CN110585149A - Preparation method and application of hydrotalcite combined medicine tablet - Google Patents

Preparation method and application of hydrotalcite combined medicine tablet Download PDF

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Publication number
CN110585149A
CN110585149A CN201910935830.6A CN201910935830A CN110585149A CN 110585149 A CN110585149 A CN 110585149A CN 201910935830 A CN201910935830 A CN 201910935830A CN 110585149 A CN110585149 A CN 110585149A
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China
Prior art keywords
hydrotalcite
lansoprazole
tablet
auxiliary materials
preparation
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CN201910935830.6A
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Chinese (zh)
Inventor
王腾飞
王祖焕
唐检珍
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CHONGQING JEWELLAND PHARMACEUTICAL DEVELOPMENT Co Ltd
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CHONGQING JEWELLAND PHARMACEUTICAL DEVELOPMENT Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Engineering & Computer Science (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention provides a preparation method and application of a magnesium hydrotalcite combined medicine tablet, and provides a magnesium hydrotalcite lansoprazole compound chewable tablet and a preparation method thereof. The main drugs are hydrotalcite and lansoprazole, and the auxiliary materials are xylitol, microcrystalline cellulose, silicon dioxide, a sweetening agent, a flavoring agent and magnesium stearate. The compound chewable tablet of the hydrotalcite lansoprazole prepared according to the preparation formula and the preparation process provided by the invention has good taste and is very beneficial to patients to take. The hydrotalcite lansoprazole compound chewable tablet obtained by the invention can effectively protect gastric mucosa, improve the healing rate and healing quality of ulcer, and has clinical advantages which are not possessed by hydrotalcite or lansoprazole single preparation.

Description

Preparation method and application of hydrotalcite combined medicine tablet
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a preparation method and application of a magnesium aluminum carbonate combined pharmaceutical tablet.
Background
Lansoprazole is a Proton Pump Inhibitor (PPI), an antacid and an antiulcer agent, and is used for treating gastric ulcer, duodenal ulcer, reflux esophagitis, Zollinger-Ellison syndrome, and anastomotic oral ulcer.
The molecular formula of the aluminum magnesium carbonate (magaldrate) is Al2Mg6(OH)16CO3·4H2O was created by west debark-galotine (Byk-Gulden) in 1960, filed in the same year for united states patent (US Pat 2923660) and marketed in the united states, was filed in 1970 in the united states of america for the national formulary (NF13 edition), was filed in 1975 in the united states pharmacopeia (USP19 edition), and was filed in all of the united states pharmacopeia versions 20, 21, 22, 23. The Brazilian pharmacopoeia is also included. Research on a plurality of experimental ulcer models proves that the hydrotalcite can not only prevent ulcer caused by gastric acid secretion increase (pylorus ligation type) and external acid type stimulant (hydrochloric acid), but also has an inhibiting effect on ulcer formation under the stimulation condition of non-gastric acid secretion (ulcer caused by ASA and ulcer caused by absolute ethyl alcohol), the preliminary pharmacodynamic experimental ulcer model comprises two aspects of strengthening gastric mucosa attacking factors and weakening defense factors, and the hydrotalcite shows obvious efficacy [7 ]]The medicine has the characteristics of rapid, mild and lasting action, high acid reaction and the like, and aluminum and magnesium in the medicine are hardly absorbed, and the concentration of aluminum ions in blood is not obviously increased.
Liao Huaijiao and Liujiankun research of Xuanhan county women health care institute of Sichuan province and Xuanhan county people hospital of Sichuan province proves that the combined use of lansoprazole and hydrotalcite has a clinical treatment effect on gastric ulcer obviously superior to that of lansoprazole alone (43 cases of combined use of lansoprazole and hydrotalcite for treating gastric ulcer are analyzed in clinical treatment effect, clinical medical engineering, No. 11 in 2011); the research on the Lizecheng in the Ringzhou hospital in Fujian province shows that the 1-year recurrence rate of lansoprazole alone after Hp eradication is 24.4%, and the 1-year recurrence rate of the lansoprazole and hydrotalcite combined group is only 3.5%. (long-term efficacy observation of lansoprazole in combination with hydrotalcite for treating peptic ulcer, strait pharmaceutical, stage 7 of 2007); research on the mercy and the perigenic cistanche of the hospital in the university of three gorges shows that the combination of lansoprazole and hydrotalcite for treating reflux esophagitis has quick response, exact recent curative effect and few adverse reactions (observation of curative effect of combination of lansoprazole and hydrotalcite for treating reflux esophagitis, modern medicine and sanitation, 11 th 2007).
In conclusion, various data researches show that the curative effect of the combination of lansoprazole and hydrotalcite on the treatment of peptic ulcer, reflux esophagitis and the like is better than that of using one medicament.
Disclosure of Invention
In order to overcome the defects of the existing preparation in clinical application, the invention aims to provide a hydrotalcite combined medicine tablet and a preparation process thereof.
In the compound chewable tablet containing hydrotalcite and lansoprazole, the specification of hydrotalcite is 500 mg/tablet, and lansoprazole is 30 mg/tablet.
In the compound chewable tablet containing hydrotalcite and lansoprazole, the dosage of auxiliary materials of xylitol is 0.5-1.5% (W/W), the dosage of microcrystalline cellulose is 0.5-1.5% (W/W), the dosage of silicon dioxide is 0.2-3% (W/W), the dosage of sweetening agent is 0.0.5-1.5% (W/W), the dosage of flavoring agent is 0.03-0.1% (W/W), and the dosage of magnesium stearate is 0.5-1.5% (W/W).
In the compound chewable tablet of the magnesium aluminocarbonate lansoprazole, the used sweetening agent is one or more of saccharin sodium, steviosin, sucralose and aspartame; the correctant is one or more of Mentholum, herba Menthae essence, fructus Musae essence, and herba Menthae Rotundifoliae essence.
Another object of the present invention is to provide a method for preparing the above preferred formulation:
1) processing the raw and auxiliary materials into granules or powder with the particle size of less than 200 microns;
2) adding the raw and auxiliary materials into a two-dimensional motion mixer, and mixing for 15-30 minutes to obtain a total mixture;
3) directly tabletting the total mixture to obtain the hydrotalcite combined medicine tablet.
The chewable tablet has simple formula, simplified process, reduced production cost, good taste, and good compliance.
The formula and the preparation process have obvious beneficial effects that: the types and the using amount of auxiliary materials in the formula are less, so that the production cost is reduced; the production process is less, the process is simple, and mass production is facilitated; the chewable tablet has large drug loading and small volume, and is convenient for carrying and transportation; the chewable tablet is a solid preparation, has stable physicochemical properties, and is more beneficial to storage.
Detailed Description
The present invention will be further described with reference to specific examples, but it should not be construed that the scope of the above-described subject matter of the present invention is limited to the examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention. The auxiliary materials in the following examples can be replaced by the same type of pharmaceutically acceptable auxiliary materials, or reduced or increased.
Example 1
Preparation of samples for use:
experimental group 1
1. Prescription:
2. the process comprises the following steps:
(1) the granularity requirement of raw materials and auxiliary materials is as follows: the particle size of the magnesium stearate is less than 180 microns; the granularity of the hydrotalcite, the xylitol, the microcrystalline cellulose, the steviosin and the menthol is less than 250 microns; the granularity of the silicon dioxide is 9-16 nm;
(2) total mixing: adding hydrotalcite, xylitol, microcrystalline cellulose activated lansoprazole mixture, steviosin, menthol and magnesium stearate into a two-dimensional mixer, and mixing for 45 minutes to obtain a total mixture;
(3) and detecting the contents of the magnesium aluminum carbonate and the lansoprazole in the total mixture, and calculating the theoretical tablet weight.
(4) The total blended powder is compressed into tablets according to the theoretical tablet weight, which should be in the range of 95-105% of the theoretical tablet weight.
Experimental group 2
1. Prescription:
2. process step
(1) The granularity requirement of raw materials and auxiliary materials is as follows: the particle size of the magnesium stearate is less than 180 microns; the granularity of the hydrotalcite, the xylitol, the microcrystalline cellulose, the steviosin and the menthol is less than 250 microns; the granularity of the silicon dioxide is 9-16 nm;
(2) total mixing: adding hydrotalcite, xylitol, microcrystalline cellulose activated lansoprazole mixture, steviosin, menthol and magnesium stearate into a two-dimensional mixer, and mixing for 45 minutes to obtain a total mixture;
(3) and detecting the contents of the magnesium aluminum carbonate and the lansoprazole in the total mixture, and calculating the theoretical tablet weight.
(4) The total blended powder is compressed into tablets according to the theoretical tablet weight, which should be in the range of 95-105% of the theoretical tablet weight.
Experimental group 3
The samples prepared in experimental groups 1 and 2 were examined in an accelerated test (conditions: 40 ℃. + -. 2 ℃ and RH 75%. + -. 5%) for 6 months, and the results are shown in the following Table 1:
table 1 accelerated test investigation results of experimental group 1 samples
Table 2 accelerated test investigation results of experimental group 2 samples
The results show that after 6 months of accelerated test investigation, the quality indexes of the samples of the experimental groups 1 and 2 have no obvious change, and the quality of the samples prepared by the formula and the process is stable.
Example 2 Activity Studies of magnesium Aluminocarbonate Lansoprazole Compound tablets
1. The effect investigation of the compound tablet of hydrotalcite and lansoprazole on experimental gastric ulcer is as follows:
referring to the study of the related literature, after peritoneal anesthesia with chloral hydrate, the stomach was removed from the abdominal cavity, and 0.02ml of 99.5% acetic acid was injected to the posterior wall of the antrum of the stomach at the sub-serosal muscularis layer, after the appearance of a translucent white spot of about 3mm in diameter, the stomach was returned to the abdominal cavity. And 3d, selecting 16 rats fasted for 24h after molding, taking out the stomach, cutting the stomach along the greater curvature of the stomach, finding a typical mucosal defect on the posterior wall of the lesser curvature of the stomach, coating whitish fur on the surface, and performing edema on the peripheral mucosa, thereby confirming that the experimental gastric ulcer rat model is successfully established. The remaining 48 successfully molded rats were randomly divided into a blank control group, a hydrotalcite chewable tablet group and a hydrotalcite lansoprazole compound chewable tablet group, each group containing 16 rats. The rats in the blank control group are subjected to intragastric administration of 1ml of physiological saline, and the administration of the hydrotalcite chewable tablet group is equivalent to 615 mg.kg-1·d-1The water suspension of the hydrotalcite chewable tablet (converted into equivalent dose of rats according to clinical dose) is infused into the stomach, and the administration of the hydrotalcite lansoprazole compound chewable tablet group is equivalent to 615 mg.kg-1·d-1The water suspension of the hydrotalcite lansoprazole chewable tablet is used for intragastric administration, and the hydrotalcite lansoprazole (equivalent dosage of rat is converted according to clinical dosage). After treatment for 14d, the rats were anesthetized and examined for ulcer healing. The test results are shown in table 3 below:
TABLE 3 Activity evaluation of magnesium Aluminocarbonate Lansoprazole Compound tablets against Experimental gastric ulcer
Animal experiment results show that the hydrotalcite lansoprazole compound chewable tablet has a very obvious effect of improving rat model gastric ulcer, and is equivalent to a single hydrotalcite chewable tablet.
2. Acidity test of hydrotalcite compound chewable tablet
Simulating the chewing process of a patient when taking the medicine, and processing the experimental sample (example 1 and example 2) into 20-mesh particles as a product to be detected; using rosThe sett rice in vitro acid resistance test method comprises adding 30ml of water and 70ml of 0.1mol.L-1 hydrochloric acid solution into a reaction vessel, controlling the reaction solution at 37 deg.C with a magnetic heating stirrer and a contact thermometer, and magnetically stirring at a stirring speed of 400 r.min-1The pH value change in the reaction container is measured by a pH meter equipped with a glass electrode and a calomel electrode, and the pH value change is measured by a constant flow pump at (2.0 +/-0.1) ml.min-1At a constant temperature of 37 ℃ of 0.1mol. L was pumped into the reaction vessel-1Hydrochloric acid solution. And immediately starting the constant flow pump and the magnetic stirrer after the antacid to be detected is added, and simultaneously recording the time and the pH value. As shown in detail in fig. 4.
TABLE 4 examination of acidity of compound chewable tablets of magnesium Aluminocarbonate and lansoprazole
And (3) test results: the time to reach pH3 for the samples of examples 1 and 2 was close to reaching the favorite, much faster than the domestic hydrotalcite chewable tablet, indicating that the hydrotalcite chewable tablet prepared according to the invention patent had fast disintegration and dispersion speed and fast onset of action.

Claims (7)

1. The hydrotalcite combined medicine tablet is characterized in that: the hydrotalcite combined medicine tablet is prepared from hydrotalcite and lansoprazole, and the auxiliary materials are xylitol, microcrystalline cellulose, silicon dioxide, a sweetening agent, a flavoring agent and magnesium stearate.
2. The hydrotalcite combination pharmaceutical tablet according to claim 1, wherein: the specification of the hydrotalcite is 500 mg/tablet, and the specification of the lansoprazole is 30 mg/tablet.
3. The hydrotalcite combination pharmaceutical tablet according to claim 1, wherein: the weight ratio of other auxiliary materials is as follows: the auxiliary materials comprise 0.5-1.5 parts of xylitol, 0.5-1.5 parts of microcrystalline cellulose, 0.1-3 parts of silicon dioxide, 0.0.5-1.5 parts of sweetening agent, 0.03-0.1 part of flavoring agent and 0.5-1.5 parts of magnesium stearate.
4. The hydrotalcite combination pharmaceutical tablet according to claim 1, wherein: the sweetener is one or more of saccharin sodium, steviosin, sucralose and aspartame.
5. The hydrotalcite combined medicine tablet as claimed in claim 1, wherein the used correctant is one or more of menthol, peppermint essence, banana essence and spearmint essence.
6. The method for preparing the hydrotalcite combined pharmaceutical tablet according to claim 1, wherein the method comprises the following steps: the method comprises the following steps:
1) processing the raw and auxiliary materials into granules or powder with the particle size of less than 200 microns;
2) adding the raw and auxiliary materials into a two-dimensional motion mixer, and mixing for 15-30 minutes to obtain a total mixture;
3) directly tabletting the total mixture to obtain the hydrotalcite combined medicine tablet.
7. Use of the magnesium aluminocarbonate combination pharmaceutical tablet according to any one of claims 1 to 4 in the manufacture of a medicament for the treatment of gastric ulcers.
CN201910935830.6A 2019-09-29 2019-09-29 Preparation method and application of hydrotalcite combined medicine tablet Pending CN110585149A (en)

Priority Applications (1)

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Application Number Priority Date Filing Date Title
CN201910935830.6A CN110585149A (en) 2019-09-29 2019-09-29 Preparation method and application of hydrotalcite combined medicine tablet

Publications (1)

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