CN100340295C - Oral administered compound colloid pectin bismuth preparation and its preparing process - Google Patents
Oral administered compound colloid pectin bismuth preparation and its preparing process Download PDFInfo
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Abstract
The present invention relates to a medical compound for curing peptic ulcer infected by pyloric helicobacter, which is prepared from colloid pectin bismuth, antibiotics and antibacterial agents. The medical compound is prepared by that after being respectively coated, the antibiotics and the micro-pill cores of the antibacterial agents are uniformly mixed with the colloid pectin bismuth and an excipient vehicle whose quantity is medically acceptable. After the oral compound medicine of the colloid pectin bismuth of the present invention is taken, the colloid pectin bismuth can form a film in the stomach in order to protect the gastric mucosa; because enteric dissolving tetracycline can not form a chelate compound in the stomach with the colloid pectin bismuth, therapeutic effects are improved, and toxic and side effects are reduced. The dosage of antibacterial medicine in the oral compound medicine of the colloid pectin bismuth of the present invention is a half of that of antibacterial medicine in a traditional trigeminy therapy method of the colloid pectin bismuth; therefore, the therapeutic effects which are equal to or better than those of the traditional trigeminy therapy method of the colloid pectin bismuth.
Description
Technical field
The present invention relates to a kind of oral administered compound colloid pectin bismuth preparation that is used for the treatment of the peptic ulcer helicobacter pylori infections, specifically related to a kind of oral administered compound colloid pectin bismuth preparation and preparation method of triple therapy of the treatment peptic ulcer helicobacter pylori infections based on colloidal bismmth pectin.
Background technology
Helicobacter pylori (being called for short Hp) is the main cause that causes gastric duodenal ulcer, and 80% gastric ulcer and 90% duodenal ulcer are caused by Hp, and WHO has determined that this bacterium is one of major reason that causes gastric cancer.Surpass 1/3 population in the world and infect this bacterium.Report recently, the infection rate in the population of China is 61%.The gastric duodenal ulcer patient has patient's ulcer recurrence of 40-80% in 1 year approximately behind existing therapy for treating, if but eliminate Hp simultaneously in treatment, 2% recurrence is then only arranged in 1 year.Therefore it is significant to research and develop the therapy that also can eliminate the Hp infection in the treatment gastric duodenal ulcer.
U.S. FDA in 1997 just ratify alkali formula salicylic acid bismuth (BSS, 525mg), tetracycline (500mg) and metronidazole (250mg) triple therapy (4 times/day, 4 weeks) be used to eliminate Hp and infect.And have assembly packaging listing [8], trade name: Helidac, each packing that 14 bubble cards are arranged, be surrounded by alkali formula salicylic acid bismuth sheet (262.4mg) * 8 slice, quadracycline capsule (500mg) * 4 and Metronidazole Tablet (250mg) * 4 slice on every bubble card.
Chinese Medical Association digests disease branch and China in 2003 whole nation Hp infection common recognition meeting is all recommended, adopt the bismuth+tetracycline 500mg+ metronidazole 400mg triple therapy (bid * 2 weeks) of standard dose, be used for the treatment of the gastric duodenal ulcer that infects with Hp, also available tinidazole 500mg replaces metronidazole.
The beam Zhong Hui of No.303 Hospital, P.L.A. etc. comprise that 99 routine peptic ulcer patients the comparative study of being carried out among duodenal ulcer and gastric ulcer and the plyability ulcer patient points out, adopt bismuth pectin 100mg+ tetracycline 500mg+ metronidazole 200mg (tid * 4 weeks) triple therapy therapist, though the endoscopy total effective rate is up to 95.8%, the Hp elimination factor only is 66.7%.
Canadian researcher to 107 routine patients carried out at random, the double blinding clinical trial of placebo points out, (all administration every day is 4 times to adopt oral colloidal bismuth subcitrate potassium 120mg (Colloidal BismuthSubcitrate)+tetracycline 500mg+ metronidazole 500mg, 14 days courses of treatment) therapist, pressing PP analyzes, the elimination factor of Hp is 90% (54/59 example), and relatively placebo group only is 3% (1/35 example).Press ITT and analyze, the Hp elimination factor of treatment group is 82% (53/65 example), and placebo group is 5% (2/34 example).The treatment group has 2 examples (4%), placebo group to have 3 examples (3%) to stop treatment because of adverse events.
Though what above-mentioned bismuth+tetracycline+metronidazole triple therapy comprised that three joint groups close that the packing therapy has infects better curative effect is arranged eliminating Hp, but drug formulation is many, quantity is big, the inconvenience of taking medicine, simultaneously tetracycline, metronidazole dosage are bigger, so untoward reaction rate height, and patient's compliance is poor.After taking said medicine, colloidal bismmth pectin, tetracycline are present in the stomach simultaneously, and colloidal bismmth pectin can form metallo-chelate with tetracycline under one's belt, lessen the curative effect, and metronidazole stimulates stomach.
Summary of the invention
The object of the present invention is to provide a kind of evident in efficacy, dosage is little, taking convenience, toxic and side effects are little, patient's compliance is good, and avoids colloidal bismmth pectin to form the oral administered compound colloid pectin bismuth preparation that is used for the treatment of the peptic ulcer helicobacter pylori infections of chelate and metronidazole stimulation stomach under one's belt with the tetracycline reaction.
Another object of the present invention provides a kind of preparation method of oral administered compound colloid pectin bismuth preparation.
The oral administered compound colloid pectin bismuth preparation that is used for the treatment of the peptic ulcer helicobacter pylori infections of the present invention comprises following components by part by weight:
Colloidal bismmth pectin 5-500 antibiotic 5-1000 antibacterial 5-1000,
Said antibiotic is a tetracycline antibiotics, and antibacterial is metronidazole or tinidazole,
Wherein antibiotic, antibacterial are the coated enteric coated micropill that is prepared from of fine pellet core.
Preferably, comprise following components by part by weight:
Colloidal bismmth pectin 40-200 antibiotic 50-500 antibacterial 50-500;
Said antibiotic is a tetracycline antibiotics, and antibacterial is metronidazole or tinidazole,
Wherein antibiotic, antibacterial are the coated enteric coated micropill that is prepared from of fine pellet core.
The method for preparing above-mentioned oral administered compound colloid pectin bismuth preparation comprises the steps:
Antibiotic, antibacterial and microcrystalline Cellulose are crossed the 80-120 mesh sieve respectively, antibiotic, antibacterial respectively with the microcrystalline Cellulose mix homogeneously, with the hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 35-40 order fine pellet core, 40-60 ℃ dry 2.5-3.5 hour; Add plasticizer with behind the dissolve with ethanol acrylic resin II number, the preparation coating solution; Above-mentioned fine pellet core placed carry out coating in the coating pan, make the enteric coated micropill of antibiotic, antibacterial; Wherein the weight of microcrystalline Cellulose be antibiotic weight 1-2 doubly, the weight of microcrystalline Cellulose be antibacterial weight 1-2 doubly; The weight of hydroxypropyl methylcellulose is 1-2 times of antibiotic weight, and the weight of hydroxypropyl methylcellulose is 1-2 times of antibacterial weight; Plasticizer is a kind of or wherein several mixture in Oleum Ricini, diethyl phthalate, the triethyl citrate; The weight percentage of acrylic resin II number alcoholic solution is 1-10%; The weight of acrylic resin II number alcoholic solution is 5-100 times of antibiotic weight, and the weight of acrylic resin II number alcoholic solution is 5-100 times of antibacterial weight; Said antibiotic is a tetracycline antibiotic, and antibacterial is metronidazole or tinidazole.
Coating preparation condition wherein: engine speed 150-180rpm, whitewashing flow: 15-25rpm, air blast flux: 88-10L/min, jet flow: 6-8L/min, bleed pressure: 0.4-0.7MPa, whiff pressure: 0.3MPa, coating temperature: 29-32 ℃;
The excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, mix homogeneously is made granule, or the excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, granulate, drying makes tablet or incapsulates through compress tablet coating and makes capsule.
After oral administered compound colloid pectin bismuth preparation of the present invention was taken, colloidal bismmth pectin can form a skim under one's belt with the protection gastric mucosa, and the enteric tetracycline can not form chelate under one's belt with colloidal bismmth pectin, has improved curative effect, reduces toxic and side effects.The dosage of the antibacterials in the oral administered compound colloid pectin bismuth preparation of the present invention be in traditional colloidal bismmth pectin triple therapy antibacterials 1/2, can reach or be better than the curative effect of traditional colloidal bismmth pectin triple therapy.
Oral administered compound colloid pectin bismuth preparation mouse stomach of the present invention acute toxicity test
Test objective
Observe single or repeatedly irritate stomach in one day, and calculate its LD to the acute toxicity effect of oral administered compound colloid pectin bismuth preparation of the present invention to mice
50Value or maximum tolerated dose.
Test material
Be subjected to the reagent thing: oral administered compound colloid pectin bismuth preparation of the present invention: colloidal bismmth pectin 0.335g, quadracycline enteric coated micropill 0.125g, metronidazole enteric coated micropill 0.125g.
Oral administered compound colloid pectin bismuth preparation of the present invention is intended clinical people's consumption per day: oral 2/time, 4 times/day, promptly consumption is 6.72g Coming-of-Age Day, presses 60kg people and calculates, and people's consumption is about 0.112g/ (kgd).
Animal subject: healthy adult Kunming mouse, age in days are 45 days, and body weight is 18～20g, and be male female half and half, provided by Mountain Western Medicine S University's animal center, and quality certification book number is the moving word the 070102nd of doctor.Animal feeding condition: 5 in every cage, 21 ± 3 ℃ of room temperatures, relative humidity 30%～70%.The mice fasting be can't help water 12 hours before the gastric infusion.
Test method and result
Preliminary experiment: 20 of mices, male female half and half, with the oral administered compound colloid pectin bismuth preparation of the present invention of 25% (this preparation maximum can be irritated stomach concentration) by 0.5ml/10g (the mice maximum can be irritated the stomach amount) single ig.The result is to be tried mice behind the medicine in 10 days and any toxic reaction all do not occur, none death of duration of test animal.But because of being subjected to drug level and the volumetrical restriction of medication, can not do the dosage that oral administered compound colloid pectin bismuth preparation of the present invention causes dead mouse, can't measure the LD of compound recipe bismuth pectin gastric infusion
50Value.
40 Kunming mouses are divided into A and two dosage groups of B at random, every group of 20 mices, male female half and half, but with gastric infusion 2 and 3 times respectively in the Cmax maximum dosage one day.Each gastric capacity of irritating is every 10g body weight 0.5ml.
A group: gastric infusion 2 times in 5 hours a day at interval, its day, total dosage was 12.5 * 2g/ (kgd);
B group: gastric infusion 3 times in 5 hours a day at interval, its day, total dosage was 12.5 * 3g/ (kgd).
The tight observation 10 behind the medicine.Observation item comprises the character and the color of active situation, the mental status, breathing situation, fur situation, urine and feces, and nose, eye, oral cavity have or not the abnormal secretion thing, has or not intoxicating phenomenons such as calmness, excitement, tic, cyanosis, has or not death.Record is tried feed consumption every day of Mus.
The result is, oral administered compound colloid pectin bismuth preparation of the present invention (25%) with Cmax can be irritated stomach amount (every 10g body weight 0.5mL to mice by maximum, mice single oral administered compound colloid pectin bismuth preparation of the present invention is 12.5g/kg), at interval 5 hours 2 times or 3 gastric infusions in one day after the fasting at night were observed 10 days then continuously.Any abnormal phenomena does not all appear in character and color that each group of duration of test is tried Mus activity, the mental status, breathing situation, fur, urine and feces, and nose, eye, the no abnormal secretions in oral cavity do not have dead the generation.Each group of experiment tried Mus body weight and every day feed consumption there are no significant difference (subordinate list).
Subordinate list. oral administered compound colloid pectin bismuth preparation gastric infusion of the present invention is to the influence of mice body weight and feed consumption
| Dosage g/kg | n | Body weight (g) | Food consumption quantity every day (g//day) | |||||||
| Before the test | The test end | Before the medicine | D1 behind the medicine | d3 | d5 | d7 | d9 | d10 | ||
| 12.5×1 12.5×2 12.5×3 | 20 20 20 | 20.2±1.4 19.8±1.3 21.1±1.5 | 31.1±1.3 32.1±1.6 30.9±1.5 | 2.7 2.5 2.6 | 3.0 2.7 3.1 | 3.0 3.3 3.4 | 3.6 3.2 3.7 | 3.8 3.6 3.9 | 4.1 3.9 4.2 | 4.4 4.2 4.7 |
Oral administered compound colloid pectin bismuth preparation of the present invention (A) and traditional bismuth pectin triple therapy (B) be pharmacodynamic experiment relatively
Wherein:
Oral administered compound colloid pectin bismuth preparation of the present invention (A):
Colloidal bismmth pectin 0.67g, quadracycline enteric coated micropill 0.25g, metronidazole enteric coated micropill 0.25g;
Tradition bismuth pectin triple therapy (B):
Colloidal bismmth pectin 0.67g, gastric solubleness quadracycline 0.5g, gastric solubleness metronidazole 0.5g.
Summary
This paper has observed oral administered compound colloid pectin bismuth preparation of the present invention (A) gastric infusion rats acetic acid has been burnt the antiulcer action of type, pyloric ligation ulcers and indometacin type gastric ulcer model, has observed intravital anti-helicobacter pylori activity by making in the ulcer model precursor inoculation helicobacter pylori simultaneously; This paper has also observed the protective effect of oral administered compound colloid pectin bismuth preparation of the present invention (A) to gastric mucosa damage due to the ethanol, and measures by the blue binding capacity of gastric content A Lisi and to have observed its influence to stomach mucus secretory volume.And oral administered compound colloid pectin bismuth preparation of the present invention (A) and traditional bismuth pectin triple therapy (B) are compared from the pharmacodynamics angle.
The result is that the ulcer surface integration that oral administered compound colloid pectin bismuth preparation of the present invention (A) 0.72 and 1.44g/ (kgd) continuous irrigation stomach made rats acetic acid burn type on the 9th does not reduce 36.6% (P＜0.05) and 60.2% (P＜0.01), and the infection rate of helicobacter pylori is reduced to 50% and 37.5% (P＜0.05) by 100% of model control group respectively.
This experiment prompting, oral administered compound colloid pectin bismuth preparation of the present invention (A) gastric infusion are burnt type, pyloric ligation ulcers and the damage of indometacin type gastric ulcer to rats acetic acid and are had significant protective effect, significantly reduce the helicobacter pylori infections rate simultaneously; To the significant protective effect that has of rat pipe film injury due to the ethanol, significantly increase stomach mucus secretory volume simultaneously.
Experiment purpose
Utilize rats acetic acid to burn the antiulcer action that type, pyloric ligation ulcers and indometacin type gastric ulcer model are observed oral administered compound colloid pectin bismuth preparation of the present invention (A) gastric infusion; The bacteriostasis of oral administered compound colloid pectin bismuth preparation of the present invention (A) to helicobacter pylori in above-mentioned 3 kinds of ulcer model body observed in inoculation in the body; Observe oral administered compound colloid pectin bismuth preparation of the present invention (A) to the protective effect of rat stomach mucosa injury due to the ethanol with to the excretory influence of stomach mucus; Compare from above experimental viewpoint and with traditional bismuth pectin triple therapy (B).
Experiment material
1, helicobacter pylori strain: the NCTC11639 type strain, Epidemiology Organic Inst., China Preventive Medical Academy provides.
2. animal subject:
The Wistar rat, body weight 200～250g is provided by Mountain Western Medicine S University's Experimental Animal Center, and the animal quality certification number is the moving word the 070101st of doctor.
Dosage is provided with and grouping
This experiment all is divided into animal 4-5 group, male and female dual-purpose at random.Matched group: irritate the 0.9% sodium chloride injection 10ml/kg that stomach is given.Oral administered compound colloid pectin bismuth preparation of the present invention (A) or the large and small dosage group of traditional bismuth pectin triple therapy (B): the dosage that mice is adopted is respectively 2.04 and 1.02g/ (kgd); Rat dosage is respectively 1.44 and 0.72g/ (kgd).Mice and rat single are irritated gastric capacity and are 10ml/kg.
Statistical analysis
(x ± s) expression carries out variance analysis relatively with the SPSS statistical software to each group result to experimental result with mean ± standard deviation.Enumeration data adopts x
2Check.
Experimental technique and result
1. pylorus spiral shell stalk bacterium is cultivated and infects qualitative
1.1 cultivation and the animal inoculation of pylorus spiral shell stalk bacterium
Pylorus spiral shell stalk bacteria strain NCTC11639 type strain is adopted in this experiment, is inoculated in the broth bouillon that contains 10% hyclone (80%N in little oxygen environment
2, 15%CO
2, 5%O
2) cultivate about 24h in 37 ℃ shaking water baths, reach 2～4 * 10 until bacterial density
7Bacterium/ml is used for inoculation then immediately.Rat inoculation is adopted and is gavaged the above-mentioned bacterium liquid of 0.5ml/100g, the next day once, continuous 3 times.Last is inoculated back second day, makes the ulcer model respectively.
1.2 helicobacter pylori infections is qualitative
The male standard of helicobacter pylori infections: helicobacter pylori cultivate positive or following 4 in wantonly 2 positives: 1. helicobacter pylori morphology (smear, histological stain or immunohistochemical staining); 2. urease relies on test; 3. serological test (ELISA or western blot test etc.); 4. special PCR detects.Two positives of RUT (rapid urease test) that this test adopts helicobacter pylori wherein to cultivate in the positive or helicobacter pylori morphology (smear, histological stain) and the urease dependence experiment are the diagnosing helicobacter pylori positive criteria.Wherein helicobacter pylori cultivate to adopt the method for Xu along good fortune etc., inoculates on culture medium after promptly directly contacting specimen with inoculating loop.
2. medicine is to anti-helicobacter pylori activity in the antiulcer action of experimental gastric ulcer and the body
2.1 rats acetic acid calcination gastric ulcer model
Inoculated the Wistar rat fasting 24 hours of helicobacter pylori, freely drunk water.Etherization, the sterile working in the positive split shed of xiphoid-process, gently pulls out stomach.Cut an osculum at stomach, on glandular stomach portion antetheca hole body boundary serosal surface, sticking the area that is soaked with glacial acetic acid is 5 * 5mm
2Circular filter paper.Take off filter paper after 90 seconds, sew up stomach, stomach is sent back to gently, sew up abdominal muscle and skin.Postoperative is normally raised, animal random packet and give relative medicine after 2 days, and gastric infusion is 9 continuously.Behind last administration 2h, put to death, cut open the belly, ligation pylorus and cardia.Get gastric content and carry out the helicobacter pylori detection.Get stomach, inject 1% formalin 5ml, stomach is immersed in 1% formalin fixedly 10min from glandular stomach portion.Cut off along greater gastric curvature then, normal saline washes away content, and anatomic microscope is observed the gastric mucosa injury situation and calculated the ulcer area, compares between each group.
The result shows that with the matched group ratio, the gastric ulcer area of the large and small dosage group of oral administered compound colloid pectin bismuth preparation of the present invention (A) has reduced 60.2% (P＜0.01) and 36.6% (P＜0.05) (table 1) respectively.The ulcer surface integration of the large and small dosage group of tradition bismuth pectin triple therapy (B) has not reduced 39.3% (P＜0.01) and 31.7% (P＜0.05).The helicobacter pylori check result shows that each medication therapy groups helicobacter pylori infections rate all decreases.
Table 1 medicine is to the influence of rats acetic acid calcination gastric ulcer and helicobacter pylori infections rate
| Group | Dosage g/ (kgd) | Number of rats (only) | Ulcer area (mm 2) | Ulcer inhibition rate (%) | Helicobacter pylori infections rate (%) |
| Model control group | Deng capacity NS | 8 | 13.64±6.39 | 100 | |
| The A small dose group | 0.72 | 8 | 8.65±4.77* | 36.58 | 50.0* |
| The heavy dose of group of A | 1.44 | 8 | 5.43±5.06** | 60.19 | 37.5* |
| The B small dose group | 0.72 | 8 | 9.32±3.97* | 31.67 | 62.5 |
| The heavy dose of group of B | 1.44 | 8 | 8.28±4.22** | 39.30 | 50.0* |
With model control group ratio, * P＜0.05, * * P＜0.01 (grouping t check, down together).
2.2 rat pylorus ligation gastric ulcer model
The Wistar rat grouping administration of having inoculated helicobacter pylori is seen before and is stated.Behind the continuous irrigation stomach 6 days, fasting 72h (can't help water, not banning drugs) under etherization afterwards, opens the abdominal cavity, the ligation pylorus, and water is prohibited in fasting, and disconnected neck is put to death rat behind the 18h.Get gastric content and carry out the helicobacter pylori detection.Stomach is got in dissection, and formaldehyde fixed is the same, and 10min tailing edge greater gastric curvature is cut off stomach, measures and calculating ulcer area, carries out statistical analysis with its summation as ulcer index.Experimental result shows, heavy dose of group of oral administered compound colloid pectin bismuth preparation of the present invention (A) and small dose group make the gastric ulcer damage index reduce 60.6% (P＜0.01) and 50.8% (P＜0.01) respectively, less 63.0% (P＜0.01) (table 2) of the heavy dose of group of traditional bismuth pectin triple therapy (B).The helicobacter pylori check result shows that each medication therapy groups helicobacter pylori infections rate all significantly reduces.
Table 2 medicine is to the influence of rat pylorus ligation gastric ulcer model and helicobacter pylori infections rate
| Group | Dosage | Number of rats | Ulcer index | Suppression ratio (%) | The helicobacter pylori sense |
| g/(kg·d) | (only) | (mm 2) | Dye rate (%) | ||
| Model control group | NS | 8 | 20.46±8.61 | 87.5 | |
| The A small dose group | 0.72 | 8 | 10.07±5.72** | 50.8 | 50.0 |
| The heavy dose of group of A | 1.44 | 8 | 8.07±4.84** | 60.6 | 37.5 |
| The heavy dose of group of B | 1.44 | 8 | 7.56±8.14** | 63.0 | 37.5 |
With the model control group ratio, * * P＜0.01.
2.3 rat indometacin gastric ulcer model
Table 3 medicine is to the influence of rat indometacin gastric ulcer model and helicobacter pylori infections rate
| Group | Dosage g/ (kgd) | Number of rats (only) | Ulcer index (mm) | Suppression ratio (%) | Helicobacter pylori infections rate (%) |
| Model control group | NS | 8 | 26.71±10.95 | 100 | |
| The A small dose group | 0.72 | 8 | 17.93±9.85* | 32.9 | 62.5 |
| The heavy dose of group of A | 1.44 | 8 | 10.86±8.56** | 59.3 | 50.0* |
| The heavy dose of group of B | 1.44 | 8 | 11.33±7.18** | 57.6 | 50.0* |
With model control group ratio, * P＜0.05, * * P＜0.01.
The Wistar rat grouping administration of having inoculated helicobacter pylori is the same.Behind the continuous irrigation stomach 7 days, fasting 36h (can't help water, not banning drugs), 1h after the last administration, lumbar injection 0.5% indometacin 1ml/100g.Behind the 7h animal is all taken off neck and put to death, cut open the belly immediately, get gastric content and carry out the helicobacter pylori detection.Behind stomach cardia and pylorus ligation, formaldehyde fixed.10min tailing edge greater gastric curvature is cut off stomach, and it is damaged to examine stomach mucosa, and anatomic microscope is measured gastric mucosa injury length (mm) down, carries out statistical analysis with its summation as ulcer index.Experimental result shows that the heavy dose of group of oral administered compound colloid pectin bismuth preparation of the present invention (A) makes ulcer index reduce by 59.3% (P＜0.05), and the energy-stagnation stomachache group makes ulcer index reduce by 57.6% (P＜0.01, table 3).The helicobacter pylori check result shows that each medication therapy groups helicobacter pylori infections rate all significantly reduces.
3. medicine is to the protective effect of rat pipe film injury due to the ethanol
Table 4. medicine is to the effect of gastric mucosa injury due to the ethanol
| Group | Dosage g/ (kgd) | Number of rats (only) | Gastric mucosa damaged area (mm 2) | Damage suppression ratio (%) |
| Model control group | NS | 8 | 87.4±35.2 | |
| The A small dose group | 0.72 | 8 | 56.2±19.0* | 35.7 |
| The heavy dose of group of A | 1.44 | 8 | 42.1±19.0** | 51.8 |
| The B small dose group | 0.72 | 8 | 67.5±19.0* | 22.8 |
| The heavy dose of group of B | 1.44 | 8 | 39.4±19.0** | 54.9 |
With model control group ratio, * P＜0.05, * * P＜0.01.
Wistar rat grouping administration is the same, but rat does not inoculate helicobacter pylori, and 40 rats are divided into 5 groups at random, and fasting 48h freely drinks water, preventative gastric infusion.Continuous use 7 days, 30min behind the last medicine, every animal ig dehydrated alcohol 1ml.Put to death rat behind the 1h, take out stomach, ligation one end injects 2% formaldehyde 2ml, the ligation other end from the other end.30min tailing edge greater gastric curvature is cut off, and drawout with the naked eye observes and measure damaged area (length * wide, mm then in conjunction with anatomic microscope
2).The result shows as extensively coming off of gastric mucosa for dehydrated alcohol causes the rat stomach major injury, and there is the hemorrhage band of a large amount of strips in gastric gland portion.The gastric mucosa injury area of oral administered compound colloid pectin bismuth preparation of the present invention (A) group and traditional bismuth pectin triple therapy (B) group all significantly is lower than model group, oral administered compound colloid pectin bismuth preparation of the present invention (A) and traditional bismuth pectin triple therapy (B) pharmacodynamic result close (table 4).
4. medicine is to the influence of gastric mucus secretion
48 rats are divided into 6 groups at random.Irritate stomach and give oral administered compound colloid pectin bismuth preparation of the present invention (A) or traditional bismuth pectin triple therapy (B) or normal saline, continuous 10d, sooner or later each was once irritated for the last time and irritated stomach respectively behind the stomach 30min and give saline (blank group) or dehydrated alcohol (each group beyond the blank group) every day.Put to death rat behind the 1h and get stomach, ligation one end injects McIlvaine buffer 2ml from the other end to gastric, gently rub jog after, with gastric content thoroughly to going into 10ml in vitro.Handling rat stomach as stated above then.In vitro add the blue 0.4ml of 1% A Lisi to what contain gastric content, add the McIlvaine buffer again to 10ml.Above-mentioned test tube is placed on 20 ℃ of water-baths 24 hours, centrifugal 3000r/min 15min, get supernatant with 752 spectrophotometers in the 615nm colorimetric.With the rat stomach content in conjunction with mucus amount in the amount of the A Lisi indigo plant reflection rat stomach.Table 5 is the result show, oral administered compound colloid pectin bismuth preparation of the present invention (A) and traditional bismuth pectin triple therapy (B) continuous irrigation stomach 10 days, and the blue binding capacity of the A Lisi that gastric is held all significantly increases, and the gastric mucosa injury area due to the ethanol is significantly reduced.In addition, ethanol significantly increases the blue binding capacity of A Lisi of gastric appearance.
Experiment conclusion
Oral administered compound colloid pectin bismuth preparation of the present invention (A) gastric infusion burns type, pyloric ligation ulcers and the damage of indometacin type gastric ulcer to rats acetic acid and has significant protective effect, significantly reduces the helicobacter pylori infections rate simultaneously; The significant protective effect that has to rat pipe film injury due to the ethanol; The gastric mucus secretion experimental result shows that the blue binding capacity of the A Lisi that oral administered compound colloid pectin bismuth preparation of the present invention (A) holds gastric all significantly increases, and the gastric mucosa injury area due to the ethanol is significantly reduced.The comparative pharmacology result of study shows that the stomach protective effect of oral administered compound colloid pectin bismuth preparation of the present invention (A) is close with traditional bismuth pectin triple therapy (B) action intensity, or is better than traditional bismuth pectin triple therapy (B).In addition, the stomach protective effect of this experiment prompting oral administered compound colloid pectin bismuth preparation of the present invention (A) may and promote that gastric mucosa secretion stomach mucus is relevant with the inhibition helicobacter pylori.
The specific embodiment
Embodiment
Embodiment 1
Colloidal bismmth pectin 5g, tetracycline 1000g, metronidazole 500g;
Tetracycline, metronidazole and microcrystalline Cellulose 1500g are crossed 80 mesh sieves respectively, tetracycline and 1000g microcrystalline Cellulose, metronidazole and 500g microcrystalline Cellulose mix homogeneously, the former adds the 1000g hydroxypropyl methylcellulose is binding agent, it is binding agent that the latter adds the 500g hydroxypropyl methylcellulose, adopt centrifugal granulator to prepare 40 order fine pellet cores respectively, 50 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds Oleum Ricini, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make tetracycline, metronidazole micropill; The weight of acrylic resin II number alcoholic solution is 100 times of tetracycline weight, and the weight of acrylic resin II number alcoholic solution is 50 times of metronidazole weight;
The excipient starch of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, mix homogeneously is made granule.
Coating preparation condition wherein: engine speed 150rpm, whitewashing flow: 25rpm, air blast flux: 10L/min, jet flow: 7L/min bleed pressure: 0.7MPa, whiff pressure: 0.3MPa, coating temperature: 32 ℃.
Embodiment 2
Colloidal bismmth pectin 335g, tetracycline 125g, metronidazole 125g;
Its preparation method is with embodiment 1, wherein tetracycline and 200g microcrystalline Cellulose, and metronidazole and 250g microcrystalline Cellulose mix homogeneously, the former adds the 150g hydroxypropyl methylcellulose is binding agent, it is binding agent that the latter adds the 150g hydroxypropyl methylcellulose.
The excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount is granulated, and drying makes tablet through compress tablet coating.
Embodiment 3
Colloidal bismmth pectin 40g, amoxicillin 5g, tinidazole 1000g;
Preparation method is with embodiment 1, wherein: amoxicillin, tinidazole and microcrystalline Cellulose 1510g cross 120 mesh sieves respectively, amoxicillin and 10g microcrystalline Cellulose, tinidazole and 1500g microcrystalline Cellulose mix homogeneously, the former adds the 5g hydroxypropyl methylcellulose is binding agent, and it is binding agent that the latter adds the 1500g hydroxypropyl methylcellulose.The weight of acrylic resin II number alcoholic solution is 50 times of amoxicillin weight, and the weight of acrylic resin II number alcoholic solution is 5 times of tinidazole weight;
The excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount is granulated, and drying incapsulates and makes capsule.
Embodiment 4
Colloidal bismmth pectin 500g, clarithromycin 500g, tinidazole 750g;
Clarithromycin, tinidazole and microcrystalline Cellulose 1500g are crossed 90 mesh sieves respectively, clarithromycin and 350g microcrystalline Cellulose, tinidazole and 1150g microcrystalline Cellulose mix homogeneously, the former adds the 300g hydroxypropyl methylcellulose is binding agent, it is binding agent that the latter adds the 1000g hydroxypropyl methylcellulose, adopt centrifugal granulator to prepare 39 order fine pellet cores respectively, 40 ℃ of dryings 3.5 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 5% with behind the dissolve with ethanol, adds the mixture of Oleum Ricini, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make clarithromycin, tinidazole micropill; The weight of acrylic resin II number alcoholic solution is 5 times of clarithromycin weight, and the weight of acrylic resin II number alcoholic solution is 80 times of first tinidazole weight;
The excipient starch of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, mix homogeneously is made granule.
Coating preparation condition wherein: engine speed 170rpm, whitewashing flow: 22rpm, air blast flux: 60L/min, jet flow: 6L/min bleed pressure: 0.5MPa, whiff pressure: 0.3MPa, coating temperature: 29 ℃.
Embodiment 5
Colloidal bismmth pectin 200g, clarithromycin 50g, metronidazole 200g;
Preparation method is with embodiment 4, wherein clarithromycin, metronidazole and microcrystalline Cellulose 400g cross 100 mesh sieves respectively, clarithromycin and 100g microcrystalline Cellulose, metronidazole and 300g microcrystalline Cellulose mix homogeneously, the former adds the 80g hydroxypropyl methylcellulose is binding agent, and it is binding agent that the latter adds the 400g hydroxypropyl methylcellulose.The weight of acrylic resin II number alcoholic solution is 30 times of clarithromycin weight, and the weight of acrylic resin II number alcoholic solution is 70 times of metronidazole weight.
Coating preparation condition wherein: engine speed 180rpm, whitewashing flow: 15rpm, air blast flux: 88L/min, jet flow: 8L/min bleed pressure: 0.4MPa, whiff pressure: 0.3MPa, coating temperature: 30 ℃.
Embodiment 6
Colloidal bismmth pectin 10g, clavulanate potassium 125g, amoxicillin 800g, metronidazole 50g;
With clavulanate potassium, the amoxicillin, metronidazole and microcrystalline Cellulose 2000g cross 110 mesh sieves respectively, clavulanate potassium and 200g microcrystalline Cellulose, amoxicillin and 1300g microcrystalline Cellulose, metronidazole and 500g microcrystalline Cellulose mix homogeneously, adding the 200g hydroxypropyl methylcellulose in clavulanate potassium and the 200g microcrystalline cellulose mixt is binding agent, adding the 1500g hydroxypropyl methylcellulose in amoxicillin and the 1300g microcrystalline cellulose mixt is binding agent, adding the 700g hydroxypropyl methylcellulose in metronidazole and the 500g microcrystalline cellulose mixt is binding agent, adopt centrifugal granulator to prepare 35 order fine pellet cores respectively, 55 ℃ of dryings 2.5 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 1% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make clavulanate potassium, amoxicillin micropill, the metronidazole micropill; The weight of acrylic resin II number alcoholic solution is that the weight of the alcoholic solution of 5 times of clavulanate potassium weight, acrylic resin II number is 5 times of amoxicillin total amount, and the weight of acrylic resin II number alcoholic solution is 100 times of metronidazole weight;
The excipient dextrin of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, mix homogeneously is made granule.
Coating preparation condition wherein: engine speed 160rpm, whitewashing flow: 18rpm, air blast flux: 40L/min, jet flow: 8L/min bleed pressure: 0.6MPa, whiff pressure: 0.3MPa, coating temperature: 29 ℃.
Embodiment 7
Colloidal bismmth pectin 200g, amoxicillin 50g, furazolidone 100g;
Amoxicillin and microcrystalline Cellulose 100g are crossed behind 110 mesh sieves and the 80g microcrystalline Cellulose, and adding the 50g hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 38 order fine pellet cores, 55 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make the amoxicillin micropill; The weight of acrylic resin II number alcoholic solution is 50 times of amoxicillin total amount, and the weight of acrylic resin II number alcoholic solution is 30 times of amoxicillin weight;
The excipient dextrin of above-mentioned micropill and colloidal bismmth pectin, furazolidone and medically acceptable amount, mix homogeneously is made granule.
Coating preparation condition wherein: engine speed 160rpm, whitewashing flow: 18rpm, air blast flux: 60L/min, jet flow: 8L/min bleed pressure: 0.6MPa, whiff pressure: 0.3MPa, coating temperature: 29 ℃.
Embodiment 8
Colloidal bismmth pectin 100g, tetracycline 250g, furazolidone 500g;
Tetracycline and microcrystalline Cellulose 100g are crossed behind 110 mesh sieves and the 80g microcrystalline Cellulose, and adding the 50g hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 38 order fine pellet cores, 55 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make the tetracycline micropill; The weight of acrylic resin II number alcoholic solution is 50 times of tetracycline weight;
The excipient of above-mentioned micropill and colloidal bismmth pectin, furazolidone and medically acceptable amount is granulated, and drying makes tablet through compress tablet coating.
Embodiment 9
Colloidal bismmth pectin 40g, clarithromycin 500g, furazolidone 50g;
Clarithromycin and microcrystalline Cellulose 1000g are crossed behind 110 mesh sieves and the 80g microcrystalline Cellulose, and adding the 800g hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 38 order fine pellet cores, 55 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make the tetracycline micropill; The weight of acrylic resin II number alcoholic solution is 100 times of tetracycline weight;
The excipient of above-mentioned micropill and colloidal bismmth pectin, furazolidone and medically acceptable amount is granulated, and drying makes tablet through compress tablet coating.
The excipient of above-mentioned micropill and colloidal bismmth pectin, furazolidone and medically acceptable amount is granulated, and drying incapsulates and makes capsule.
Embodiment 10
Colloidal bismmth pectin 40g, gentamycin 500g, metronidazole 50g;
Metronidazole and microcrystalline Cellulose 100g are crossed behind 110 mesh sieves and the 80g microcrystalline Cellulose, and adding the 80g hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 38 order fine pellet cores, 55 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make the tetracycline micropill; The weight of acrylic resin II number alcoholic solution is 100 times of metronidazole weight;
The excipient of above-mentioned micropill and colloidal bismmth pectin, gentamycin and medically acceptable amount is granulated, and drying makes tablet through compress tablet coating.
Embodiment 11
Colloidal bismmth pectin 100g, gentamycin 250g, tinidazole 500g;
Tinidazole and microcrystalline Cellulose 1000g are crossed behind 110 mesh sieves and the 80g microcrystalline Cellulose, and adding the 800g hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 38 order fine pellet cores, 55 ℃ of dryings 3 hours; Acrylic resin II number the weight percentage of acrylic resin II number alcoholic solution is 10% with behind the dissolve with ethanol, adds the mixture of diethyl phthalate, triethyl citrate, the preparation coating solution; Above-mentioned fine pellet core placed respectively carry out coating in the coating pan, make the tetracycline micropill; The weight of acrylic resin II number alcoholic solution is 100 times of tinidazole weight;
The excipient of above-mentioned micropill and colloidal bismmth pectin, furazolidone and medically acceptable amount is granulated, and drying incapsulates and makes capsule.
Embodiment 12
Colloidal bismmth pectin 200g, gentamycin 50g, tinidazole 300g;
Wherein the preparation method of tinidazole enteric coated micropill is with embodiment 11, with the proportionate relationship of other raw materials with embodiment 11.
The excipient of above-mentioned micropill and colloidal bismmth pectin, gentamycin and medically acceptable amount, mix homogeneously is made granule
Claims (7)
1, a kind of oral administered compound colloid pectin bismuth preparation that is used for the treatment of the peptic ulcer helicobacter pylori infections is characterized in that comprising following components by part by weight:
Colloidal bismmth pectin 5-500 antibiotic 5-1000 antibacterial 5-1000,
Said antibiotic is a tetracycline antibiotics, and said antibacterial is metronidazole or tinidazole, and wherein antibiotic, antibacterial are the coated enteric coated micropill that is prepared from of fine pellet core.
2,, it is characterized in that comprising following components by part by weight according to the oral administered compound colloid pectin bismuth preparation of claim 1:
Colloidal bismmth pectin 40-200 antibiotic 50-500 antibacterial 50-500.
3,, it is characterized in that described tetracycline antibiotics is: tetracycline according to arbitrary oral administered compound colloid pectin bismuth preparation of claim 1 or 2.
4,, it is characterized in that described tetracycline is an enteric coated micropill according to the oral administered compound colloid pectin bismuth preparation of claim 3.
5,, it is characterized in that described metronidazole or tinidazole are enteric coated micropill according to arbitrary oral administered compound colloid pectin bismuth preparation of claim 1 or 2.
6, be a kind of preparation in capsule, tablet and the granule according to arbitrary oral administered compound colloid pectin bismuth preparation of claim 1 or 2.
7, the preparation method of a kind of claim 1 or 2 oral administered compound colloid pectin bismuth preparation comprises the steps:
Antibiotic, antibacterial and microcrystalline Cellulose are crossed the 80-120 mesh sieve respectively, antibiotic, antibacterial respectively with the microcrystalline Cellulose mix homogeneously, with the hydroxypropyl methylcellulose is binding agent, adopts centrifugal granulator to prepare 35-40 order fine pellet core, 40-60 ℃ dry 2.5-3.5 hour; Add plasticizer with behind the dissolve with ethanol acrylic resin II number, the preparation coating solution; Above-mentioned fine pellet core placed carry out coating in the coating pan, make antibiotic enteric coated micropill, antibacterial enteric coated micropill;
The excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, mix homogeneously is made granule, or the excipient of above-mentioned micropill and colloidal bismmth pectin and medically acceptable amount, granulate, drying makes tablet or incapsulates through compress tablet coating and makes capsule;
Wherein antibiotic is a tetracycline antibiotics, and antibacterial is metronidazole or tinidazole.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN101607086B (en) * | 2009-07-21 | 2011-11-02 | 山西安特生物制药股份有限公司 | Compound bismuth composition and preparation method thereof |
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| CZ302789B6 (en) | 2009-11-25 | 2011-11-09 | Zentiva, K. S. | Method of increasing solubility of pharmaceutically active compounds and targeted (controlled) transport thereof into intestine |
| CN103156880B (en) * | 2013-03-21 | 2014-08-20 | 青岛正大海尔制药有限公司 | Pharmaceutical composite containing colloidal bismuth pectin |
| CN103142637A (en) * | 2013-03-21 | 2013-06-12 | 青岛正大海尔制药有限公司 | Capsule containing colloidal bismuth pectin |
| CN104606208B (en) * | 2015-02-02 | 2017-08-15 | 长春海悦药业股份有限公司 | A kind of pharmaceutical composition containing CBS |
| CN104825419B (en) * | 2015-05-27 | 2017-11-21 | 浙江得恩德制药股份有限公司 | A kind of agent of low hygroscopicity Couoidal bismuth pectin capsules agent and its preparation technology |
| CN105833153A (en) * | 2016-05-27 | 2016-08-10 | 郑州思辩科技有限公司 | Colloidal bismuth pectin capsule containing galangal extract and preparation method of colloidal bismuth pectin capsule |
| CN105769982A (en) * | 2016-05-27 | 2016-07-20 | 郑州思辩科技有限公司 | Colloidal pectin bismuth capsule and preparation method thereof |
| CN105920195A (en) * | 2016-05-27 | 2016-09-07 | 郑州思辩科技有限公司 | Sucralfate-colloidal bismuth pectin compound pharmaceutical tablets and preparation method thereof |
| CN105998050A (en) * | 2016-05-27 | 2016-10-12 | 郑州思辩科技有限公司 | Traditional Chinese medicinal compound colloidal bismuth pectin capsule for treating peptic ulcer and preparation method thereof |
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