative preparation process.

The technical scheme of the invention is as follows:

a domperidone suspension for children comprises domperidone, an antibacterial agent, a flavoring agent, a suspending agent, a taste masking agent and a diluting agent, wherein the suspending agent and the taste masking agent are montmorillonite, the average particle size of the montmorillonite is 8-27 mu m, and the dosage of the montmorillonite is 0.22-4.34% (w/w) of the total amount of preparation raw materials.

According to the invention, in the preferable pediatric domperidone suspension, the average particle size of the domperidone is 21-45 μm.

According to the invention, in the pediatric domperidone suspension, the antibacterial agent is selected from glycerin and/or sorbitol; the flavoring agent is selected from saccharin sodium and/or vanillin; the diluent is selected from deionized water.

The invention provides the following more preferable technical scheme:

a pediatric domperidone suspension is prepared from the following raw materials in parts by mass:

according to the invention, it is further preferred that:

according to the invention, it is even further preferred that:

or the pediatric domperidone suspension is prepared from the following raw materials in parts by mass:

the raw materials of the pediatric domperidone suspension are all conventional commercially available products without special indication.

A preparation method of a pediatric domperidone suspension comprises the following steps:

(1) crushing domperidone, and sieving the domperidone with a sieve of 140-160 meshes to obtain particles with the average particle size of 21-45 mu m for later use;

(2) crushing montmorillonite, and sieving by 90-110 meshes to obtain the montmorillonite with the average particle size of 8-27 mu m for later use;

(3) weighing the domperidone in the step (1) and the montmorillonite in the step (2) according to the proportion, adding 1/2 purified water in the total water amount, and carrying out ultrasonic treatment for 10-30 minutes under stirring; the ultrasonic frequency is 30-45 KHz, stirring is continued for 1-2 h, and standing is carried out for 2-3 h for later use;

(4) weighing saccharin sodium, vanillin, glycerol and sorbitol according to a ratio, fully and uniformly mixing, adding into the step (3), then adding 1/3 purified water of the total water amount, grinding the liquid in a colloid mill under full stirring, and sieving with a 200-300-mesh sieve for later use;

(5) and (3) sterilizing the material obtained in the step (4) for 30-40 min at the temperature of 121-130 ℃ under the action of 30-45 KHz ultrasonic waves to obtain a sterilized material, adding sterilized residual purified water until the content of domperidone in the suspension is 1-5% (w/w), and subpackaging to obtain the domperidone suspension.

According to the preferable method, the domperidone in the step (1) is crushed, sieved by a 150-160-mesh sieve, and then subjected to laser particle size measurement to obtain the domperidone powder with the average particle size of 21-32 microns.

According to the invention, the montmorillonite in the step (2) is crushed, sieved by a 100-110-mesh sieve, and then subjected to laser particle size measurement to obtain the montmorillonite with the average particle size of 8-16 microns.

According to a further preferred embodiment of the present invention, the preparation method of the pediatric domperidone suspension comprises the following steps:

(1) crushing domperidone, and sieving the domperidone with a 150-mesh sieve to obtain particles with the average particle size of 28-32 mu m for later use;

(2) crushing montmorillonite, and sieving with a 100-mesh sieve to obtain the montmorillonite with the average particle size of 12-16 mu m for later use;

(3) weighing the domperidone in the step (1) and the montmorillonite in the step (2) according to the mixture ratio, adding 1/2 purified water of the total water amount, and carrying out ultrasonic treatment for 20 minutes under stirring; continuously stirring for 1-2 h with the ultrasonic frequency of 40KHz, and standing for 2-3 h for later use;

(4) weighing saccharin sodium, vanillin, glycerol and sorbitol according to a ratio, fully and uniformly mixing, adding into the step (3), then adding 1/3 purified water of the total water amount, grinding the liquid in a colloid mill under full stirring, and sieving with a 200-mesh sieve for later use;

(5) and (3) sterilizing the material obtained in the step (4) for 30-40 min at the temperature of 121-130 ℃ under the action of 40KHz ultrasonic waves to obtain a sterilized material, adding sterilized purified water until the content of domperidone in the suspension is 1% (w/w) or 5% (w/w), and subpackaging to obtain the domperidone suspension.

The present invention will be further described with reference to the following examples, but is not limited thereto.

Experimental example 1: determination experiment of particle size and particle size distribution of domperidone

Domperidone is a multi-synthetic benzimidazole derivative, is almost insoluble in water, and is a technical difficulty in a suspension preparation process in order to uniformly disperse domperidone in water and achieve a qualified sedimentation volume ratio. Therefore, domperidone is selected and is subjected to superfine grinding.

1. Domperidone particle size and particle size distribution

The particle size distribution of domperidone was determined using sieve analysis, 50g of domperidone particles were measured per batch. The measurement was carried out using a sieve analyzer and a standard test sieve, the amplitude was 1.5mm and the vibration time was 20 min. The size of the sieve is 110 meshes, 120 meshes, 130 meshes, 140 meshes, 150 meshes and 160 meshes. The average particle size of the domperidone particles was determined by sieving using a laser diffraction particle size analyzer from Marlven2000, and the average particle size and particle size distribution of the domperidone were as shown in table 1.

Particle size distribution determination (D50) by Malvern2000 or equivalent laser particle size analyzer, taking about 0.12g of the product, adjusting the light shielding rate of the detector to 8-20%, adding 800mL of water, stirring at 3000 rpm for 15 min or 3000 rpm, simultaneously performing ultrasound for 2-3 min (16W ultrasonic power, 3 μm amplitude), checking by law, and taking the average value of 3 continuous measurements, which should meet the following table.

TABLE 1 mean particle size and particle size distribution of domperidone

And (4) analyzing results: with the increase of the mesh number, the amount of the domperidone particles is increased, and the average particle size of the sieved particles is reduced continuously.

2. Observation of particle size

2.1 Domperidone particle preparation

Sample preparation sample 1: 130-mesh domperidone is prepared according to the method of the step (3) of the example 1; sample 2: 140 mesh domperidone was prepared according to the procedure of step (3) of example 1.

2.2 Domperidone crystallite particle size

The prepared samples 1 and 2 were dropped on a glass slide, covered with a cover slip, and the crystallite size was observed under a microscope (magnification l0 × 10 or 10 × 40). The objective lens with smaller magnification is selected to observe the uniformity degree of the particle distribution. Then selecting representative parts to take pictures, wherein the number of the pictures is not less than 15, and the total number of the microcrystalline crystal type particles is observed to be more than 50. And calculating the grain count and the grain size of the microcrystalline crystal form by using an Image-pro calculation program. And (4) centrally arranging the distribution data of the particles of each photo so as to obtain the distribution proportion of the sizes of the microcrystalline crystal form particles.

3. Results

The results are shown in FIG. 1 (sample 1) and FIG. 2 (sample 2); as can be seen from FIGS. 1 and 2, the microcrystalline crystal particles obtained from sample 2 are significantly smaller, the proportion of the microcrystalline crystal particles with the particle size of less than 38 μm is up to 93%, the proportion of the microcrystalline crystal particles with the particle size of more than 47 μm obtained from sample 2 is less than 7%, and the proportion of the microcrystalline crystal particles with the particle size of more than 52 μm is only 0.3%. In contrast, sample 1 gave 55% of particles with a size > 38 μm and 19% of particles with a size > 52 μm. The statistical test shows that the grain sizes of the two microcrystalline crystal forms have significant difference (P is less than 0.01).

And (4) evaluating the results: the microcrystalline crystal form particles are white powder, and have fine and smooth hand feeling and no obvious granular feeling. The microcrystalline particles were observed by an optical microscope to be free from the sticking phenomenon. The crystallite size formed by 130-mesh domperidone is larger, so that particles above 140 meshes are selected.

Experimental example 2: measurement experiment of average particle diameter and particle diameter distribution of montmorillonite

Montmorillonite is a hydrous phyllosilicate mineral drug, and tests prove that the non-crushed montmorillonite used as the active ingredient of the suspension can leave uncomfortable gritty feeling in the oral cavity no matter what the active ingredient occupies the prescription, so the montmorillonite is crushed.

The particle size distribution of montmorillonite was determined using sieve analysis. Montmorillonite particle was measured for each batch. The measurement was carried out using a sieve analyzer and a standard test sieve, the amplitude was 1.5mm and the vibration time was 20 min. The size of the sieve is 60 meshes, 70 meshes, 80 meshes, 90 meshes, 100 meshes and 110 meshes. The average particle size of the smectite particles was measured by sieving using a laser diffraction particle size analyzer from Marlven2000, and the average particle size and the particle size distribution of the smectite were shown in Table 1.

Particle size distribution determination method: malvern2000 or a laser particle size analyzer with equivalent performance, about 0.12g of the product is taken, the light shielding rate of a detector is controlled within the range of 8-20%, 800mL of water is added, the mixture is stirred for 15 minutes at 3000r/min or is stirred at 3000r/min, and is subjected to ultrasonic treatment for 2-3 minutes (ultrasonic power is 16W, amplitude is 3 mu m) at the same time, the average value of 3 continuous measurements is checked according to a law, and the average value meets the requirements of the following table and is shown in table 2.

TABLE 2 mean particle diameter and particle diameter distribution of montmorillonite

And (4) analyzing results: as the mesh number increases, the residue of montmorillonite particles also increases, and the average particle size of the sieved particles decreases continuously.

The preparation method of example 1 is used, the prescription is unchanged, the different mesh numbers of montmorillonite particles are selected to prepare the suspension, and the taste of the domperidone suspension is inspected; see table 3:

TABLE 3 influence of different mesh sizes on mouthfeel

The purpose of this experimental example is to evaluate the influence of different average particle size ranges on the domperidone suspension characteristics and to confirm that the selected particle mesh range, i.e. 90 mesh to 110 mesh, i.e. the particle size of montmorillonite with an average particle size of 8 to 27 μm is reasonable for the present invention.

Experimental example 3: research experiment of domperidone suspension antibacterial agent

The domperidone suspension provides nutrients for the growth of microorganisms in an aqueous medium, so that the breeding of the microorganisms is promoted, the structure of the suspension is damaged, and the quality problems of water diversion, water expansion and the like of the suspension are caused. In order to inhibit microorganisms and meet the control requirements of national standards on the microorganisms in suspension, some antiseptic and antibacterial agents are often necessary in the formula. The invention mainly starts from the proportion of glycerin and sorbitol in the formula and researches the antibacterial relation between suspension and glycerin.

1. Test of antibacterial Properties

Glycerin and sorbitol were selected as the suspension antimicrobial agents, respectively, and suspension preparation was performed according to the formulation of table 4 without any preservative.

TABLE 4 suspension formulations of various antimicrobial agents

2. Preparation of strains for experiments

The test microorganisms, Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa, were inoculated on the broth medium, and cultured at 35 deg.C for 24 hr to obtain a bacterial solution with a bacterial count of 1.0 × 10/mL. Inoculating Candida albicans and Aspergillus niger on agar medium of Sabouraud's agar, culturing Candida albicans at 35 deg.C for 48 hr, culturing Aspergillus niger at 25 deg.C for 72 hr, and diluting with normal saline to obtain bacterial liquid with bacterial count of 1.0 × 10/mL.

3. Criteria for effectiveness

The microorganism index and time curve should show attenuation, the microorganism concentration is less than 0.1% of the original concentration on the 4 th day and continuously decreases, and the microorganism concentration is less than 500/g after the 28 th day, which accords with the national standard.

4. Measurement of

Taking the strain liquid, mixing the strain liquid with the following components in a proportion of 1: adding the suspension into the test suspension at a volume ratio of 100, stirring uniformly, measuring the instant microorganism content of the suspension after inoculation as the initial content of the sample, and culturing the inoculated sample suspension in an incubator at 35 ℃. Samples were taken on days 3, 7, 14, 2l, 28, 60 and 9O after inoculation to determine the microbial content of the sample suspension, and the effectiveness of the antimicrobial system of the suspension was evaluated based on the results of the determination.

5. Results and analysis

(1) Results

The suspensions were tested for microbial content as described above and the results are shown in Table 5.

TABLE 5 antibacterial effectiveness evaluation data for different bacteriostats

The results show that: over time, the antimicrobial effects of different bacteriostats begin to manifest different effects. Sorbitol is used as a bacteriostatic agent in the formulas 1 and 2, and the dosage is different, so that the antibacterial effect is different, the result shows that microorganisms are not effectively killed, the standards are not met, and the antibacterial property of a suspension formula system is judged to be ineffective. The glycerin of the formulas 3, 4 and 5 is added, and the antibacterial effect is the best. The results of formulas 3 to 5 show that the microorganisms are effectively killed, the standards are met, and the suspension formula system is effective in antibiosis.

(2) Analysis of results

The test method shows that: the glycerol can be used as the first choice of a suspension bacteriostatic agent, and the antibacterial effect is best; if the sorbitol is used alone, the addition amount of the sorbitol must reach a larger amount to obtain a better antibacterial effect.

From the cost and effect considerations, the test formulations 3, 4, 5 can be used in suspension production.

Experimental example 4: research experiment of domperidone taste-masking agent

The taste bud is the taste receptor, and is mainly distributed in the lingual papilla on the back and edge of the tongue, and also scattered in the mucous membrane of the oropharynx. The taste buds are onion-shaped and contain 50-100 taste cells. Surface proteins of taste receptors interact with pore-like proteins called ion channels, causing changes in intracellular potentials that trigger their transmission of chemical signals that are in turn converted into neurotransmitters for transmission to the brain.

The experiment adopts the technology of taking montmorillonite as the taste masking agent, reduces the dissolution and the release of the medicine in saliva, reduces the combination of medicine molecules and taste buds, and masks the bitter taste of the medicine.

The product is oral suspension, and according to the property of domperidone suspension, montmorillonite adjuvant is primarily selected for prescription design to carry out prescription screening and optimization, and prescription screening is carried out by taking bitter-free, delicious and tasty taste as investigation indexes. The design recipe is as follows: see table 6; and the screening results of the dosages of the raw and auxiliary materials are shown in Table 7.

TABLE 6 table of raw and auxiliary materials

TABLE 7 screening results (W/W) for the amounts of raw and auxiliary materials

Prescription evaluation and results:

prescription 1: the color is uniform, the taste is cool and the bitterness is strong;

prescription 2: the color and luster are uniform, the cool feeling is proper, and the bitter feeling is achieved;

prescription 3: the color and luster are uniform, the cool feeling is proper, and the tea is slightly bitter and completely acceptable;

prescription 4: the color and luster are uniform, the cool feeling is strong, and the bitter feeling is avoided;

prescription 5: has uniform color, good refreshing feeling, and no bitter feeling.

As a result: the prescription evaluation shows that the prescription is optimized, the prescriptions 3, 4 and 5 are optimized, and the dosage of the montmorillonite in the prescriptions 3, 4 and 5 is determined as the prescription optimal dosage of the taste masking agent of the suspension.

Experimental example 5: suspending agent research experiment of domperidone suspension

According to the Strokes' law, the main factors affecting the suspension properties of a drug are the size of the drug particle size and the properties of the dispersion medium. The proper amount of suspending agent is added into the suspension, so that the medicine is easy to disperse and the sedimentation of particles is slowed down.

1. In the test, 5 polymer materials of montmorillonite, CMC-Na (sodium carboxymethylcellulose), MC (methyl cellulose), PVP (polyvinylpyrrolidone) and xanthan gum are selected as suspending agents, domperidone with the same particle size and different suspending agents are prepared into corresponding suspensions according to the prescription, and sedimentation volume ratio and redispersibility tests are respectively carried out, and the experiments are shown in Table 8;

TABLE 8 Effect of suspending agent on domperidone suspension Properties

As shown in Table 8, among the 5 polymer materials, CMC-Na has better dispersion-aiding effect, but is easy to agglomerate and agglomerate, thereby influencing the dispersion and sedimentation of the suspension; the suspension of MC and PVP has overlarge viscosity and is difficult to redisperse after sedimentation; suspensions obtained from xanthan gum are relatively stable; the suspending agent montmorillonite has the best suspending effect on domperidone suspension.

2. Study on influence of different dosages of montmorillonite on prescription

The results are shown in Table 9, and the experiment shows that: the montmorillonite accounting for 0.22-4.34% (W/W) of the total amount of the prescription can generate better suspending effect.

TABLE 9 Effect of montmorillonite dosage on Domperidone suspension Properties

3. Rheological property and particle size distribution of domperidone suspension

The viscosity of the domperidone suspension is 22MPa & s measured by an Ndj-1 rotary viscometer, the domperidone suspension is pseudoplastic fluid which can be seen from a flow curve, and the fluidity of the suspension is good.

4. Stability test

The suspensions were formulated by placing 3 batches of the bottled sealed domperidone suspension at 40 deg.C and 75% humidity for 6 months, measuring the content (percentage of the indicated amount) and the particle size, and the drug particle size distribution was measured with a Malvern2000 laser light scattering instrument and compared to the initial samples (see Table 10).

Table 10 domperidone suspension stability accelerated test results

The result shows that the content of the domperidone suspension is not obviously changed, the particle size is not obviously increased, and the number of particles with certain particle size is not obviously changed. The suspension was found to have good stability.

Montmorillonite is added into the domperidone suspension as a suspending agent, the suspension is pseudoplastic fluid, the redispersibility is good, the sedimentation volume ratio is more than 0.9, the viscosity is increased during standing, and the particles are not easy to settle; and the viscosity becomes lower after shaking, and the product is easy to pour. Meanwhile, the density difference between solid particles and a dispersion medium is reduced, the hydrophilicity of domperidone is improved, and the stability of the system is enhanced.

Experimental example 6: ultrasonic treatment research experiment for domperidone suspension

The sedimentation volume ratio is generally used to evaluate the sedimentation stability of a suspension and the effect of using a stabilizer, and the item is examined to ensure the physical stability. The Chinese pharmacopoeia 2010 edition stipulates that the sedimentation volume ratio is H/H. The value should not be less than 0.90, the larger the value, the closer the height of the sediment is to the original height of the suspension, and the more stable the suspension. The invention comprises the following steps of different preparation methods: 1. an ultrasonic method; 2. colloid milling; 3. a homogenizer method; preparing domperidone suspension for analysis;

1. experimental methods and results

(1) Dynamic stability study of suspensions

Sedimentation volume ratio: the height H of the settled layer of the suspension after standing for 180 days is measured and compared with the original height H of the suspension. In contrast, F is H/H. And F is the sedimentation volume ratio. The larger F, the more stable the suspension;

micro brownian motion: taking 1 drop of the suspension which is placed for 180 days, adding 10mL of water for dilution and shaking up, taking one drop of the suspension from the drop of the suspension on a glass slide, covering the glass slide, observing under a high power lens, and indicating that the suspension is well dispersed if micro Brownian motion exists;

redispersion capability: the suspension was allowed to settle in a 50mL stoppered tube for 180 days and then spun at 360 degrees, 20 r/min. After a certain time, sediment at the bottom of the graduated tube should disappear, indicating that the dispersion is good;

caking condition: standing the suspension for 180 days, and shaking with hand to disperse uniformly for less than 10 times; the mixture can not be dispersed after shaking for 30 times, and can be dispersed after stirring; non-stirrable, lumpy;

particle size: the sample was suspended in warm filtered agar solution, a drop was placed on a glass slide (agar prevents particle migration and Brownian motion), and the number of particles measured was 500 after the slide was covered.

The above results are shown in Table 11;

TABLE 11 comparison of dynamic stability of domperidone suspensions by different preparation methods

The experimental results show that: the suspending effect of the ultrasonic dispersion method on the domperidone suspension is superior to that of other colloid preparation methods.

The dynamics experiment shows that the volume of the suspending effect of the domperidone suspension by the ultrasonic dispersion method is the largest, the suspension is easy to disperse after being placed for 180 days, no caking phenomenon exists, the suspending effect is superior to that of a colloid mill method and a homogenizer method, and the dynamics stability of the preparation is enhanced.

The ultrasonic dispersion method is selected to have stronger thixotropy, so that the preparation is easy to disperse by shaking, and the method is an ideal suspension-suspending dispersion method of domperidone suspension.

Experimental example 7: research experiment for influence of ultrasonic and high-temperature synergistic effect on sterilization effect

Preparing a domperidone suspension according to the preparation method of the embodiment 1, and sterilizing the material for 30-40 min at 140-150 ℃ under the action of 30-45 KHz ultrasonic waves;

comparative example 1 experiment: preparing a domperidone suspension according to the preparation method of the embodiment 1, and sterilizing the materials at the temperature of 140-150 ℃ for 30-40 min;

taking the domperidone suspension obtained above, and carrying out microbial limit inspection according to a microbial limit inspection method in addendum XIJ of 2010 version of Chinese pharmacopoeia, wherein inspection results are shown in table 12;

TABLE 12 results of microbial detection

As can be seen from the analysis in Table 12, the effect of the ultrasonic treatment and the high-temperature treatment in cooperation with sterilization is significantly better than that of the high-temperature sterilization treatment alone.

Experimental example 8: compatibility test of raw materials and auxiliary materials

The compatibility test of the raw materials and auxiliary materials selected in the domperidone suspension medicament research process is as follows;

the raw materials and the selected auxiliary materials are physically mixed according to a certain proportion, the mixture is placed for 10 days under the conditions of high temperature of 60 ℃ plus or minus 2 ℃, humidity of 90 percent plus or minus 5 percent and strong light of 4500 plus or minus 500lx according to an experimental method of influencing factors in the guiding principle of the stability test of the raw material medicines and the pharmaceutical preparations in the 2010 version two of Chinese pharmacopoeia (appendix XIXC), and changes before and after placement are checked. The test results are as follows:

1. compatibility test of raw and auxiliary materials under high temperature conditions

Mixing the raw materials and auxiliary materials according to a certain proportion, exposing the mixture to the high temperature of 60 +/-2 ℃ for 10 days, and sampling the mixture in 0, 5 and 10 days respectively, wherein the test results are shown in the table 13 below.

TABLE 13 compatibility test of raw and auxiliary materials at high temperature (60 ℃. + -. 2 ℃) for 10 days

The compatibility test of 10 days at the high temperature of 60 +/-2 ℃ shows that the properties, related substances and contents of the auxiliary materials are not changed.

The results show that the domperidone has good compatibility with the auxiliary materials at the high temperature of 60 +/-2 ℃.

2. Compatibility test of raw and auxiliary materials under high humidity conditions

Mixing the raw materials and adjuvants at a certain ratio, exposing to high humidity (90% +/-5%) for 10 days, sampling at 0, 5 and 10 days, and determining indexes, the results are shown in Table 14.

The sample is weighed and divided into three parts for three condition tests, so the result of 10 days under high humidity is the same as that of 10 days under high temperature.

TABLE 14 high humidity (90% +/-5%) for 10 days of raw and auxiliary materials compatibility test

The compatibility test of 10 days under the condition of high humidity of 90% +/-5% shows that the properties, related substances and contents of the auxiliary materials are not changed.

The results show that the domperidone has good compatibility with the auxiliary materials under the condition of high humidity of 90% +/-5%. The comprehensive test result shows that the preparation should be stored hermetically.

3. Compatibility test of raw and auxiliary materials under illumination condition

Mixing the raw materials and adjuvants at a certain ratio, exposing to light (4500 + -500 lx) for 10 days, sampling at 0, 5, 10 days, and determining domperidone content and comparing with 0 day, the results are shown in Table 15.

The result is obtained after 0 day of illumination and 0 day of high temperature.

TABLE 15 compatibility test of raw and auxiliary materials illumination (4500 + -500 lx) for 10 days

The compatibility test of 10 days under the condition of illumination (4500 +/-500 lx) shows that the properties, related substances and contents of all auxiliary materials are unchanged.

The results show that the domperidone has good compatibility with the auxiliary materials under the condition of illumination (4500 +/-500 lx).

The compatibility test of the raw materials and the auxiliary materials shows that under the three test conditions, the main indexes of all samples have no obvious change compared with the raw materials, which shows that the domperidone and the auxiliary materials have good compatibility and the selected auxiliary materials are reasonable.

Experimental example 9: determination of domperidone suspension in vitro release degree and research experiment of release mechanism

1. Instruments and drugs: an ultraviolet visible spectrophotometer and a dissolution tester; domperidone suspension (prepared in example 1);

2. experimental methods

Selecting the measurement wavelength, precisely weighing a proper amount of domperidone reference substance, dissolving with methanol, and diluting into a solution with a mass concentration of 20 mg/L; and preparing a blank substrate solution with the same dilution concentration according to the prescription proportion, taking methanol as a blank, and scanning in the wavelength range of 200-400 nm respectively, wherein the result shows that the maximum absorption of the domperidone is at 287nm, and the substrate has no absorption at the wavelength. Thus, 287nm was chosen as the measurement wavelength, see FIG. 3.

3. Establishment of a standard curve: the 25mg domperidone reference substance was precisely weighed, placed in a 25mL measuring flask, dissolved and diluted to the scale by adding about 20mL of methanol solution, and shaken up. Precisely measuring 5mL of the diluent, placing the diluent in a 50mL measuring flask, diluting the diluent to a scale with methanol, and shaking up.

The diluted solutions 1, 1.5, 2, 2.5, and 3mL were precisely measured and placed in 10mL measuring bottles, and the volume was determined with methanol (mass concentrations were 10, 15, 20, 25, and 30mg/L, respectively). Measuring absorbance at a wavelength of 287nm with methanol as a blank, and performing linear regression on the absorbance (A) and the drug concentration (C) to obtain a regression equation:

A＝25.747C+0.0108r＝0.9999(n＝6)

the linear relation between the absorbance and the concentration of domperidone in the measuring range is good.

4. And (3) precision test: domperidone sample solutions (corresponding to mass concentrations of 10, 20 and 30mg/L) were prepared and the absorbance of the solutions was measured daily and during the day. The measurement was carried out 6 times a day for 5 days continuously, and the results are shown in Table 16.

TABLE 16 results of precision test

5. Stability of the solution: domperidone sample solutions (corresponding to mass concentrations of 10, 20 and 30mg/L) are prepared, and the absorbance is measured at 0, 6 and 12 hours respectively, and the results are shown in Table 17.

TABLE 17 stability results of the solutions

6. And (3) recovery rate determination: the domperidone reference substance is precisely weighed, blank matrixes are respectively added according to the prescription proportion, then methanol is used for constant volume to prepare domperidone solutions with the mass concentrations of 10 mg/L, 20mg/L and 30mg/L respectively, methanol is used as a blank, the absorbance (A) is measured at the position of 287nm wavelength, the absorbance is substituted into a regression equation to calculate the recovery rate, and the result is shown in table 18.

Table 18 recovery test results (n ═ 9)

7. Content measurement about 0.5g of each of the samples of example 1, example 2 and example 3 was precisely weighed, placed in a 25mL measuring flask, diluted to the scale with methanol, shaken up and filtered. The absorbance was measured at a wavelength of 287nm using methanol solution as a blank, and the measured data was substituted into a regression equation to calculate the domperidone content, the results are shown in Table 19.

TABLE 193 measurement of sample content

To summarize: according to the experiment, the domperidone suspension is prepared by taking montmorillonite and the like as auxiliary materials, has the effect of enhancing gastric motility, has the effect of protecting esophagus and gastric mucosa, and is more beneficial to treatment of reflux esophagitis. The product has certain fluidity, and can be used for infants and dysphagia patients.

Experimental example 10: human body pharmacokinetics and bioequivalence research experiment of domperidone suspension

In recent years, researchers of drugs at home and abroad have conducted extensive studies on taste masking techniques and prescription design for reducing unpleasant taste. Among them, the solid dispersion is the most direct and simple taste masking method, providing a physical barrier for drug particles, thereby reducing the contact between the drug and taste buds, and in addition, can play a role in increasing the dissolution of some insoluble drugs. The domperidone has extremely bitter taste, influences the medication of patients, can effectively cover the bitter taste by using a dispersion technology for taste-masking treatment, further improves the taste by adding a proper amount of flavoring agent, and greatly improves the medication compliance of patients, particularly children. The suspension prepared by the test has good taste, and the research performs the research on the relative bioavailability of the domperidone suspension (test preparation) and the domperidone tablet (molsidine and reference preparation) produced by the Simon Yang pharmacy company Limited on the human body to evaluate the bioequivalence of the two preparations.

1. Materials and methods

1.1 medicine: test formulation (T): domperidone suspension with the specification of 10mg/1mL, prepared in example 1; reference formulation (R): domperidone tablets (Xian Yang Sen pharmaceutical Co., Ltd., specification: 10 mg/tablet), domperidone reference (provided by China pharmaceutical biologicals assay); the test water is ultrapure water; the methanol, the acetonitrile, the formic acid and the ammonium acetate are chromatographically pure, and the others are analytically pure.

1.2 methods

1.2.1 subject selection: 24 healthy male volunteers are selected, wherein the male volunteers are 22-31 years old, 158-185 cm high and 51.0-76.0 kg body mass, and the physical examination proves that the liver and kidney functions are normal and the electrocardiogram is normal, which all meet the requirements of the subjects for human selection. The informed consent was signed and approved by the ethics committee.

1.2.2 methods of administration and sample Collection: smoking, alcohol and any other medication were prohibited from the first 2 weeks to the entire trial. A single dose, random, 2 x 2 crossover trial design was used. The subjects were divided into 2 groups on a randomized basis, with 2 cycles crossing at intervals of l weeks. The 24 subjects took 20mg of the test preparation or the reference preparation orally at 8:00 in the morning and took 200mL of warm boiled water, and after taking the medicine for 2 hours, the subjects could take water and after 4 hours, the subjects had a meal in unison. The period of taking medicine and taking blood is left in the clinical ward of stage I for observation. Extracting blank blood sample 4mL before oral administration, collecting venous blood 4mL after administration for 0.1667, 0.333, 0.5, 0.75, 1, 1.5, 2, 3, 5, 8, 12, 24, 30 and 36h respectively, placing into heparin anticoagulation test tube, centrifuging, separating plasma, and storing at-75 deg.C for blood concentration measurement.

1.2.3 treatment of plasma samples: precisely adding 0.5mL of plasma sample into a 10.0mL glass test tube with a plug, swirling for 10S, adding 100 μ L of sodium hydroxide alkaline solution (0.5mol/L), mixing, adding 4.0mL of ethyl acetate, and swirling for 3 min. Centrifuge at 3000r/min for 10min and aspirate the upper organic phase 3.5 mL. Concentrating at 4O deg.C, evaporating to dryness, adding 100 μ L of 50% methanol solution, re-dissolving, vortex for 1min, centrifuging at 12000r/min for 5min, and collecting supernatant for LC-MS/MS analysis with sample amount of 5 μ L.

1.3 statistical treatment, in which the blood concentration is treated by BAPP3.0 software, the pharmacokinetic parameters and the relative bioavailability are calculated, the actual peak reaching concentration (Cmax) of the tested preparation and the reference preparation is measured, and the AUC obtained by the calculation of a trapezoidal method_0-36hAfter logarithmic transformation, analysis of variance and double-single-side t test are carried out, 90% confidence interval investigation is carried out, and non-parameter method inspection is carried out on the time to peak (tmax). Thus, whether the test agent and the reference agent are bioequivalent or not was evaluated.

2. Results

2.1 methodological examination results

2.1.1 specificity, under the LG-MS/MS condition adopted by the test, the retention time of domperidone is about 2.5min, and the retention time of internal standard venlafaxine is about 3.0 min. The domperidone and the internal standard peak have good shapes, no interference of miscellaneous peaks and stable base line.

2.1.2 Standard Curve and Linear Range: the standard curve range is 0.321-82.24 mu g/L, and the lowest quantitative limit is as follows: 0.321. mu.g/L.

2.1.3 precision and accuracy: the Relative Standard Deviation (RSD) in the day for low, medium and high (0.648, 6.48 and 64.8 μ g/L)3 concentrations of domperidone was 7.04%, 2.91% and 1.90% (n ═ 5), respectively; the daytime RSDs were 9.25%, 7.81%, and 6.18%, respectively (n ═ 15). The accuracy of the low, medium and high 3 concentrations of domperidone is 97.29-101.75%.

2.1.4 extraction recovery: the extraction recovery rates of the domperidone with low, medium and high concentrations are 88.24%, 79.78% and 67.77% respectively (n is 3);

2.1.5 Medium Effect: the medium effects of low, medium and high domperidone LC-MS/MS at 3 concentrations were 100.00%, 96.63%, 99.25%, respectively (n ═ 3);

2.1.6 stability of the sample: the experimental results show that the low, medium and high concentrations of domperidone plasma samples are left at room temperature for 24 h. Repeated freeze thawing for 3 times, and standing at-75 ℃ for 15 days, all the stability is good.

2.2 human pharmacokinetics study

2.2.1 pharmacokinetic parameters: plasma drug concentrations of test and reference formulations were processed by BAPP3.0 program and pharmacokinetic parameters were estimated using a non-compartmental model. The main pharmacokinetic parameters of the single dose oral test and reference domperidone tablets in 24 healthy volunteers are shown in table 20.

TABLE 20 Main pharmacokinetic parameters of Single dose oral test and reference domperidone tablets

2.2.2 plasma concentration-time curve: 24 healthy volunteers were randomized to a single oral dose of 20mg domperidone test and reference formulations. Mean plasma drug concentration-time profiles of domperidone were measured at different times using LC-MS/MS.

2.2.3 bioequivalence evaluation: parameters Cmax and AUC for domperidone in two formulations_0-36hAfter logarithmic transformation, analysis of variance is performed first, and then double-unilateral t-test is performed. The result Cmax 90% confidence interval is 95.08% -125.29%, T1 ═ 5.53, T2 ═ 3.36, and to.1(22) ═ 1.72; AUC_0-36The h 90% confidence interval is 102.39% -120.49%, T1 is 6.92, T2 is 2.49, and to 1.72. The above results are in line with the relevant requirements of SFDA, indicating that the 2 parameters described above for the 2 formulations are bioequivalent. The tmax of the two preparations was statistically insignificant (P > 0.05) by non-parametric tests.

The test shows that: the domperidone suspension developed in example 1 is bioequivalent to domperidone tablets produced by siennan pharmaceutical co.

The invention has the following beneficial effects:

1. the domperidone suspension prepared by the invention has fewer auxiliary materials and is stable in medicine.

2. The suspending agent used in the domperidone suspension selected by the invention is montmorillonite which is difficult to absorb, the sedimentation volume ratio of the suspension is more than or equal to 0.90 by controlling the granularity and the viscosity of the suspension, and the stability of the suspension in an accelerated experiment is high.

3. The preparation of the domperidone suspension consists of 3 mutually independent and closely related unit process flows: (1) the preparation of the domperidone and montmorillonite hydrogel realizes that a large amount of water is contained in a montmorillonite layer in the technical process to form the polymer hydrogel; (2) under the action of ultrasonic wave, montmorillonite generates acoustic cavitation with water, which causes the formation, growth and explosion compression of bubbles in montmorillonite slurry, so that solid montmorillonite is dispersed in water, and the process can prepare hydrogel particles with a rapid diffusion controlled drug release mechanism; (3) the preparation of the drug-containing suspension, the process evenly disperses the drug-containing particles obtained in the previous process in the water dispersion system to prepare the stable suspension.

4. The bitterness of the domperidone which is used as the powder in the original formula is completely released after the domperidone is crushed, so that the difficulty of taking the domperidone is increased, and the compliance of patients, particularly children patients, to the medicine is poor. The improved prescription raw material adopts the domperidone crystal grains with extremely fine grain size, and is processed by an innovative method, the domperidone is suspended in the crystal grains with extremely small grain size, when the bitter taste is not sensed, the medicine enters the human body, the residual medicine is only aromatic, the special bitter taste of the domperidone is overcome and covered, and the compliance of taking medicine is greatly increased.

5. The prescription after improvement selects montmorillonite as a suspending agent and a taste masking agent, which is very important and key, not only solves the problem of suspension, but also helps to solve the problem of bitter taste.

6. The domperidone suspension of the invention meets the long-term antibacterial requirement through the scientific proportion of glycerin and sorbitol, and avoids adding antibacterial substances into the domperidone suspension.

The results show that by adopting the innovative formula and the innovative process, the indexes of the finished product rate, the suspensibility, the mouthfeel and the like of the suspension are obvious, which fully indicates that the innovative formula and the innovative process are feasible.

Drawings

FIG. 1 is an electron micrograph of microcrystalline particles of domperidone (sample 1) of Experimental example 1;

FIG. 2 is an electron micrograph of microcrystalline particles of domperidone (sample 2) of Experimental example 1;

FIG. 3 shows the UV absorption spectrum (1-domperidone suspension; 2-blank matrix) of domperidone suspension, the abscissa wavelength and the ordinate absorbance.

Detailed Description

The present invention will be further described with reference to the following detailed description of embodiments thereof, but not limited thereto, in conjunction with the accompanying drawings.

Description of raw materials and auxiliary materials in the examples:

the devices and equipment involved in the examples are all solid formulation production universal equipment, commercially available, and are described below:

stainless steel reaction kettle (model 200L), universal high-efficiency pulverizer (model 30B) and Xinhua medical equipment, Inc. are sold; colloid mill (model JT-200) available from Shandong Longxing chemical and mechanical group, Inc.; the ultrasonic machine (model ZK-F528H) is available from Kyoli technology, Inc. (Beijing). Laser particle size analyzer (model Mastersizer3000) (uk).

The present invention will be further described with reference to the following specific examples. It is to be understood that the following examples are illustrative of the present invention only and are not intended to limit the scope of the present invention.

Example 1 preparation method of pediatric domperidone suspension

1. A pediatric domperidone suspension is prepared from the following raw materials in parts by mass:

2. the preparation method comprises the following steps:

Example 2 preparation method of pediatric domperidone suspension

2. the preparation method comprises the following steps:

(1) crushing domperidone, and sieving with a 155-mesh sieve to obtain particles with the average particle size of 24-28 microns for later use;

(2) crushing montmorillonite, and sieving with a 110-mesh sieve to obtain the montmorillonite with the average particle size of 8-10 mu m for later use;

(3) weighing the domperidone in the step (1) and the montmorillonite in the step (2) according to the mixture ratio, adding 1/2 purified water of the total water amount, and carrying out ultrasonic treatment for 25 minutes under stirring; the ultrasonic frequency is 30KHz, stirring is continued for 1-2 h, and standing is carried out for 2-3 h for later use;

(4) weighing saccharin sodium, vanillin, glycerol and sorbitol according to a ratio, fully and uniformly mixing, adding into the step (3), then adding 1/3 purified water of the total water amount, grinding the liquid in a colloid mill under full stirring, and sieving with a 250-mesh sieve for later use;

(5) and (3) sterilizing the material obtained in the step (4) for 30-40 min at the temperature of 121-130 ℃ under the action of 30KHz ultrasonic waves to obtain a sterilized material, adding sterilized residual purified water until the content of domperidone in the suspension is 1% (w/w) or 5% (w/w), and subpackaging to obtain the domperidone suspension.

Example 3 preparation method of pediatric domperidone suspension

2. the preparation method comprises the following steps:

(1) crushing domperidone, and sieving the domperidone with a 160-mesh sieve to obtain particles with the average particle size of 21-24 mu m for later use;

(3) weighing the domperidone in the step (1) and the montmorillonite in the step (2) according to the mixture ratio, adding 1/2 purified water of the total water amount, and carrying out ultrasonic treatment for 10 minutes under stirring; continuously stirring for 1-2 h with the ultrasonic frequency of 45KHz, and standing for 2-3 h for later use;

(4) weighing saccharin sodium, vanillin, glycerol and sorbitol according to a ratio, fully and uniformly mixing, adding into the step (3), then adding 1/3 purified water of the total water amount, milling the liquid in a colloid mill under full stirring, and sieving with a 300-mesh sieve for later use;

(5) and (3) sterilizing the material obtained in the step (4) for 30-40 min at the temperature of 121-130 ℃ under the action of 45KHz ultrasonic waves to obtain a sterilized material, adding sterilized residual purified water until the content of domperidone in the suspension is 1% (w/w) or 5% (w/w), and subpackaging to obtain the domperidone suspension.

Claims

1. A pediatric domperidone suspension comprises domperidone, an antibacterial agent, a flavoring agent, a suspending agent, a taste masking agent and a diluent, and is characterized in that the suspending agent and the taste masking agent are both montmorillonite, the average particle size of the montmorillonite is 8-27 mu m, and the dosage of the montmorillonite is 0.22-4.34% (w/w) of the total amount of preparation raw materials.

2. The pediatric domperidone suspension of claim 1, wherein the domperidone has an average particle size of 21-45 μm.

3. The pediatric domperidone suspension of claim 1, wherein the antibacterial agent is selected from glycerin and/or sorbitol; the flavoring agent is selected from saccharin sodium and/or vanillin; the diluent is selected from deionized water.

4. The pediatric domperidone suspension according to any one of claims 1 to 3, which is prepared from the following raw materials in parts by mass:

5. the pediatric domperidone suspension of claim 4, which is prepared from the following raw materials in parts by mass:

6. the pediatric domperidone suspension of claim 5, which is prepared from the following raw materials in parts by mass:

or,

7. a method of preparing a pediatric domperidone suspension as described in any of claims 4-6, comprising the steps of:

8. The preparation method of pediatric domperidone suspension as claimed in claim 7, wherein the domperidone in step (1) is pulverized and sieved with a 150-160 mesh sieve.

9. The method for preparing pediatric domperidone suspension according to claim 7, wherein the montmorillonite in step (2) is crushed and sieved with a 100-110 mesh sieve.

10. A method of preparing a pediatric domperidone suspension of claim 7, comprising the steps of: