CN108727312A - The new indication of ranitidine oral preparation for treating erosive esophagitis - Google Patents

The new indication of ranitidine oral preparation for treating erosive esophagitis Download PDF

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Publication number
CN108727312A
CN108727312A CN201810877470.4A CN201810877470A CN108727312A CN 108727312 A CN108727312 A CN 108727312A CN 201810877470 A CN201810877470 A CN 201810877470A CN 108727312 A CN108727312 A CN 108727312A
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Prior art keywords
ranitidine
preparation
weight
agent
parts
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CN201810877470.4A
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CN108727312B (en
Inventor
上官日红
戴浙敏
陆成
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Shanghai Jincheng Suzhi Pharmaceutical Co.,Ltd.
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Jinhua Dry Medical Information Consulting Partnership (limited Partnership)
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/52—Radicals substituted by nitrogen atoms not forming part of a nitro radical
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
    • 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
    • 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

Abstract

The invention discloses a kind of ranitidine and preparation method thereof and a kind of ranitidine formulation, compound preparations and preparation method thereof.Wherein, the impurity content of ranitidine is low, and stability is high, and preparation method is simple；The bioavilability of ranitidine formulation and compound preparation prepared therefrom and safety are higher.Ranitidine, ranitidine formulation and compound preparation provided by the invention can be treated effectively and maintaining treatment erosive esophagitis.

Description

The new indication of ranitidine oral preparation for treating erosive esophagitis
Technical field
The invention belongs to field of medicaments, and in particular to ranitidine, ranitidine formulation, preparation method and its usage.
Background technology
Ranitidine also known as ranitidine, entitled N'- methyl-N- [2- [[[5- [(dimethylamino) the methyl] -2- furans of chemistry Mutter base] methyl] thio] ethyl] -2- nitro -1,1- ethylene diamine hydrochlorides, it is a kind of potent histamine H2 receptor antagonist.Energy Caused gastric acid secretion after histamine, pentagastrin and carbaminoylcholine stimulation is effectively inhibited, hydrochloric acid in gastric juice and gastric activity are reduced, It is mainly used for hyperhydrochloria, heartburn treatment, the potency of gastric acid secretion inhibiting is 5~12 times of Cimetidine by mol.
With the development of society, the accelerating rhythm of life, part population because of unsound life style (such as：It stays up late, mood It is nervous, smoke, drink) cause gastrointestinal disease breaking-out frequent, incidence accounts for about the 10~20% of population, in addition have by Year raised trend.Ranitidine is widely popularized and is used in gastrointestinal disease crowd, and presently commercially available ranitidine is mostly piece Agent or capsule.
Erosive esophagitis (erosive esophagitis, EE) is one kind of gastroesophageal reflux disease, is referred to visible under scope Oesophagus distal section mucous membrane is damaged.Erosive esophagitis can merge lemostenosis, ulcer and hemorrhage of digestive tract, and it is strong to seriously endanger human body Health.Currently, there is no the drug of effectively treatment erosive esophagitis.
In addition, pointed out according to correlative study, ranitidine does not show the effect of patients of some gastrointestinal tract mucosa badly brokens It writes, bioavilability is relatively low, needs longer treatment cycle, and is easy to cause other complication over the course for the treatment of, such as：It can hold It is continuous to reduce gastric acidity, cause bacterium to be bred in gastrointestinal tract, it is nitrite that can also make the nitrate reduction in food, is formed N- nitroso compounds influence the health of patient；The absorption that vitamin B12 can also be reduced generates some vitamin B12s and lacks Illness caused by weary, such as digestive tract ulcer, mucous membrane indolence.
Therefore, at present urgent need to resolve the problem of be to provide a kind of bioavilability and thunder safe, that therapeutic effect is good Buddhist nun replaces fourth preparation, and preparation method is simply controllable.
Invention content
In order to overcome the above problem, present inventor has performed sharp studies, as a result, it has been found that：In ranitidine preparation process In, by shortening the operations such as raw material reaction time, the operation for increasing recrystallization and control reaction solution drop rate, can effectively subtract The content of few related impurities, improves the stability of ranitidine；Preparation is made in ranitidine and is re-dubbed compound preparation simultaneously, Bioavilability and the safety that preparation can be effectively improved, are conducive to extend drug treating time, effectively can treat and tie up Treatment erosive esophagitis is held, so as to complete the present invention.
Specifically, of the invention first is designed to provide a kind of ranitidine, and purity is more than 99.0 weight %.
Wherein, in ranitidine,
Impurity AContent is 0.05%~0.3 weight %；
Impurity BContent is 0.02~0.2 weight %.
Wherein, further include impurity C in the ranitidineContent is 0.03%~0.2 weight Measure %.
Second object of the present invention is to provide a kind of preparation method of ranitidine, and the method includes following steps Suddenly：
Step I, by 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- methyl-1s-methyl mercapto - 2- nitroethylenes amine is dissolved in solvent and solution is made respectively, then mixes the two, is heated to certain temperature and is reacted；
After reaction hydrochloric acid is added, then extracted in step II in reaction solution, isolated organic phase and water phase；
Step III, water phase is handled, and ranitidine is prepared.
Third object of the present invention is to provide a kind of ranitidine formulation, and main component is that above-mentioned thunder Buddhist nun replaces Fourth, wherein the dosage form of the ranitidine formulation includes oral preparation and injection, wherein the oral preparation include tablet, Capsule, granule, solution.
Fourth object of the present invention is to provide a kind of ranitidine compound preparation, wherein the compound preparation is by wrapping The raw material for including following weight proportion component is made：
100 parts by weight of ranitidine, 0~60 parts by weight of mucosa protection agent, 0~30 parts by weight of bacteriostatic agent；
Preferably, the compound preparation is made of the raw material including following weight proportion component：
100 parts by weight of ranitidine, 30~50 parts by weight of mucosa protection agent, 15~25 parts by weight of bacteriostatic agent, blocking agent 5~9 parts by weight.
The 5th of the present invention is designed to provide a kind of preparation method of ranitidine compound preparation, the method includes Following steps：
Step 1, ranitidine is prepared into drug containing vegetable pill；
Step 2, above-mentioned drug containing vegetable pill is prepared into pellet, processing is then dried；
Step 3, mucosa protection agent, bacteriostatic agent, blocking agent and additive are mixed, the pellet after being dried with step 2 Mixing, obtains confection；
Step 4, the confection of above-mentioned preparation is dispensed, obtains ranitidine oral preparation.
The 6th of the present invention is designed to provide above-mentioned ranitidine, ranitidine formulation and compound preparation and is preparing medicine Purposes in object, it is preferable that the drug is for treating and maintaining treatment erosive esophagitis.
Advantageous effect possessed by the present invention includes：
(1) ranitidine provided by the invention, impurity content is low, and stability and drug release property are good；
(2) preparation method of ranitidine provided by the invention, step is simple, easy to operate, and the requirement to equipment is low, system The ranitidine purity obtained is high；
(3) ranitidine formulation provided by the invention, stability is high, and bioavilability is high, and drug safety is high；
(4) ranitidine compound preparation provided by the invention, mucosa protection agent, bacteriostatic agent and the blocking agent of addition are day Right substance, Product Safety is high, Small side effects；
(5) ranitidine compound preparation provided by the invention, mucosa protection agent can avoid conventional mucosa protection drug from leading The appearance of the illnesss such as indigestion, the bile regurgitation of cause, and vitamin B12 deficiency caused by taking ranitidine can be reduced and drawn The diseases such as the digestive tract ulcer risen；
(6) ranitidine compound preparation provided by the invention can be protected using natural bacteriostatic agent during Long-term taking medicine Hold the activity of anti-helicobacter pylori；
(7) ranitidine compound preparation provided by the invention, is added to blocking agent, can slow down long-term use ranitidine The symptom that caused internal N- digests increase, to reduce harm of the nitroso compound to human body；
(8) ranitidine provided by the invention, ranitidine formulation and compound preparation, stability is high, drug treating time It is long, it can effectively treat and maintaining treatment erosive esophagitis.
Description of the drawings：
Fig. 1 shows the testing result figure of blood concentration in experimental example 2 of the present invention.
Specific implementation mode
Below by preferred embodiment and embodiment, the present invention is described in more detail.Pass through these explanations, this hair Bright feature and advantage will become more apparent from clear.
Dedicated word " exemplary " means " being used as example, embodiment or illustrative " herein.Here as " exemplary " Illustrated any embodiment should not necessarily be construed as preferred or advantageous over other embodiments.
In a first aspect, the present invention provides a kind of ranitidine, purity is more than 99.0 weight %, wherein in the thunder Buddhist nun replaces in fourth, impurity AIts content is 0.05~0.3 weight %, preferably 0.05~0.2 weight %, more preferably 0.05~0.15 weight %；
Impurity BIts content be 0.02~0.2 weight %, preferably 0.02~ 0.15 weight %, more preferably 0.02~0.10 weight %；With
Impurity CIts content be 0.03~0.2 weight %, preferably 0.03~0.14 weight %, More preferably 0.03~0.12 weight %.
In the present invention, the content of the impurity A, B and C are its percentage relative to ranitidine weight.
Second aspect, the present invention provides a kind of preparation methods of ranitidine, and this approach includes the following steps：
Step I, by 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- methyl-1s-methyl mercapto - 2- nitroethylenes amine is dissolved in solvent and solution is made respectively, and the two is mixed, certain temperature is heated to and is reacted.
According to a kind of and preferred embodiment of the invention, the solvent is organic solvent and/or water.
In further preferred embodiment, the solvent is water, preferably distilled water.
In the present invention, impurity BFor the complete 2- of unreacted [[[5- (two Methylamino) methyl -2- furans] methyl] sulfenyl] ethamine, the present inventor's process is the study found that select distilled water as dissolving raw material Solvent, be conducive to shorten the reaction time, improve yield, so that synthetic reaction is fully carried out, therefore containing for impurity B can be effectively reduced Amount, keeps the color of final product shallower.
According to a kind of preferred embodiment of the present invention, described 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulphur Base] molar ratio of ethylamine solution and N- methyl-1s-methyl mercapto -2- nitroethylene amine aqueous solutions is (1.0~3.0)：1, preferably (1.1~2.5)：1, more preferably (1.2~2.0):1.
In the present invention, impurity CFor the complete N- methyl-1s of unreacted-methyl mercapto -2- nitro second Enamine, the present inventor is by the study found that by 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- first Base -1- methyl mercapto -2- nitroethylene amine is set as (1.0~3.0)：1, preferably (1.1~2.5)：1, more preferably (1.2~ 2.0):1 molar ratio can make raw material reaction abundant, and residue is few, the content of impurity B and impurity C is effectively reduced, to improve The medicine stability for the ranitidine being prepared.
In further preferred embodiment, the 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] Ethylamine solution and N- methyl-1s-methyl mercapto -2- nitroethylenes amine aqueous solution are added dropwise with identical volume and are mixed under stirring.
It is described to be added dropwise as 2- [[[5- (dimethylamino) methyl -2- furans stated in embodiment still more preferably Mutter] methyl] sulfenyl] ethylamine solution is added dropwise in N- methyl-1s-methyl mercapto -2- nitroethylene amine aqueous solutions, and the drop rate is 1.5~4mL/min, the stir speed (S.S.) are 100~250r/min.
The present inventor by the study found that by material solution with drop rate be 1.5~4mL/min, stir speed (S.S.) 100 ~250r/min carries out dropwise addition mixing, can speed up the progress of reaction, improves raw material availability, while can reduce impurity B and C Content.
Preferably, the drop rate is 2.0~3.5mL/min, and the stir speed (S.S.) is 150~200r/min.
It is highly preferred that the drop rate is 2.2~2.6mL/min, the stir speed (S.S.) is 160~190r/min.
According to a kind of preferred embodiment of the present invention, the certain temperature that is heated to is to be heated to 35~50 DEG C, preferably It is 38~47 DEG C, more preferably 40~45 DEG C.
Described to be heated to be slow heating heating in further preferred embodiment, the heating is slowly heating, is risen Warm rate is 1~5 DEG C/min.
In embodiment still more preferably, the heating rate is 2~4 DEG C/min.
In the present invention, impurity ADeduction is because in reaction process Temperature rise is too fast and generates, and therefore, the present invention preferably will heat up rate and be set as 1~5 DEG C/min, preferably 2~4 DEG C/ Min can reduce the content of impurity A, improve the stability of product.
According to a kind of preferred embodiment of the present invention, after being warming up to predetermined temperature, it is 5~8 small to be kept for the reaction time When, preferably 6-7 hours, such as 6.5 hours.
The present inventor passes through the study found that 5~8 hours, preferably 6~7 hours, such as 6.5h will be set as in the reaction time, Be conducive to raw material fully to react, improve conversion ratio, so as to reduce the generation of impurity B.When being less than 5h between when reacted, instead It should be incomplete；Between when reacted be more than 8h when, continue extend the reaction time can be caused in solution due to the unstability of product Oxygenolysis occurs for the portion of product of state, reduces yield, and the content of impurity B can increase.
After reaction hydrochloric acid is added, then extracted in step II in reaction solution, isolated organic phase and water phase.
The present inventor passes through the study found that since ranitidine itself is unstable, easy tos produce oxygenolysis at high temperature, Generate impurity C, therefore, the present invention in preferably using extraction method obtain ranitidine crude product, compared with the existing technology in Vacuum distillation, can improve the stability of product, and the generation of impurity C is advantageously reduced during extraction.
According to a kind of preferred embodiment of the present invention, a concentration of 1~3mol/L that hydrochloric acid is added, preferably 1.5 ~2.5mol/L, more preferably 2mol/L.
In further preferred embodiment, the pH to 3~5 of adjusting reaction solution after addition hydrochloric acid, preferably 3.5~ 4.5。
According to a kind of preferred embodiment of the present invention, the extractant extracted is dichloromethane.
The present inventor is by the study found that use dichloromethane for extractant, after isolated ranitidine more easily It removes, residual is less, makes product purity higher obtained.
In further preferred embodiment, the extractant of the addition and the volume ratio of reaction solution are (10~15)： 9, preferably (11~13)：9.
Step III, handles water phase, and ranitidine is prepared.
In the present invention, the step III includes following sub-step：
Step III-1 adjusts the pH of water phase, is extracted again, isolated organic phase and water phase.
According to a kind of preferred embodiment of the present invention, the pH of water phase is adjusted to alkalinity, preferably to 9~10.
In further preferred embodiment, water phase is adjusted using solution of potassium carbonate, sodium carbonate liquor or phosphoric acid solution PH,
It is preferred that adjusting the pH of water phase using solution of potassium carbonate.
In embodiment still more preferably, the mass fraction of the solution of potassium carbonate is 10~20%, preferably 15%.
According to a kind of preferred embodiment of the present invention, the extractant extracted again is dichloromethane, the extraction The volume ratio of agent and water phase is (3~5)：1, preferably 4:1.
Wherein, organic phase and water phase are obtained after extracting again.
The obtained organic phases of step III-1 are dried, filtered and concentrated, obtain dope by step III-2.
According to a kind of preferred embodiment of the present invention, preferably anhydrous magnesium sulfate and organic phase are sufficiently mixed, to remove Moisture in organic phase.
In the present invention, the organic phase after drying is filtered, then concentrates, obtains faint yellow dope, be ranitidine Crude product.
Step III-3, dope is dissolved, and solid is precipitated in crystallization, through filtering, being dried to obtain ranitidine.
According to a kind of preferred embodiment of the present invention, dope is dissolved using n-hexane and/or ethyl acetate.
In further preferred embodiment, dope is dissolved using the mixture of n-hexane and ethyl acetate.
The present inventor is by the study found that dissolve dope using the mixture of n-hexane and ethyl acetate, being conducive to The precipitation of ranitidine crystal.
In embodiment still more preferably, the volume ratio of the n-hexane and ethyl acetate is (3~7)：1, it is excellent It is selected as (4~6)：1, more preferably 5:1.
In the present invention, it after dissolving dope, is stirred under condition of ice bath, until precipitating crystal.
Wherein, the stir speed (S.S.) is 150~200r/min.
According to a kind of preferred embodiment of the present invention, the crystal of precipitation is dissolved again, is preferably solved in isopropanol, steamed Azeotropic dehydration is evaporated to there is no water to distillate, and stirring, slow cooling makes ranitidine crystal be precipitated to 0~3 DEG C.
Wherein, the temperature of the distillation is 89~95 DEG C, preferably 91~93 DEG C.
In further preferred embodiment, by the product after distillation dehydration first in the stirring of 100~120r/min 50 degrees Celsius are down to the rate of temperature fall of 10~15 DEG C/min under rate, then 20 DEG C are down to the rate of temperature fall of 4~6 DEG C/min, Constant temperature keeps 3h, is finally down to 0~3 DEG C under the stir speed (S.S.) of 30~50r/min with the rate of temperature fall of 4~6 DEG C/min, then permanent Temperature keeps 4h, until precipitating crystal.
In embodiment still more preferably, by the stirring in 110~115r/min first of the product after distillation dehydration It mixes and is down to 50 degrees Celsius under rate with the rate of temperature fall of 11~13 DEG C/min, then 20 are down to the rate of temperature fall of 4~6 DEG C/min DEG C, constant temperature keeps 3h, is finally down to 0~3 DEG C under the stir speed (S.S.) of 35~45r/min with the rate of temperature fall of 4~6 DEG C/min, Constant temperature keeps 4h again, until precipitating crystal.
The present inventor in different temperature ranges by the study found that during recrystallizing, using different Rate of temperature fall is conducive to remove the impurity A in ranitidine, improves the purity and medicine stability of ranitidine.
According to a kind of preferred embodiment of the present invention, the crystal being recrystallized to give is washed, the washing is use Organic solution is washed.
Preferably, the one kind of the organic solution in methanol, ethyl alcohol or isopropanol.
In further preferred embodiment, the washing is absolute ethyl alcohol with organic solution, it is preferable that described anhydrous The temperature of ethyl alcohol is 4~6 DEG C.
In embodiment still more preferably, the washing times are 3~5 times.
According to a kind of preferred embodiment of the present invention, the drying is vacuum drying, and the drying temperature is 25~32 DEG C, drying time is 3~6 hours.
In further preferred embodiment, the drying temperature is 28~30 DEG C, and drying time is 4~5 hours.
In embodiment still more preferably, the vacuum drying vacuum degree is 0.008~0.035MPa, preferably For 0.012~0.028MPa, more preferably 0.015~0.025MPa.
The preparation method of ranitidine of the present invention, step is simple, and condition is controllable, and intermediate product is few, can be effective Reduce the content of impurity A, B and C.
The ranitidine being prepared using the above method, wherein the content of impurity A can be controlled 0.05~0.3%, Impurity B content can be controlled 0.02~0.2%, and the content of impurity C can be controlled 0.03~0.2%.
The third aspect, the present invention provides a kind of preparation of ranitidine, the dosage form of the ranitidine formulation includes mouth Formulation and injection, wherein the oral preparation includes tablet, capsule, granule, solution.
According to a kind of preferred embodiment of the present invention, the ranitidine oral preparation is by including following weight proportion group The raw material divided is made：
100 parts by weight of ranitidine, filler 20-50 parts by weight, disintegrant 5-15 parts by weight, wetting agent 10-30 Parts by weight, lubricant 3-5 parts by weight.
Wherein, the filler is selected from lactose, starch, microcrystalline cellulose, sorbierite, mannitol, dextrin, Icing Sugar and phosphoric acid It is one or more in calcium dihydrogen；Preferably microcrystalline cellulose and mannitol；
The disintegrant is one kind in dried starch, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose, crospovidone Or it is a variety of；Preferably crospovidone；
The wetting agent is selected from distilled water and/or ethyl alcohol；
The lubricant is one or more in magnesium stearate, polyethylene glycols or magnesium laurylsulfate；Preferably Magnesium stearate.
In further preferred embodiment, the preparation method of the ranitidine oral preparation includes the following steps：
Step 1, each raw material is stirred evenly in proportion, wet granular is made；
Step 2, oven drying is added in wet granular；
Step 3, dry particle is sieved, it is then total mixed；
Step 4, total mixed particle preparation is obtained into ranitidine oral preparation.
Wherein, in step 2, the drying is the dry 2-2.5h at 50-60 DEG C；In step 3, the dry particle sieving To cross 30~35 mesh sieve, such as 32 mesh.
Fourth aspect, the present invention also provides a kind of ranitidine compound preparations, by including following weight proportion component Raw material be made：
100 parts by weight of ranitidine
0~60 parts by weight of mucosa protection agent
0~30 parts by weight of bacteriostatic agent,
Preferably：
100 parts by weight of ranitidine
20~60 parts by weight of mucosa protection agent
10~30 parts by weight of bacteriostatic agent,
The present inventor is by the study found that in the therapeutic process of enterogastric diseases, ranitidine is mainly by inhibiting stomach Acid is secreted to reduce the stimulation to damaging mucosal, and cannot fundamentally repair damaging mucosal.Therefore, in the present invention, preferably exist Thunder body replaces mucosa protection agent of the addition with Mucous rehabilitation effect in fourth preparation, to improve therapeutic effect.
In addition, the inventors discovered that, enterogastric diseases patient is accompanied by helicobacter pylori infections more, in ranitidine formulation Middle addition bacteriostatic agent is conducive to improve therapeutic effect.
Preferably, the ranitidine compound preparation is made of the raw material including following weight proportion component：
100 parts by weight of ranitidine, 20~60 parts by weight of mucosa protection agent, 10~30 parts by weight of bacteriostatic agent, blocking agent 4~10 parts by weight.
In the present invention, to reduce internal nitrosification caused by taking ranitidine for a long time, guarantee health is excellent It is selected in ranitidine formulation and adds blocking agent, to block the generation of patient's body nitroso compound.
It is highly preferred that the ranitidine compound preparation is made of the raw material including following weight proportion component：
100 parts by weight of ranitidine, 30~50 parts by weight of mucosa protection agent, 15~25 parts by weight of bacteriostatic agent, blocking agent 5~9 parts by weight.
It is further preferred that the ranitidine compound preparation is made of the raw material including following weight proportion component：
100 parts by weight of ranitidine, 40~45 parts by weight of mucosa protection agent, 18~22 parts by weight of bacteriostatic agent, blocking agent 6~8 parts by weight.
According to a kind of preferred embodiment of the present invention, the mucosa protection agent is vegetable-derived components.
The present inventor passes through the study found that common mucosa protection drug, such as denol, ulcerlmin, Bismuth Potassium Citrate, Mucomembranous surface can be adsorbed, hydrochloric acid in gastric juice is neutralized, inhibits the secretion of acid digestion liquid in alimentary canal, to promote alimentary canal mucous membrane epithelium thin The regeneration and reparation of born of the same parents.But these mucosa protection drugs are likely to result in diarrhea or constipation, are by sacrificing function of intestinal canal Come reach treatment non-cancer lesion function, generate indigestion, bile regurgitation, dietary structure change equivalent damage mucous membrane factor, Lead to vicious circle, makes disease protracted course of disease.
Therefore, preferably select vegetable-derived components as promotion Mucous rehabilitation, regenerated drug, safety in the present invention Height, without side-effects, Mucous rehabilitation effect is significant.
In further preferred embodiment, the mucosa protection agent be extractive of olive growing leaves, Fructus Rubi extract, It is one or more in Turmeric P.E, Gotu Kola P.E, Herb Gynostemmae Pentaphylli extract or Radix Codonopsis extract.
Wherein, the extract of each vegetable-derived components is commercially available substance alcohol extract, and preferably ethyl alcohol carries Take object.
In embodiment still more preferably, the mucosa protection agent is extractive of olive growing leaves, Turmeric P.E Or it is one or more in Radix Codonopsis extract.
The present inventor passes through the study found that extractive of olive growing leaves contains phenol (tyrosol, hydroxytyrosol and its derivative), meat Cinnamic acid, flavonoids (apiolin, cyanidenon and its glycosides derivatives, rutin, Quercetin), lignan, secoiridoid (olive The driffractive ring loganin analog of bitter glycosides, oleuropein and its derivative, Olivanic Acid).
Wherein, oleuropein and flavonoids have strong anti-inflammatory property, can inhibit segmental inflammation enzyme, and the mucous membrane of damage is promoted to repair Multiple healing.
In the present invention, the content of oleuropein is preferably 20~40% in the extractive of olive growing leaves, flavonoids Content is preferably 40~50%.
Curcumin in Turmeric P.E is a kind of pigment in the rhizome of turmeric, with inoxidizability, anti-inflammatory, Anti-angiogenesis, anti proliferative and wound healing promoting, and there is no cytotoxicity in normal cell, Turmeric P.E can To inhibit the generation of inflammatory reaction in ulcer surface and there is protective effect to cell.
In the present invention, in the Turmeric P.E content of curcumin 95% or more.
Radix Codonopsis is herbaceos perennial, contained by chemical composition type it is various, including carbohydrate, triterpenes, steroid, Alkaloids, lignin and flavonoids etc. have and adjust stomach contraction, the protection pharmacological actions such as gastrointestinal tract mucosa and antiulcer, It is by improving the amount of prostaglandin come the sour effect of secreting to anti-gastrin, and stimulation gastric mucosa synthesizes and release epidermal growth factor Son.
In the present invention, by the way that the mucosa protection agent of vegetable-derived components is added, long-term use ranitidine can be solved and led Symptom caused by the vitamin B12 deficiency of cause can effectively facilitate reparation and the ulcer healing of gastrointestinal tract breakage mucous membrane.
The present inventor by the study found that when the mucosa protection agent of addition be less than 20 parts by weight when, the mucous membrane of the preparation It is not notable to repair effect；When the mucosa protection agent of addition is more than 60 parts by weight, the bioavilability of ranitidine can be influenced.
According to a kind of preferred embodiment of the present invention, the bacteriostatic agent is natural bacteriostatic agent, the preferably blue flower extraction in west Object, Flos Caryophylli extract, Herba Abri extract, hippophae rhamnoides, Corydalis P.E, bupleurum extract, Rhizoma Chuanxiong extract or cloud It is one or more in Radix Aucklandiae extract.
Wherein, each natural bacteriostatic agent is commercially available substance alcohol extract, preferably ethanol extract.
The present inventor, which passes through the study found that taking antisecretory for a long time, to cause bacterium to be bred in gastrointestinal tract, wherein deep and remote Helicobacter pylori is the primary pathogenic event of the enterogastric diseases such as chronic gastritis and taste-blindness rate.And inhibit helicobacter pylorus The common drug of bacterium is mainly clarithromycin, Amoxicillin, tetracycline, metronidazole etc., and long-term use can lead to helicobacter pylori Generate drug resistance.
Therefore, natural bacteriostatic agent is preferably selected to inhibit helicobacter pylori, with efficient, safe raising preparation in the present invention The activity of anti-helicobacter pylori.
In further preferred embodiment, the bacteriostatic agent carries for the blue flower extract in west, Flos Caryophylli extract, Canton love-pea vine It takes one or more in object, hippophae rhamnoides, Corydalis P.E or Aplotaxis auriculata extract.
In embodiment still more preferably, the bacteriostatic agent is the blue flower extract in west, Flos Caryophylli extract or chicken bone It is one or more in careless extract.
Wherein, contain isothiocyanates in the blue flower extract in west, growth of H. pylori can be inhibited, west is blue to spend in tender shoots Contain more isothiocyanates.
In the present invention, in the blue flower extract in west isothiocyanates and content is not less than 10%.It is main in Flos Caryophylli extract To include the ingredients such as eugenol, aceteugenol, caryophyllene alcohol, cloves olefinic oxide, gaultherolin, wherein eugenol Content is more, has stronger anti-helicobactor pylori activity.
Wherein, the content of eugenol is 15~25% in Flos Caryophylli extract.
Herba Abri extract includes mainly the chemical combination such as saponins, Anthraquinones, sterols, flavonoids, amino acids and tannic acid Object, wherein Flavonoid substances mainly play the effect for inhibiting helicobacter pylori.
In the present invention, the content of flavonoids is 60~80% in Herba Abri extract.
The present inventor is by the study found that when the addition of bacteriostatic agent is less than 10 parts by weight, inhibiting helicobacter pylori Effect unobvious；When the addition of bacteriostatic agent is higher than 30 parts by weight, can have an impact to the bacterial activity of other in gastrointestinal tract, hold Easily lead to intestinal bacilli illness.
According to a kind of preferred embodiment of the present invention, the blocking agent is to contain vitamin C or flavonoids active material Natural materials, preferably ginkgo biloba p.e, Kiwi extract, lemon extract, Bitter Melon P.E, Fragaia ananassa Duchesne extract, It is one or more in cabbage extract, Fructus Rosae Normalis extract or sweet orange extract.
Wherein, above-mentioned natural materials are commercially available substance water extract.
The present inventor passes through the study found that vitamin C and nitrite can prevent nitrous in vivo with high affinity Change acts on, to block the generation of nitroso compound；Flavonoids active material has stronger antioxidation, so as to Inhibit oxygen free radical reaction and peroxidatic reaction of lipid.
In the present invention, using the natural materials for containing vitamin C or flavonoids active material as blocking agent, people is blocked The generation of internal N- nitroso compounds can slow down the disease that N- digests increase in vivo caused by taking ranitidine for a long time Shape, to reduce harm of the nitroso compound to human body.
In further preferred embodiment, the blocking agent is ginkgo biloba p.e, Kiwi extract, balsam pear carry It takes one or more in object, Fragaia ananassa Duchesne extract, Fructus Rosae Normalis extract or sweet orange extract.
In embodiment still more preferably, the blocking agent is ginkgo biloba p.e and/or Fructus Rosae Normalis extract.
Wherein, the principle active component of ginkgo biloba p.e is flavonoids and terpene compound, contains reproducibility hydroxyl Functional group has stronger antioxidation, to inhibit oxygen free radical reaction and peroxidatic reaction of lipid.
Preferably, the content of flavonoids is 20%~30% in the ginkgo biloba p.e, and terpene compound content is 6%~10%.
The vitamin content of Fructus Rosae Normalis extract is higher, and contains higher bioflavonoid, can prevent ascorbic oxygen Change and destroy, there is higher blocking rate to the synthesis of N- nitroso compounds.
The present inventor by the study found that when the amount of the blocking agent of addition be less than 4 parts by weight when, to nitroso compound Barrier effect unobvious；When the amount of the blocking agent of addition is higher than 10 parts by weight, barrier effect promotion is not notable, and can increase stomach The acidity of liquid weakens the acid suppression effect of ranitidine.
Ranitidine compound preparation provided by the present invention, formula is simple, and additive is natural component, safe, Incompatibility is few, and toxic side effect is small, and bioavilability is high and therapeutic effect is good.
5th aspect, the present invention also provides a kind of preparation methods of above-mentioned ranitidine compound preparation, including following step Suddenly：
Step 1, ranitidine is prepared into drug containing vegetable pill；
Step 2, above-mentioned drug containing vegetable pill is prepared into pellet, processing is then dried；
Step 3, mucosa protection agent, bacteriostatic agent, blocking agent and multiple additives are mixed, after being dried with step 2 Pellet mixes, and obtains confection；
Step 4, the confection of above-mentioned preparation is dispensed, obtains ranitidine formulation.
Specifically, the preparation method of ranitidine compound preparation of the present invention is further described：
Step 1, ranitidine is prepared into drug containing vegetable pill.
According to a kind of preferred embodiment of the present invention, ranitidine is mixed with filler, adhesive, is prepared and contains Medicine vegetable pill.
In further preferred embodiment, the ranitidine is 100 with the weight ratio of filler and adhesive： (20~60)：(25~50), preferably 100：(30~50)：(30~45), more preferably 100：(35~45)：(33~40).
According to a kind of preferred embodiment of the present invention, the filler is lactose, starch, calcium monohydrogen phosphate, chitosan, sugarcane It is one or more in sugar or microcrystalline cellulose.
In the present invention, the filler is filled primarily with and dilutes the effect of ranitidine, and the present invention carrys out filler Source is not particularly limited, and is commercially available.
In further preferred embodiment, the filler is one in lactose, starch, sucrose or microcrystalline cellulose Kind is a variety of.
In embodiment still more preferably, the filler is one kind in lactose, starch or microcrystalline cellulose Or it is a variety of.
According to a kind of preferred embodiment of the present invention, described adhesive is starch slurry, ethyl alcohol, water, povidone alcoholic solution Or it is one or more in hydroxypropyl methyl cellulose.
Wherein, described adhesive mainly plays cementation, is commercially available.
In further preferred embodiment, described adhesive is in starch slurry, ethyl alcohol, water or povidone alcoholic solution It is one or more.
In embodiment still more preferably, described adhesive is one or more in starch slurry, ethyl alcohol or water.
In the present invention, after mixing by the ranitidine of weight proportion, filler and adhesive, softwood is made, so Drug containing vegetable pill is made by fluid bed.
Wherein, spare after obtained drug containing vegetable pill being crossed 15~20 mesh sieve.
Step 2, above-mentioned drug containing vegetable pill is prepared into pellet, processing is then dried.
In the present invention, the pellet is made by coating coating material outside drug containing vegetable pill.
The present inventor is by that the study found that coat coating material outside the ranitidine drug containing vegetable pill, can avoid Influence of the various additives to main pharmacodynamics improves medicine stability, and coating material can cover the smell of ranitidine, Reduce vomiting side effect during taking, improves the compliance of patient's medication.
According to a kind of preferred embodiment of the present invention, the coating material is ethyl cellulose, acrylic resin, hydroxypropyl It is one or more in ylmethyl cellulose, cellulose acetate or polyacrylic resin polymer.
In further preferred embodiment, the coating material is ethyl cellulose, hydroxypropyl methyl cellulose, vinegar It is one or more in acid cellulose or polyacrylic resin polymer.
In embodiment still more preferably, the coating material is that ethyl cellulose and/or hydroxypropyl methyl are fine Dimension element.
The present inventor passes through the study found that ethyl cellulose is as coating material, and pellet smooth appearance obtained, film forming is Even, controlled-release effect is good；Hydroxypropyl methyl cellulose has good film-forming quality, and the film of formation has intensity appropriate, less brittle It splits, property is stablized, and is readily dissolved in gastro-intestinal Fluid.
According to a kind of preferred embodiment of the present invention, the weight ratio of the ranitidine and coating of pellets material is 100： (10~20), preferably 100：(12~18), more preferably 100：(14~16).
In the present invention, the pellet is prepared using fluid bed bottom spray coating method, and the coating flow velocity is 1~4ml/ Min, coating solution temperature are 30~40 DEG C, and atomizing pressure is 180~300Kpa.
The present inventor is by the study found that when coating solution temperature is less than 30 DEG C, coating carries out insufficient；When coating solution temperature When degree is higher than 40 DEG C, electrostatic phenomenon is easy tod produce, coating quality is influenced.
In addition, when coating flow velocity is less than 1ml/min, Coating times can be extended, and then subsequent coating is caused to be glued Even phenomenon；When the flow velocity of coating solution is higher than 4ml/min, it may appear that pellet glues the phenomenon that ball, at this point, even if increasing atomizing pressure And intake volume, it can not also solve the problems, such as viscous ball.
Preferably, the coating flow velocity is 2~3ml/min, and coating solution temperature is 33~37 DEG C, atomizing pressure 200 ~250Kpa.
According to a kind of preferred embodiment of the present invention, processing, the dry temperature are dried to the pellet being prepared Degree is 35~40 DEG C, and the moisture after the pellet drying is less than 2.5%.
The present inventor by the study found that the obtained pellet of preparation is dried processing after again with mucosa protection agent, The mixing such as bacteriostatic agent, blocking agent and additive, the dilution for being conducive to the stability for improving drug and reducing drug.
In further preferred embodiment, the grain size for the pellet being prepared is 0.5~2.5mm.
Wherein, the grain size of 70% or more pellet is 0.8~1.5mm, and the pellet that grain size is 2.0~2.5mm is less than 5%.Make The ranitidine pellet that must be prepared has higher stability and uniformity.
Step 3, mucosa protection agent, bacteriostatic agent, blocking agent and additive are mixed, the pellet after being dried with step 2 Mixing, obtains confection.
According to a kind of preferred embodiment of the present invention, the additive include gel forming agent, curing agent, corrigent and Preservative.
In further preferred embodiment, based on the ranitidine of 100 parts by weight, the gel forming agent, solidification The amount that agent, corrigent and preservative are added is respectively (80~300) parts by weight, (5~40) parts by weight, (200~1000) weight Part and (2~15) parts by weight.
The present inventor is by the study found that the ranitidine based on 100 parts by weight, when the amount of the gel forming agent of addition is low When 80 parts by weight, the pellet of preparation can not be dispersed in gel；When the amount of the gel forming agent of addition is higher than 1000 weights When measuring part, the dilution of drug can be caused, causes dosage insufficient.
In embodiment still more preferably, based on the ranitidine of 100 parts by weight, the gel forming agent is consolidated The amount that agent, corrigent and preservative are added is respectively (120~250) parts by weight, (10~30) parts by weight, (400~800) weight Measure part and (3~10) parts by weight.
It is preferably based on the ranitidine of 100 parts by weight, the gel forming agent, curing agent, corrigent and preservative add The amount entered is respectively (150~200) parts by weight, (15~25) parts by weight, (500~700) parts by weight and (4~8) parts by weight.
According to a kind of preferred embodiment of the present invention, the gel forming agent be carragheen, pectin, konjac glucomannan, gelatin, It is one or more in xanthans or agar,
The curing agent be calcium chloride and/or potassium chloride,
The corrigent is one in sucrose, xylitol, glucose, Aspartame, steviol glycoside, honey element or sorbierite Kind is a variety of, and/or
The preservative is aethyl parabenum, propylparaben, sorbic acid, potassium sorbate, calcium propionate, dehydrogenation second It is one or more in sour sodium, sodium Diacetate, benzoic acid, sodium benzoate or sodium lactate.
In further preferred embodiment, the gel forming agent is in carragheen, pectin, konjac glucomannan or agar It is one or more,
The curing agent be calcium chloride and/or potassium chloride,
The corrigent be sucrose, xylitol, glucose or steviol glycoside in it is one or more,
The preservative is in propylparaben, sorbic acid, potassium sorbate, sodium Diacetate, benzoic acid or sodium lactate It is one or more.
Wherein, carragheen, pectin, konjac glucomannan or the agar in the gel forming agent, is low calorie high dietary-fiber Healthy food, be rich in high dietary-fiber and water-soluble semi fiber, absorption be easily digested in human body, play that " stomach and intestine are clear The effect of doffer ".
According to a kind of preferred embodiment of the present invention, the mucosa protection agent, bacteriostatic agent, blocking agent and additive with Before pellet is mixed, needs to cross 40~100 mesh sieve respectively, preferably cross 50~80 mesh sieve.
Wherein, each component will be sieved before mixing, and will be conducive to stir evenly after subsequently mixing with pellet.
According to a kind of preferred embodiment of the present invention, by mucosa protection agent, bacteriostatic agent, blocking agent, gel forming agent, consolidate After agent, corrigent and preservative are sieved respectively, the pellet prepared with step 2 mixes, and is sufficiently stirred, it is made to be uniformly mixed, system It is standby to obtain pellet xerogel confection.
Wherein, ranitidine compound preparation is prepared into the dosage form of pellet xerogel, the mouthfeel of preparation can be improved, is improved Patient's Compliance；Taking dose can also be made accurate, reduce the generation of medication accident.
Ranitidine compound preparation provided by the invention takes after mixing it with water when taking and forms gelatinous thick liquid temporarily, It is convenient to take, it will not cause to vomit and suffocate, and ensure that the accuracy of medication dose.
According to another preferred embodiment of the present invention, the preparation of the ranitidine compound preparation includes following step Suddenly:
(i) mucosa protection agent, bacteriostatic agent, blocking agent, curing agent, corrigent and preservative are added to the water stirring and dissolving, Gel forming 15~35min of solvent swell is added, with 75~90 DEG C of 20~40min of heating water bath, stirring and dissolving；
(ii) pH to 5~7 for adjusting above-mentioned mixed solution, is then sieved while hot；
(iii) ranitidine coating micro-pill is added in solution after sizing, stirs evenly to get pellet gel mixing medicine Agent.
Wherein, the pellet gel preparation can improve the mouthfeel of preparation, improve patient's Compliance；It can also make Taking dose is accurate, reduces the generation of medication accident.
Step 4, the confection of above-mentioned preparation is dispensed, obtains ranitidine compound preparation.
In the present invention, to ensure the accuracy of dosage and preventing the secondary pollution of drug, using minimum dose pair Confection is individually packed so that it is quantitatively accurate that single is taken, and dose stability is safe.
Wherein, the minimum package unit of the ranitidine compound preparation is 1g/ bags.
The preparation method of ranitidine compound preparation provided by the invention, step is simple, easy to operate, the requirement to equipment Low, production efficiency is high.
The present invention also provides purposes of the ranitidine compound preparation of above-mentioned preparation in treating erosive esophagitis.
Heretofore described ranitidine compound preparation, character are stablized, and content is uniform, and gel can attach to when taking It on esophageal wall, slowly flows down along esophageal wall, forming certain food on Esophageal Mucosa surface manages barrier, the mucosa protection agent in preparation There are protection and repair for damaged Esophageal Mucosa；Meanwhile gelling agent can neutralize a part of hydrochloric acid in gastric juice, reduce epigastric and oesophagus The acidity of lower end, the ranitidine main ingredient in pellet can play Acidinhibitor, further protect Esophageal Mucosa.In addition, compound Bacteriostatic agent in preparation can also inhibit the activity of helicobacter pylori, fundamentally reduce the generation of esophagel disease.
6th aspect, ranitidine, ranitidine formulation and ranitidine compound preparation provided by the invention are controlled in preparation Treat the application in the drug with maintaining treatment erosive esophagitis.
Embodiment
The present invention is further described below by way of specific example, but these examples are only exemplary, not to this The protection domain of invention constitutes any restrictions.
Raw materials used in embodiment of the present invention is commercially available gained：
2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine, N- methyl-1s-methyl mercapto -2- nitro second Enamine is purchased from the Shanghai bio tech ltd Xi Yuan；Extractive of olive growing leaves, Flos Caryophylli extract, ginkgo biloba p.e, turmeric Extract, the blue flower extract in west are purchased from Hunan Lang Lin living resources limited liability company；SD rats, BALB/c small white mouses are purchased from triumphant Learn biotechnology (Shanghai) Co., Ltd..
The preparation of 1 ranitidine of embodiment
(1) by the 2- of 170g [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and 90.3gN- methyl - 1- methyl mercapto -2- nitroethylenes amine is dissolved in respectively in 100ml distilled water, and solution is made, takes same volume (taking 50mL respectively) The solution configured, with the drop rate of 2.4mL/min, the stir speed (S.S.) of 180r/min carries out dropwise addition mixing, after mixing, 42 DEG C are warming up to the heating rate of 2.5 DEG C/min, is kept for 6 hours, until reaction terminates, obtains crocus reaction solution；
(2) hydrochloric acid of 50mL, 2mol/L are added into above-mentioned reaction solution, then adjusts pH and adds to 3.5, then into reaction solution Enter 200mL dichloromethane to be extracted, after mixing, stand, isolated organic phase and water phase, wherein water phase are 180mL； The pH to 9 of water phase is adjusted using 15% solution of potassium carbonate, the dichloromethane that 720mL is then added is extracted again, is mixed It after uniformly, stands, isolated organic phase and water phase；
(3) anhydrous magnesium sulfate is added into isolated organic phase and processing is dried, then after filtering, concentrating, Obtain faint yellow dope；
(4) dope is dissolved in the mixed liquor of n-hexane (250mL) and ethyl acetate (50mL), under condition of ice bath It is stirred with the stir speed (S.S.) of 180r/min, until precipitating crystal；
The crystal of precipitation is redissolved in 200mL isopropanols, then extremely there is no water to evaporate for azeotropic dehydration at 92 DEG C Go out, is then down to 50 degrees Celsius under the stir speed (S.S.) of 110r/min with the rate of temperature fall of 12 DEG C/min, then with the drop of 5 DEG C/min Warm rate is down to 20 DEG C, and constant temperature keeps 3h, finally 0 is down to the rate of temperature fall of 5 DEG C/min under the stir speed (S.S.) of 40r/min~ 3 DEG C, then constant temperature holding 4h, until precipitating crystal；
(5) crystal is washed 4 times with 4 DEG C of absolute ethyl alcohol, then vacuum degree be 0.02MPa, at 29 DEG C it is dry 4 small When, obtain ranitidine.
Wherein, the content of impurity A is 0.05% in ranitidine, and the content of impurity B is 0.03%, and the content of impurity C is 0.02%.
The preparation of 2 ranitidine formulation of embodiment
Ranitidine 100g made from Example 1, add 30g mannitol, 10g crospovidone, 25g distilled water and 4g magnesium stearates are placed in drying box at 55 DEG C dry 2.5h after mixing；Particle after drying is crossed into 32 mesh sieve, is passed through Efficient mixer-granulator (HLSG-300P) is always mixed, and is then prepared into drug in oscillating granulator (YK-160A) Grain carries out capsule filling in capsule filler (ZANASI 40F), Ranitidine Capsules is made.
The preparation of 3 ranitidine compound preparation of embodiment
(1) ranitidine compound preparation is made of the raw material including following weight proportion component in the present embodiment：Thunder Buddhist nun replaces Fourth 100g, extractive of olive growing leaves 45g, Flos Caryophylli extract 20g, ginkgo biloba p.e 6g.
Wherein, ranitidine is that embodiment 1 is prepared, and the content of oleuropein is 30% in extractive of olive growing leaves, The content of flavonoids is 45%；The content of Flos Caryophylli extract eugenol is 20%；The content of flavonoids is in ginkgo biloba p.e 26%, terpene compound content is 7%.
(2) preparation method：
(1) ranitidine 100g made from Example 1, mixes with 40g lactose and 35g starch slurries, after stirring evenly, warp Drug containing vegetable pill is made in fluid bed, and it is spare then to cross 20 mesh sieve.
(2) above-mentioned drug containing vegetable pill and 15g ethyl celluloses are mixed, is placed in fluid bed, setting coating flow velocity is 2.5ml/min, temperature are 35 DEG C, and ranitidine coating micro-pill is prepared in atomizing pressure 250Kpa.
(3) by 45g extractive of olive growing leaves, 20g Flos Caryophylli extracts, 6g ginkgo biloba p.es, 175g carragheens, 20g chlorine Change potassium, 600g sucrose and 6g aethyl parabenums and cross 60 mesh sieve respectively, then mixes with ranitidine coating micro-pill, fully stir After mixing mixing, packing obtains ranitidine formulation.
Wherein, ranitidine formulation manufactured in the present embodiment is that the thunder Buddhist nun containing 100mg replaces in 1g pellet xerogel preparations Fourth.
Embodiment 4
The present embodiment method therefor is similar to Example 1, differs only in, N- methyl-1s-methyl mercapto -2- in step (1) The additive amount of nitroethylene amine is 113.3g.
Wherein, the content of impurity A, B and C is respectively 0.05%, 0.04% and 0.03% in the ranitidine being prepared.
Embodiment 5
The present embodiment method therefor is similar to Example 1, differs only in, N- methyl-1s-methyl mercapto -2- in step (1) The additive amount of nitroethylene amine is 58.8g.
Wherein, the content of impurity A, B and C is respectively 0.05%, 0.03% and 0.04% in the ranitidine being prepared.
Embodiment 6
The present embodiment method therefor is similar to Example 1, differs only in, and the drop rate in step (1) is 1.5mL/ Min, the stir speed (S.S.) are 100r/min.
Wherein, the content of impurity A, B and C is respectively 0.05%, 0.04% and 0.03% in the ranitidine being prepared.
Embodiment 7
The present embodiment method therefor is similar to Example 1, differs only in, and the drop rate in step (1) is 4mL/ Min, the stir speed (S.S.) are 250r/min.
Wherein, the content of impurity A, B and C is respectively 0.05%, 0.03% and 0.03% in the ranitidine being prepared.
Embodiment 8
The present embodiment method therefor is similar to Example 1, differs only in, the heating rate in step (1) be 4 DEG C/ min。
Wherein, the content of impurity A, B and C is respectively 0.07%, 0.04% and 0.03% in the ranitidine being prepared.
Embodiment 9
The present embodiment method therefor is similar to Example 1, differs only in, and in step (1), 7 are kept after being warming up to 42 DEG C Hour.
Wherein, the content of impurity A, B and C is respectively 0.08%, 0.03% and 0.05% in the ranitidine being prepared.
Embodiment 10
The present embodiment method therefor is similar to Example 1, differs only in, in step (4), by the product after distillation dehydration 50 degrees Celsius are down to the rate of temperature fall of 15 DEG C/min first under the stir speed (S.S.) of 120r/min, then with the cooling of 6 DEG C/min Rate is down to 20 DEG C, and constant temperature keeps 3h, is finally down to 0~3 under the stir speed (S.S.) of 45r/min with the rate of temperature fall of 6 DEG C/min DEG C, then constant temperature holding 4h, until precipitating crystal.
Wherein, the content of impurity A, B and C is respectively 0.06%, 0.03% and 0.06% in the ranitidine being prepared.
Embodiment 11
The present embodiment is raw materials used and method is similar to Example 3, differs only in, and what mucosa protection agent was selected is turmeric Extract (turmeric cellulose content is 98%).
Embodiment 12
The present embodiment is raw materials used and method is similar to Example 3, differs only in, and what bacteriostatic agent was selected is that Xi Lanhua is carried Take object (content of isothiocyanates is 10%).
Embodiment 13
The present embodiment is raw materials used and method is similar to Example 3, differs only in, the addition of the ginkgo biloba p.e Amount is 8g.
Comparative example
Comparative example 1
This comparative example method therefor is same as Example 1, and difference lies in the reaction time in step (1) is 10 hours.
Comparative example 2
This comparative example method therefor is same as Example 1, and difference lies in step (2) after adjusting pH to 3.5, to anti- It answers and 4-methylpenta-2-one is added in liquid, azeotropic distillation water removal, then proceeds by step (4) under decompression (34.65kPa) Be down to 50 degrees Celsius under the stir speed (S.S.) of 110r/min with the rate of temperature fall of 12 DEG C/min, then with the cooling speed of 5 DEG C/min Rate is down to 20 DEG C, and constant temperature keeps 3h, is finally down to 0~3 DEG C under the stir speed (S.S.) of 40r/min with the rate of temperature fall of 5 DEG C/min, Constant temperature keeps 4h again, until precipitating crystal.
Comparative example 3
This comparative example method therefor is same as Example 1, and difference lies in step (4), no longer carry out after precipitating crystal Recrystallization directly carries out step (5).
Comparative example 4
This comparative example is raw materials used and method is similar to Example 3, differs only in, the extractive of olive growing leaves in raw material (mucosa protection agent) changes into denol.
Comparative example 5
This comparative example is raw materials used and method is similar to Example 3, differs only in, the Flos Caryophylli extract (suppression in raw material Microbial inoculum) change into clarithromycin.
Comparative example 6
This comparative example is raw materials used and method is similar to Example 3, differs only in, and is extracted without containing ginkgo leaf in raw material Object (blocking agent).
Comparative example 7
This comparative example is raw materials used and method is similar to Example 3, differs only in, ginkgo biloba p.e (blocking agent) Addition is 12g.
Comparative example 8
This raw materials used comparative example only includes ranitidine, preparation method and the ranitidine compound system in embodiment 3 The preparation method of agent is identical, is added without extractive of olive growing leaves, Flos Caryophylli extract and ginkgo biloba p.e.
Comparative example 9
This comparative example is raw materials used and method is similar to Example 3, differs only in, is carried without containing olive growing leaves in raw material Take object (mucosa protection agent).
Experimental example
1 Detection of Stability of experimental example
Foundation《Chinese Pharmacopoeia》In 2015 editions《Material medicine and preparation stability test direction principle》Specified in medicine Object stability conditions are prepared in the ranitidine and embodiment 2 to middle preparation in embodiment 1,7~10, comparative example 1~3 Ranitidine Capsules agent carry out accelerated stability (January, 2 months, March, June) and long-time stability (March, June, September, December) It is detected, the results are shown in Table 1；
Table 1
As shown in Table 1, in the method described in the embodiment of the present invention 1,7~10 is prepared ranitidine and embodiment 2 The Ranitidine Capsules of preparation are accelerating 6 months in, and in long-term 12 months, significant changes do not occur for content, show to utilize this The stability of ranitidine formulation made from invention the method is preferable.
Moreover, the content of impurity B is apparently higher than in embodiment 1 in the ranitidine that 1 the method for comparative example is prepared , the content of impurity C is apparently higher than in embodiment 1 in the ranitidine that 2 the method for comparative example is prepared, comparative example 3 The content of impurity A is apparently higher than in embodiment 1 in the ranitidine that the method is prepared, and illustrates thunder Buddhist nun of the present invention There is remarkable result in terms of reducing impurity A, B and C content for the preparation method of fourth.
In addition, to accelerated stability (January, 2 months, 3 of the ranitidine compound preparation obtained by embodiment 3,11 and 12 Month, June) and long-time stability (March, June, September, December) be detected, the results are shown in Table 2：
Table 2
As shown in Table 2, the impurity in ranitidine compound preparation made from the embodiment of the present invention 3,11 and 12 and mainly have Effective component content is accelerating 6 months in, and significant changes do not occur in long-term 12 months, shows to utilize the method for the invention system The stability of the compound preparation obtained is preferable.
2 blood concentration of experimental example detects
(1) capsule chosen in embodiment 2 is sample, with commercially available Ranitidine Capsules agent (the limited public affairs of Foshan palm of the hand pharmacy Department, C12200004668) it is control.
(2) choose healthy male volunteers 20, the age (20 ± 0.5) year, weight (65 ± 4) kg, height (170 ± 5) cm.Tested preceding physical examination and blood, routine urinalysis, the inspections such as the heart, Liver and kidney function are normal, do not taken during tested the last fortnight and experiment Any drug, subject is without habits of smoking and alcohol drinking.
Subject is randomly divided into 2 groups, by crossover experimental design dosage regimen, the elution phase between two groups is one Week.Empty stomach oral drugs after fasting 12 hours, one of which is with the preparation in 240ml warm water delivery service 300mg embodiments 2, note For experimental group；Another set is denoted as control group with the commercially available Ranitidine Capsules of 240ml warm water delivery services 300mg.Experimental group and right According to group fasting in medication 2h.
Respectively 0.5, each moment of 1,1.5,2,3,4,5,6,8,10,12h before medication and after medication, acquire experimental group With the venous blood 3ml of control group subject, blood concentration is measured, as a result as shown in table 3 and Fig. 1：
Table 3
By table 3 and Fig. 1 it is found that the blood concentration of Ranitidine Capsules agent made from the embodiment of the present invention 2 is higher than commercially available glue The concentration of wafer shows that the ranitidine formulation in the present invention is significantly improved in the bioavilability of patient's body.
3 Mucous rehabilitation of experimental example detects
Choose healthy SD rat 30, be randomly divided into 5 groups (are denoted as group 1~group 5), adaptability culture after a week, using second Alcohol induces gastric mucosa damage, establishes model.Dosage is 2.0g/kg/d (by ranitidine active ingredient by crude drug gauge Calculate), wherein the preparation of the embodiment 3 of equivalent, comparative example 4, comparative example 8 and comparative example 9 is given in group 1~groups 4 respectively, and group 5 is given Give the 0.5%CMC-Na solution of equivalent.
The daily gavage of above each group 1 time takes off neck after continuous 7d and puts to death rat, cuts open the belly take stomach rapidly, and ligation is beautifully adorned, complete after pylorus Whole taking-up mouse stomach cuts off gastric wall in rats along greater curvature, collects gastric content and is placed in centrifuge tube, and 15min is centrifuged with 3000rpm, Supernatant is taken to survey peptic activity of stomach.With normal saline flushing stomach wall, filter paper blots, and flattening observes and records mucosal lesion Degree calculates ulcer area, the results are shown in Table 4.
Table 4
Group Mucosa injury area (mm2) Peptic activity of stomach (U)
Group 1 45.21±10.82 1.20±0.84
Group 2 43.58±9.78 1.39±0.49
Group 3 64.23±11.20 3.56±1.65
Group 4 59.48±12.74 2.98±1.26
Group 5 96.48±25.24 8.56±1.76
In addition, choose healthy SD rat 15 again, it is randomly divided into 3 groups (are denoted as group 6~group 8), adaptability culture one week Afterwards, using alcohol-induced gastric mucosa damage, model is established.Dosage is 2.0g/kg/d (by ranitidine by crude drug gauge Active ingredient calculates), wherein group 6 and the preparation for organizing embodiment 3 and comparative example 4 that 7 give equivalent respectively, group 8 give equivalent 0.5%CMC-Na solution.
Neck is taken off after every 3 days gavages of above each group 1 time, continuous 6 months and puts to death rat, cuts open the belly take stomach rapidly, ligature beautifully adorned, pylorus Mouse stomach is completely taken out afterwards, gastric wall in rats is cut off along greater curvature, is collected gastric content and is placed in centrifuge tube, is centrifuged with 3000rpm 15min takes supernatant to survey peptic activity of stomach.With normal saline flushing stomach wall, filter paper blots, and it is glutinous to observe and record stomach for flattening Membrane damage degree calculates ulcer area, and the results are shown in Table 5：
Table 5
Group Mucosa injury area (mm2) Peptic activity of stomach (U)
Group 6 5.42±2.12 1.01±0.25
Group 7 12.62±1.93 1.25±1.06
Group 8 105.45±25.98 9.07±1.47
By table 4 and table 5 it is found that the ranitidine compound preparation of embodiment 3 shows as stronger resist compared with other groups Gastric ulcer acts on, and can significantly repair the gastric mucosa of damage；Comparative example 4 treats gastric mucosa damage in a short time with embodiment 3 Effect difference with insignificance, but in long-term therapeutic process, the preparation of embodiment 3 repairs the significant effect of gastric mucosa higher than comparison Example 4, illustrate that the ranitidine compound preparation of embodiment 3 can reduce the side effect of Long-term taking medicine, safety is higher.
The detection of 4 stopping nitrosation reaction of experimental example
50 6~8 week old BALB/c small white mouses of health, 17~20g of weight are chosen, adaptability culture after a week, divides at random For 5 groups (groups 1~group 5), wherein the mixed liquor of 1 gavage embodiment of group, 3 preparation, sodium nitrite and aminopyrine is (by 1g embodiments 3 preparations are dissolved in the mixed liquor of sodium nitrite and aminopyrine, by 10ml/kgd gavages)；Group 2 gavage comparative examples 6 system The mixed liquor 10ml/kgd (being same as above) of agent, sodium nitrite and aminopyrine；3 gavage comparative example of group, 7 preparation, sodium nitrite and ammonia The mixed liquor 10ml/kgd (being same as above) of Ji Bilin；The mixed liquor 10ml/ of group 4 gavage sodium nitrites and aminopyrine mixed liquor kg·d；The physiological saline of 5 gavage same volumes 0.9% of group.1~group 5 daily gavages 1 time, continuous gavage 5d of group, took in the 6th day Eyeball of mouse blood, 2500r/min centrifugation 20min separation are prepared serum, are measured the third ammonia of paddy in serum at 505nm using reitman-frankel method The content of sour enzyme, testing result are as shown in table 6：
Table 6
Group Glutamic-pyruvic transaminase
Group 1 38.4512±1.0201
Group 2 122.5244±2.1170
Group 3 39.2100±1.0352
Group 4 124.1083±3.0726
Group 5 34.4573±1.0472
Wherein, in vivo in acidic environment, nitrite synthesizes nitrosamine with secondary amine, and nitrosamine is entered by blood circulation Liver cell destroys liver cell, the glutamic-pyruvic transaminase in hepatic tissue is caused to enter in blood.
As shown in Table 6, the preparation in the embodiment of the present invention 3 is compared with comparative example 6, in the mouse blood of gavage processing The content of glutamic-pyruvic transaminase is significant lower, illustrates that the preparation of embodiment 3 is higher to the blocking rate of nitrosation reaction；Embodiment 3 with The blocking rate difference of comparative example 7 is not notable, illustrates the addition of blocking agent in preparation more than after doses, stopping nitrosation is anti- The blocking rate answered will not be obviously improved.
The clinical test of 5 erosive esophagitis of experimental example
(1) the Ranitidine Capsules agent in embodiment 2 is used to carry out the clinical trial of erosive esophagitis：
Selection 40 suffer from erosive esophagitis patients, the age be 20~50 years old, selected case have heartburn, sour regurgitation or The symptoms such as anti-food, for subject in tested preceding physical examination and blood, routine urinalysis, the inspections such as the heart, Liver and kidney function are normal, tested the last fortnight And any drug is not taken during experiment, subject is without habits of smoking and alcohol drinking.
Subject is randomly divided into two groups, one group of Ranitidine Capsules agent (note for orally taking the preparation of the embodiment of the present invention 2 For experimental group), dosage is calculated as 150mg by ranitidine active ingredient, 2 times a day；One group of placebo (peace by oral administration It is starch piece to console agent, is denoted as control group), dosage 150mg forbids taking other influences treatment 2 times a day, during medication Drug.
After being administered six weeks, by endoscopic diagnosis standard and grade scale in reflux esophagitis diagnoses and treatment guide, by reflux Property esophagitis by Esophageal Mucosa it is endoscopic performance be divided into 0~III grade, wherein：0 grade is normal (can learn change in a organized way)；Ⅰ Grade is that dotted or strip is rubescent；II grades strip is rubescent, rotten to the corn to have, and has fusion, but not week, merges < 75%；III Grade is that lesion is extensive, and rubescent, rotten to the corn fusion is in week, fusion >=75%.By endoscopy oesophagus erosion treatment, It the results are shown in Table 7.
Esophagitis endoscopic grading compares before and after 7 medication of table
As shown in Table 7,40 patients of experimental group have 00 grade, 15 I grades, 22 II grades and 3 III before the treatment Grade has 26 patients to cure (showing as 0 grade) after taking the Ranitidine Capsules agent of the preparation of the embodiment of the present invention 2.
Wherein, endoscopic grading going up one level is effectively (to rise to II grades by III level, rise to I by II grades after treatment Grade by I grade rises to 0 grade), rising two-stage or more is effective (to rise to I grades or 0 grade by III level, rise to 0 by II grades Grade).
In experimental group：Being shown as after 26 healings has 15 in 0 grade of patient be patient's healing that I grades are shown as before treating (being effective), it is patient's healing (as effective) that II grades are shown as before treating to have 11, has 0 to be shown as before treatment The patient of III level cures；Being shown as after 9 treatments has 9 in I grade of patient be patient's healing that II grades are shown as before treating (being effective)；It is patient's healing that II grades are shown as before treating to have 2 in 3 II grade of patients, has 1 to be shown as before treatment The patient of III level cures (being effective).
In control group：The patient that I grades are shown as before being treated in 13 patients for showing as I grades after healing has 13, treatment The patient for showing as I grades before being treated in 25 patients for showing as II grade afterwards has 2, and the patient for showing as II grades has 22, table Now have 1 (being effective) for the patient of III level；2 are the patient for being shown as before being treated in III level patient III level after treatment There are 2.
It can be seen from the above, effective 11 in experimental group, effective 25, total effective rate 90%, wherein total effective rate= (effective number of cases+effective number of cases)/(total number of cases) × 100%；Effective 0 in control group, effective 1, total effective rate 2.5%. It is found that experimental group treatment the with obvious effects of erosive esophagitis is better than control group.
Above-mentioned 26 be cured patient is randomly divided into two groups, one group sleep before take ranitidine 150mg and (be denoted as reality Test group), another group is taken placebo (placebo is starch piece, is denoted as control group), and after continuously taking 6 months, statistics is multiple Heat condition, the results are shown in Table 8.
8 erosive esophagitis recurrence rate of table
0-3 months 0-6 months
Experimental group 8% 23%
Control group 15% 38%
As shown in Table 8, the Ranitidine Capsules agent described in the embodiment of the present invention 2 can effectively reduce erosive esophagitis Recurrence rate, it is also effective in cure in terms of the maintaining treatment of erosive esophagitis.
(2) compound preparation in embodiment 3 is used to carry out the clinical trial of erosive esophagitis：Selection 60 is with erosion Property esophagitis and gastroesophageal reflux disease (GERD) patient, the age is 20~50 years old, and selected case has heartburn, sour regurgitation or anti-food Etc. symptoms.For subject in tested preceding physical examination and blood, routine urinalysis, the inspections such as the heart, Liver and kidney function are normal, tested the last fortnight and examination Any drug is not taken during testing, and subject is without habits of smoking and alcohol drinking.
Subject is randomly divided into two groups, one group of ranitidine compound preparation for orally taking the preparation of the embodiment of the present invention 3 (being denoted as experimental group), dosage are calculated as 150mg/d by ranitidine active ingredient, 2 times a day；One group of placebo by oral administration (placebo is starch piece, is denoted as control group), dosage 150mg forbids taking other shadows 2 times a day, during medication Ring the drug for the treatment of.
After being administered six weeks, by endoscopic diagnosis standard and grade scale in reflux esophagitis diagnoses and treatment guide, by reflux Property esophagitis by Esophageal Mucosa it is endoscopic performance be divided into 0~III grade, wherein：0 grade is normal (can learn change in a organized way)；Ⅰ Grade is that dotted or strip is rubescent；II grades strip is rubescent, rotten to the corn to have, and has fusion, but not week, merges < 75%；III Grade is that lesion is extensive, and rubescent, rotten to the corn fusion is in week, fusion >=75%.By endoscopy oesophagus erosion treatment, It the results are shown in Table 9：
Esophagitis endoscopic grading compares before and after 9 medication of table
As shown in Table 9,60 patients of experimental group have 00 grade, 15 I grades, 38 II grades and 7 III before the treatment Grade has 40 patients to cure (showing as 0 grade) after taking the ranitidine compound preparation of the preparation of the embodiment of the present invention 3.
Wherein, in experimental group：Have in 40 0 grade of patients 25 be treatment before show as II grade patient cure (as show Imitate), it is patient's healing (being effective) that I grades are shown as before treating to have 15, and it is the trouble for being shown as before treating III level to have 0 Person cures；It is patient's healing (being effective) that II grades are shown as before treating to have 12 in 15 I grade of patients, has 3 to treat Before show as III level patient cure (as effective)；It is the patient that II grades are shown as before treating to have 1 in 3 II grade of patients, It is the patient's healing (being effective) for being shown as before treating III level to have 2；Have in 2 III level patients 2 be treatment before be III Grade.
In control group, the patient that I grades are shown as before being treated in 14 patients for showing as I grades after treatment has 14, treatment 37 have 1 for the patient for showing as I grades before treatment in II grade of patient afterwards, and the patient for showing as II grades has 36；9 after treatment Patient to show as II grades before treatment in III level patient has 2, and the patient for showing as III level has 7.
It can be seen from the above, effective 28 in experimental group, effective 29, total effective rate 95%；Effective in control group is 0 Example is effectively 0.As can be seen that experimental group treatment the with obvious effects of erosive esophagitis is better than control group.
Above-mentioned 40 be cured patient is randomly divided into two groups, one group sleep before take ranitidine 150mg and (be denoted as reality Test group), another group is taken placebo (placebo is starch piece, is denoted as control group), and after continuously taking 6 months, statistics is multiple Heat condition, the results are shown in Table 10.
10 erosive esophagitis recurrence rate of table
0-3 months 0-6 months
Experimental group 15% 25%
Control group 25% 40%
As shown in Table 10, the ranitidine formulation described in the embodiment of the present invention 3 can effectively reduce erosive esophagitis Recurrence rate is able to maintain that treatment erosive esophagitis.
It is described the invention in detail above in association with detailed description and exemplary example, but these explanations are simultaneously It is not considered as limiting the invention.It will be appreciated by those skilled in the art that without departing from the spirit and scope of the invention, Can be with various equivalent substitutions, modifications or improvements are made to the technical scheme of the invention and its embodiments, these each fall within the present invention In the range of.

Claims (10)

1. a kind of ranitidine, which is characterized in that its purity is more than 99.0 weight %.
2. ranitidine according to claim 1, which is characterized in that in ranitidine,
Impurity AContent is 0.05%~0.3 weight %；
Preferably,
Impurity BContent is 0.02~0.2 weight %.
3. ranitidine according to claim 1 or 2, which is characterized in that further include impurity C in the ranitidineContent is 0.03%~0.2 weight %.
4. a kind of preparation method of ranitidine as described in one of claims 1 to 3, which is characterized in that the method includes Following steps：
Step I, by 2- [[[5- (dimethylamino) methyl -2- furans] methyl] sulfenyl] ethamine and N- methyl-1s-methyl mercapto -2- nitre Base vinylamine is dissolved in solvent and solution is made respectively, then mixes the two, is heated to certain temperature and is reacted；
After reaction hydrochloric acid is added, then extracted in step II in reaction solution, isolated organic phase and water phase；
Step III, water phase is handled, and ranitidine is prepared.
5. a kind of ranitidine formulation, main component is the ranitidine described in one of claims 1 to 3, which is characterized in that The dosage form of the ranitidine formulation includes oral preparation and injection, wherein the oral preparation include tablet, capsule, Granule and solution.
6. ranitidine formulation according to claim 5, which is characterized in that the oral preparation is by including that following weight is matched Raw material than component is made：
Preferably, the preparation method of the ranitidine oral preparation includes the following steps：
Step 1, each raw material is stirred evenly in proportion, wet granular is made；
Step 2, oven drying is added in wet granular；
Step 3, dry particle is sieved, it is then total mixed；
Step 4, total mixed particle preparation is obtained into ranitidine oral preparation.
7. a kind of ranitidine compound preparation, main component is the ranitidine described in one of claims 1 to 3, feature It is, the compound preparation is made of the raw material including following weight proportion component：
100 parts by weight of ranitidine
0~60 parts by weight of mucosa protection agent
0~30 parts by weight of bacteriostatic agent.
Preferably, the compound preparation is made of the raw material including following weight proportion component：
8. a kind of preparation method of ranitidine compound preparation as claimed in claim 7, which is characterized in that the method includes Following steps：
Step 1, ranitidine is prepared into drug containing vegetable pill；
Step 2, above-mentioned drug containing vegetable pill is prepared into pellet, processing is then dried；
Step 3, mucosa protection agent, bacteriostatic agent, blocking agent and additive being mixed, the pellet after being dried with step 2 mixes, Obtain confection；
Step 4, the confection of above-mentioned preparation is dispensed, obtains ranitidine oral preparation.
9. according to the method described in claim 8, it is characterized in that, in step 3, the additive includes gel forming agent, consolidates Agent, corrigent and preservative,
Based on the ranitidine of 100 parts by weight, the amount that the gel forming agent, curing agent, corrigent and preservative are added is distinguished For (80~300) parts by weight, (5~40) parts by weight, (200~1000) parts by weight and (2~15) parts by weight.
10. the ranitidine formulation as described in one of ranitidine or claim 5 to 7 as described in one of claims 1 to 3 Or the purposes of compound preparation in medicine preparation, it is preferable that the drug is for treating and maintaining treatment erosive esophagitis.
CN201810877470.4A 2018-08-03 2018-08-03 New indication of ranitidine oral preparation for treating erosive esophagitis Active CN108727312B (en)

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Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0697411A1 (en) * 1994-06-24 1996-02-21 Ranbaxy Laboratories Limited Process for the manufacture of pharmaceutical grade ranitidine base

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0697411A1 (en) * 1994-06-24 1996-02-21 Ranbaxy Laboratories Limited Process for the manufacture of pharmaceutical grade ranitidine base

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
M.A. KELLY ET AL.: "Optimisation, validation and application of a capillary electrophoresis method for the determination of ranitidine hydrochloride and related substances", 《JOURNAL OF CHROMATOGRAPHY A》 *

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