CN103006596A - Domperidone maleate tablet and preparation process thereof - Google Patents

Abstract

The invention discloses an active ingredient domperidone maleate, a diluent selected from microcrystalline cellulose and starch, a disintegrant selected from sodium carboxymethyl starch, a binder selected from povidone, a Glidant and magnesium stearate selected from lubricants. The disintegration of the present invention obviously improves the dissolution effect rapidly and improves its stability at the same time.

Description

A kind of domperidone maleate tablet and preparation technology thereof

technical field

The invention belongs to the field of pharmaceutical preparations, in particular to a domperidone maleate tablet and a preparation process thereof.

Background technique

Domperidone is a drug for digestive system diseases developed by the Belgian Janssen Pharmaceutical Company. This product is a peripheral dopamine receptor antagonist with strong effect, acts directly on the gastrointestinal wall, can moderately increase the tension of the lower esophageal sphincter, prevent gastro-esophageal reflux, regulate and restore the movement of the upper part of the gastrointestinal tract; Suppresses nausea, vomiting. Does not affect gastric acid secretion. Absorbed rapidly after oral administration.

According to literature reports, domperidone is not only used for chronic gastritis, atrophic gastritis, biliary reflux meteor gastritis and reflux esophagitis for indigestion, nausea, vomiting, stomach burning sensation; it is also used for functional, infectious, dietary And drug-induced nausea and vomiting.

At present, domperidone has common tablets and suspensions, but these preparations have defects in varying degrees. The common tablets are not convenient enough to take, and the suspensions will be precipitated when stored for a long time, which will affect the absorption of the medicine. Due to the above dosage forms There are above obvious deficiencies, and there is an urgent need to develop new oral preparations with better effects.

CN 1850079A discloses a preparation method of domperidone maleate, but the method mainly provides bioavailability by micronizing raw materials, and unconventional equipment must be used to realize micronization, which increases production costs.

Contents of the invention

The technical problem to be solved by the present invention is to provide a domperidone maleate tablet that not only has a simple prescription process, but also can further improve disintegration and stability.

The domperidone maleate tablet provided by the invention consists of active ingredient domperidone maleate, a diluent selected from microcrystalline cellulose and starch, a disintegrant selected from sodium carboxymethyl starch, a binder selected from povidone A glidant selected from silicon dioxide and magnesium stearate selected from lubricants, wherein domperidone maleate, microcrystalline cellulose, starch, sodium carboxymethyl starch, povidone, silicon dioxide, The weight ratio of magnesium stearate is: 13:35～45:25～35:5～15:3-7:0.5～1.5:0.2～0.8, and the preferred weight ratio is 13:40:30:10:4.6: 1:0.25, 13:35:35:5:7:0.5:0.213:45:25:15:3:1.5:0.8.

The present invention provides a kind of preparation method of described domperidone maleate tablet in addition, it is characterized in that after the microcrystalline cellulose of formula quantity, starch, the carboxymethyl starch sodium of half amount are mixed, with the pure povidone The aqueous solution is used as a binder for granulation; then it is mixed with the prescribed amount of silicon dioxide, magnesium stearate and half of the prescribed amount of sodium carboxymethyl starch, and then compressed into tablets.

Specifically speaking, it is prepared by the following method: first pass domperidone maleate and all auxiliary materials through a 100 mesh sieve for subsequent use; Mesh sieve and the main ingredient are mixed evenly, and the pure aqueous solution of povidone is used as a binder to make a soft material, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated at 16 mesh; Magnesium fatty acid is mixed with sodium carboxymethyl starch which is half of the prescribed amount, and then compressed into tablets.

The concentration of the pure aqueous solution of povidone of the present invention is 8%～14%, preferably 9%, 10.7%, 13% based on the chemical properties of high humidity stability of domperidone maleate and other auxiliary materials and the poor physical properties of fluidity. Considering the nature, the present inventor screened out the prescription of the present invention, and the consumption selection of adjuvant is based on the consideration of the effect of each adjuvant in the prescription, the mechanism of action and other parameters of the tablet, and the preparation process is carried out by conventional tablet technology means. The test prescription composition and results are shown in Table 1:

Table 1 Results of domperidone maleate tablet prescription screening test

Results: Prescription 1 adopts the direct compression method, the result is that the powder is loose and has poor fluidity, and the material cannot flow down from the feeding hopper during the tableting process; Prescription 2 adopts wet granulation, using starch slurry as the binder, and it is found that during the tableting process, the material is not discharged Uneven and too much accumulation on the tablet press; prescription 3 is the same as prescription 2 except that the binder concentration is increased from 5mg/tablet to 10mg/tablet. The granule formation is better than prescription 2, but it is still too soft The fluidity of the tablet is good, but it is found that there is sticking and punching during the tableting process; prescription 4 uses povidone as the binder, and the granules are well formed. There is no problem in the feeding and tableting process, and all parameters meet the regulations. It can be seen that the use of pure aqueous solution of povidone as a binder instead of pure water as a binder is crucial to the granulation effect. In addition, adding a certain amount of sodium starch glycolate after granulation has a good effect on the disintegration effect of the tablet.

The domperidone maleate tablet prepared by the invention obviously improves the dissolution effect and improves its stability, and provides patients with the domperidone maleate tablet with superior quality and suitable for industrial production.

specific embodiment

The following examples are intended to illustrate certain preferred embodiments of the present invention and are not intended to limit the scope of the present invention.

Reference example 1

Preparation Process

Pass domperidone maleate and all auxiliary materials through a 100-mesh sieve, and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, sodium carboxymethyl starch, pass through a 80-mesh sieve and mix with the main ingredient, and add povidone K30 The pure aqueous solution made of 38ml of pure water is a binder soft material, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated at 16 mesh; Slice and serve.

Reference example 2

Preparation Process

Pass domperidone maleate and all auxiliary materials through a 100-mesh sieve respectively, and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, and half of the sodium carboxymethyl starch, pass through a 80-mesh sieve and mix with the main ingredient, and use polyvinyl chloride The pure aqueous solution prepared by adding 38ml of pure water to ketone K30 is a soft material made of adhesive, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated with a 16-mesh; weigh the prescribed amount of silicon dioxide, magnesium stearate and Half of the prescription amount of sodium carboxymethyl starch is blended and compressed into tablets.

Example 1

Preparation Process

Pass domperidone maleate and all auxiliary materials through a 100-mesh sieve respectively, and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, and half of the sodium carboxymethyl starch, pass through a 80-mesh sieve and mix with the main ingredient, and use polyvinyl chloride The pure aqueous solution prepared by adding 38ml of pure water to ketone K30 is a soft material made of adhesive, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated with a 16-mesh; weigh the prescribed amount of silicon dioxide, magnesium stearate and Half of the prescription amount of sodium carboxymethyl starch is blended and compressed into tablets.

Example 2

Preparation Process

Pass domperidone maleate and all auxiliary materials through a 100-mesh sieve respectively, and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, and half of the sodium carboxymethyl starch, pass through a 80-mesh sieve and mix with the main ingredient, and use polyvinyl chloride The pure aqueous solution prepared by adding 71ml of pure water to ketone K30 is a soft material made of adhesive, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated with a 16-mesh; weigh the prescribed amount of silica, magnesium stearate and The sodium carboxymethyl starch remaining in the prescription is blended and compressed into tablets.

Example 3

Preparation Process

Pass domperidone maleate and all auxiliary materials through a 100-mesh sieve respectively, and set aside; weigh the prescribed amount of microcrystalline cellulose, starch, and half of the sodium carboxymethyl starch, pass through a 80-mesh sieve and mix with the main ingredient, and use polyvinyl chloride The pure aqueous solution prepared by adding 20ml of pure water to ketone K30 is a soft material made of adhesive, granulated with a 16-mesh sieve, dried at 65°C for 1 hour, and granulated with a 16-mesh; weigh the prescribed amount of silicon dioxide, magnesium stearate and The sodium carboxymethyl starch remaining in the prescription is blended and compressed into tablets.

Embodiment 4 Dissolution test

With reference example 1, embodiment 1, the sample of embodiment 2, adopt pH1.2 hydrochloric acid solution 500ml to be dissolution medium, take samples at 5, 10, 15, 30, 45min, use ultraviolet spectrophotometer to measure dissolution rate, the result is as follows :

Embodiment 5 Stability experiment

Chromatographic conditions and system suitability test solution Use octadecylsilane bonded silica gel as filler, methanol-0.05% ammonium acetate (60:40) as mobile phase, detection wavelength at 285nm, column temperature at 30°C. Number of theoretical plates According to the peak of domperidone, it should not be less than 3000.

Take an appropriate amount of this product (approximately equivalent to 25mg of domperidone), put it in a 50ml measuring bottle, add 25ml of mobile phase to dissolve it, and then constant volume is the test solution; accurately measure 1ml of the test solution and dilute it to 100ml. Reference substance solution. Take 20 μl of the reference substance solution and inject it into the liquid chromatograph, adjust the detection sensitivity so that the peak height of the main component chromatographic peak is about 20% of the full scale; in addition, accurately measure 20 μl of each of the test substance and the reference substance solution, and inject them into the liquid chromatograph respectively. Instrument, record the chromatogram to 2 times the retention time of the main component chromatographic peak. If there are impurity peaks in the chromatographic peak of the test solution, the sum of the peak areas of each impurity shall not be greater than the main peak area of the control solution (1.0%).

The samples of Reference Example 1, Example 1, and Example 2 were placed at 40°C and 75% for 6 months, and samples were taken in January, February, March, and June to determine related substances.

Example 6 Bioequivalence Test of Domperidone Maleate Tablets

1. Drugs and reagents

Domperidone maleate tablets (specification 10 mg, obtained by coating the plain tablets prepared in Example 1) were provided by Nanjing Changao Pharmaceutical Co., Ltd. Domperidone tablets (10 mg, domperidone), commercially available, produced by Xi'an Janssen Pharmaceutical Co., Ltd., and other reagents used are domestic AR grade reagents.

2. Selection of volunteer subjects

Choose healthy men, 18-40 years old, and the age difference should not be 10 years old. The weight should be similar, and the unit of weight is in kilograms (kg). Good health, no heart, liver, kidney, digestive tract, metabolic abnormalities, nervous system diseases and other diseases, and a physical examination should be normal. No history of allergies, no history of orthostatic hypotension. No other drugs were taken two weeks ago to the test period, and smoking, alcohol and caffeinated beverages were prohibited during the test period. The number of subjects was 20 cases.

3. Drug administration design

The experiment adopted a two-period, two-drug crossover design to offset the influence of the test period and individual differences on the test results. 20 healthy volunteers were divided into 2 groups, 10 in each group. After fasting for 10 hours, one group took 1 tablet of domperidone orally in the morning on an empty stomach, and the other group took 1 tablet of domperidone maleate at the same time, and delivered it with 250ml of warm water. Clothes. You can drink water 2 hours after taking the medicine, and eat a unified standard meal 4 hours later. Take blank blood before taking medicine in each group, take 3.0ml of venous blood in experimental group and 1, 2, 4, 6, 10, 12, 14, 18, 20, 24, 36 hours after taking medicine, and control group at 1, 2, 36 hours after taking medicine. Take 3.0ml of venous blood at 4, 6, 10, 12, 14, 18, 20, 24, and 36 hours, centrifuge the blood to get serum, and store it in a freezer for future testing.

4. Results

The AUC and Cmax data were subjected to logarithmic transformation analysis of variance and double-sided t-test. Compared with the control group, the AUC of the experimental group was 99.4%, which met the requirements of bioequivalence (89-125%), so the degree of absorption is biologically equivalent. effect.

Claims (10)

1. A domperidone maleate tablet is composed of active ingredient domperidone maleate, a diluent selected from microcrystalline cellulose and starch, a disintegrant selected from sodium carboxymethyl starch, a binding agent selected from povidone A glidant selected from silicon dioxide and magnesium stearate selected from lubricants, wherein domperidone maleate, microcrystalline cellulose, starch, sodium carboxymethyl starch, povidone, silicon dioxide, The weight ratio of magnesium stearate is: 13:35-45: 25-35: 5-15: 3-7: 0.5-1.5: 0.2-0.8. 2. domperidone maleate sheet as claimed in claim 1 is characterized in that the weight of domperidone maleate, microcrystalline cellulose, starch, sodium carboxymethyl starch, povidone, silicon dioxide, magnesium stearate The ratio is: 13:40:30:10:4.6:1:0.25. 3. domperidone maleate sheet as claimed in claim 1 is characterized in that the weight of domperidone maleate, microcrystalline cellulose, starch, sodium carboxymethyl starch, povidone, silicon dioxide, magnesium stearate The ratio is: 13:35:35:5:7:0.5:0.2. 4. domperidone maleate sheet as claimed in claim 1 is characterized in that the weight of domperidone maleate, microcrystalline cellulose, starch, sodium carboxymethyl starch, povidone, silicon dioxide, magnesium stearate The ratio is: 13:45:25:15:3:1.5:0.8. 5. the preparation method of domperidone maleate sheet described in claim 1 is characterized in that after the microcrystalline cellulose of recipe quantity, starch, the carboxymethyl starch sodium of half amount are mixed, with the pure aqueous solution of povidone Granulate for the binder; then mix with the prescribed amount of silicon dioxide, magnesium stearate and half of the prescribed amount of sodium carboxymethyl starch, and tablet it. 6. the preparation method of the described domperidone maleate sheet of claim 5 is characterized in that it is prepared by the following method: first cross 100 mesh sieves respectively with domperidone maleate and all adjuvants, for subsequent use; Take by weighing prescription quantity Microcrystalline cellulose, starch, and half of sodium carboxymethyl starch are passed through a 80-mesh sieve and mixed with the main ingredient, and the pure aqueous solution of povidone is used as a binder to make a soft material, granulated with a 16-mesh sieve, and dried at 65°C for 1 hour, 16 mesh whole grains; weigh the silicon dioxide, magnesium stearate and half of the prescription amount of sodium carboxymethyl starch, mix them, and compress into tablets. 7. the preparation method of the described domperidone maleate sheet of claim 6-7 is characterized in that the pure aqueous solution concentration of described povidone is 8%～14%. 8. the preparation method of the described domperidone maleate sheet of claim 6-7 is characterized in that the pure aqueous solution concentration of described povidone is 9%. 9. the preparation method of the described domperidone maleate sheet of claim 6-7 is characterized in that the pure aqueous solution concentration of described povidone is 10.7%. 10. the preparation method of the described domperidone maleate sheet of claim 6-7 is characterized in that the pure aqueous solution concentration of described povidone is 13%.