CN104906128B

CN104906128B - Compound famotidine calcium and magnesium chewable tablets and preparation method

Info

Publication number: CN104906128B
Application number: CN201510304463.1A
Authority: CN
Inventors: 熊晓滨; 张永光; 柳莉; 张丽
Original assignee: YANTAI RONGCHANG PHARMACY CO Ltd
Current assignee: YANTAI RONGCHANG PHARMACY CO Ltd
Priority date: 2015-06-04
Filing date: 2015-06-04
Publication date: 2017-08-11
Anticipated expiration: 2035-06-04
Also published as: CN104906128A

Abstract

The present invention relates to compound famotidine calcium and magnesium chewable tablets and preparation method, famotidine, calcium carbonate, magnesium hydroxide are included in the famotidine calcium and magnesium chewable tablets.Specifically, the invention belongs to pharmaceutical technology field, it is related to a kind of pharmaceutical composition for being used to treat stomach trouble, more particularly to famotidine (Famotidine), calcium carbonate, the compound medicament composition of magnesium hydroxide, more particularly to it is a kind of with excellent pharmaceutical properties comprising famotidine, calcium carbonate, magnesium hydroxide famotidine calcium and magnesium chewable tablets.Famotidine calcium and magnesium chewable tablets of the present invention not only has excellent galenic pharmacy property, and with excellent chemical stability.Famotidine calcium and magnesium chewable tablets of the present invention clinically can be used for sour regurgitation, hydrochloric acid in gastric juice, heartburn (heartburn), stomachache, gasteremphraxis, belch and other treatment or prevention having a stomach upset.The invention further relates to the preparation method of the famotidine calcium and magnesium chewable tablets.

Description

Compound famotidine calcium and magnesium chewable tablets and preparation method

Technical field

The invention belongs to pharmaceutical technology field, it is related to a kind of pharmaceutical composition for being used to treat stomach trouble, more particularly to method Fourth (Famotidine), calcium carbonate, the compound medicament composition of magnesium hydroxide are not replaced, is had more particularly to one kind excellent Pharmaceutical properties include famotidine, calcium carbonate, the famotidine calcium and magnesium chewable tablets of magnesium hydroxide.Famotidine calcium and magnesium of the present invention Chewable tablets not only has excellent galenic pharmacy property, and with excellent chemical stability.Famotidine calcium and magnesium nozzle of the present invention Chew piece and clinically can be used for sour regurgitation, hydrochloric acid in gastric juice, heartburn (heartburn), stomachache, gasteremphraxis, belch and other treatments having a stomach upset Or prevention.

Background technology

Stomach trouble is very common illness, during breaking-out generally have epigastric discomfort, stomachache or burn feeling, heartburn sense, abdominal distension, Nausea etc. is had a stomach upset symptom.According to the relevant information, the external incidence of disease of disease of digestive system is in 20% or so, China's morbidity Rate about 30%, this greatly affects the normal study and work of people, therefore, protects the stomach of oneself, prevents the hair of stomach trouble Raw or recurrence is to keeping the normal quality of life of people to have highly important meaning.

The generation of stomach trouble has close relationship with hydrochloric acid in gastric juice, and hydrochloric acid in gastric juice is the parietal cell secretion by gastric mucosa, with a variety of work( Energy：Activate propepsin, promote it to be converted into pepsin, this enzyme energy aminosal, in favor of small intestine decomposition and Absorb；The bacterium entered with food in stomach is killed in order to avoid do harm to huamn body；Small intestine is promoted to absorb iron and calcium system, it is long-term to lack Few hydrochloric acid in gastric juice can cause hypoferric anemia and low blood calcium；Hydrochloric acid in gastric juice enters after small intestine, can promote the secretion of pancreatic juice, intestinal juice and bile.Though Right hydrochloric acid in gastric juice has very important effect in digestive system, but excessive hydrochloric acid in gastric juice can then cause certain harm to human body.

Clinical studies show, because hyperhydrochloria generation, or hydrochloric acid in gastric juice are to the place (such as gastroesophageal reflux) that should not be gone Occurs the basic reason of stomach trouble.Certainly, although also the growing amount of someone's hydrochloric acid in gastric juice does not increase, due to there is hydrochloric acid in gastric juice excretory function Obstacle, makes the hydrochloric acid in gastric juice residence time long, or because body is strong to the sensitiveness of acid so that actual not excessive hydrochloric acid in gastric juice is to stomach Stimulation is produced, so as to produce various malaise symptoms.So, control hydrochloric acid in gastric juice is the key for protecting stomach.The patient of hyperhydrochloria, due to stomach The stimulation of acid, stomach has burn feeling, that is, the heartburn symptom that as the saying goes, this is due to that gastric acid reflux enters chest interruption caused by oesophagus Or rest pain, typically occur in night.

The medicine that in the market acts on hydrochloric acid in gastric juice mainly has two major classes：One class is antiacid, directly neutralizes hydrochloric acid in gastric juice, conventional medicine Thing (containing compound preparation) has aluminium hydroxide, calcium carbonate, magnesia, magnesium trisilicate, alumina silicate, aluminum phosphate, aluminum magnesium hydroxide etc..Separately An outer class is acid inhibitor, plays effect of effecting a permanent cure, and acts on slower, does not participate in directly neutralizing hydrochloric acid in gastric juice, mainly there is H₂Receptor antagonist is such as Cimetidine, ranitidine and famotidine etc., this kind of drug potency are larger, are mainly used in the serious gastrointestinals such as gastric ulcer The treatment of disease.

2000, Johnson ＆ Johnson-Merck ＆ Co., Inc. is proposed treated heartburn and gastroxia type through being used for of ratifying of FDA Dyspeptic Pepcid Complete chewable tablets, the chewable tablets is non-prescribed medicine, by 10mg famotidines, 800mg calcium carbonate Constituted with 165mg magnesium hydroxides, be in the world first be also uniquely to integrate long-acting and short-acting hydrochloric acid in gastric juice drugs with function Hydrochloric acid in gastric juice complete inhibition agent so that hydrochloric acid in gastric juice can only temporarily be neutralized by fundamentally overcoming exclusive use antiacid, and antiacid Need the contradiction situation that certain time could start to work.The chewable tablets has following several features：1st, act on rapid, take with It is rapid afterwards to neutralize hydrochloric acid in gastric juice, relief of symptoms.2nd, it is long-acting, rear gastric acid secretion inhibiting is taken up to more than 12 hours.3rd, it is easy to use, only Taking a piece of can solve problem.4th, two kinds of mechanism of action are provided, both gastric acid secretion inhibiting, hydrochloric acid in gastric juice can be neutralized immediately again.

Pepcid Complete be it is a kind of both can quick acting, heartburn compound for the treatment of that symptom can be kept not recur again Thing.Before this medicine, in the American for about having burn feeling symptom 100,000,000, most people has used more than one medicine to delay more Symptom is solved, they should consider that quick acting considers duration of efficacy again, now with Pepcid Complete just without handing over For using other medicines, consumer only take it is a piece of can kill two birds with one stone, both can quickly prove effective, when can remain longer again Between.

Boston medical college, gastroenterology Section director Michael doctors of medicine Wolfe of Boston University medical center Explain：Nothing can quickly control hydrochloric acid in gastric juice than Pepcid Complete, in addition, also not having other medicines ratio Pepcid Complete have the stronger effect for preventing burn feeling and the dyspeptic recurrence of gastroxia type.

Pepcid Complete chewable tablets famotidine containing 10mg, occurs after Cimetidine and ranitidine Third generation H₂Receptor antagonist.Famotidine was developed in 1981 by Japanese Yamanouchi (Yamanoouchi) Pharmaceutical Co., Ltd Exploitation, produces and lists for 1985, at present in the countries and regions application of more than 60, the world.The action intensity of famotidine is than western miaow Big 32 times for fourth, bigger than ranitidine 9 times, action time is also longer than Cimetidine and ranitidine by 1/3.Famotidine can be blocked Histamine and the H on parietal cell film₂Acceptor combine so that dosage correlation suppress basal gastric acid secretion and by food, pentapeptide The gastric acid secretion that gastrin, histamine, insulin and caffeine are stimulated.Take after 20,40mg famotidines in the evening, point of hydrochloric acid in gastric juice Secrete and be suppressed 86% and 94% respectively, take 20,40mg famotidines morning after 3~5 hours, the secretion of hydrochloric acid in gastric juice is suppressed respectively It is 25% and 30% after 76% and 84%, 8~10 hours.In this product, famotidine Sustainable Control acid was up to 12 hours.

Endless hypersorption after famotidine is oral, reaches blood medicine peak value, t in 2~3 hours_1/2About 3 hours.Famotidine is in body It is interior widely distributed, there is high concentration distribution in alimentary canal, kidney, liver, salivary gland and pancreas, but be not through placental barrier, oral bio Availability is about 40~45%, and plasma protein binding rate is 15~20%.The removing half-life period of famotidine is 2.5~3.5 small When, 65~70% dosage is by kidney excretion, and kidney clearing amount is 250~450ml/min, and 25~30% occur with prototype In urine.The bile excretion amount of famotidine is few, can be discharged from milk.In addition, the removing half-life period of famotidine and kidney Clearing amount has substantial connection, kidney clearing amount<The removing half-life period of 10ml/min patient will be extended down to more than 20 hours.

Calcium carbonate 800mg in the compound chewable tablets, calcium carbonate is that an external class is very common to be controlled for enterogastric diseases The medicine for the treatment of, it has good efficacy and saferry.It is domestic to have Duo Jia pharmaceutical factories production calcium carbonate at present, for replenishing the calcium or resisting Sour medicine.Calcium carbonate can neutralize hydrochloric acid in gastric juice, to gastric acid secretion without direct repression, mainly eliminate hydrochloric acid in gastric juice by improving hydrochloric acid in gastric juice pH The feedback that parietal cell secretes is suppressed, specific mechanism of action is：1st, H is neutralized⁺, reduce H⁺To the back diffusion of gastric mucosa；2nd, improve The activity of gastric juice pH, reduction hydrochloric acid in gastric juice and pepsin.

After calcium carbonate is taken, combined in stomach with hydrochloric acid in the calcium chloride of generation ease of solubility, 90% calcium chloride and small intestine Secondary carbonic acid act on forming insoluble calcium salt, the calcium chloride of residue 10% is rapidly absorbed into body circulation after being combined with secondary carbonic acid. Calcium carbonate is main by intestinal absorption, in alkaline intestinal juice or in the presence of having an abundant fatty acid, easily forms calcium soap and reduces absorption.80% Dosage drained from excrement, 20% from urine drains.Compared with taking calcium carbonate under the conditions of empty stomach, 1 hour after the meal or preceding clothes are slept It is longer with the time of its effect lasts.

The compound chewable tablets also contains magnesium hydroxide 165mg, and its antiacid effect is strong compared with sodium acid carbonate, neutralizes hydrochloric acid in gastric juice effect slow It is slow and lasting, do not produce carbon dioxide.Act on hydrochloric acid in gastric juice after taking and generate soluble magnesium chloride, release magnesium ion, magnesium ion thorn Gastrointestinal peristalsis is swashed, with laxative effective, it is adaptable to the hyperchlorhydria of constipation；For with constipation person, this product is not made seldom Used for single antiacid medicine, typically share to eliminate its hypocatharsis effect with calcium carbonate.

Magnesium hydroxide is non-systemic antacid thing, has very small amount to be changed into soluble magnesium chloride in stomach after taking, few Amount is discharged after absorbing through kidney.

Controlled clinical trial is shown, compared with other antiacid products or acid suppression product, Pepcid Complete chewable tablets tool There are two major features：1st, it is rapid-action：30 minutes after drug administration, Pepcid Complete chewable tablets group (1205), famotidine The burn feeling remission rate of group (1229), antiacid medicine (calcium carbonate and magnesium hydroxide) (1212) and placebo (1217) Respectively 45.3%, 37.8%, 40.9% and 33.0%.2nd, acting duration is long：After drug administration 7 hours, Pepcid Complete chewable tablets group, famotidine group, the remission rate difference of antiacid medicine (calcium carbonate and magnesium hydroxide) and placebo For 70.4%, 68.3%, 61.3% and 59.0%.

In above-mentioned compound chewable tablets, in view of the amount of every middle calcium carbonate is up to 800mg and the amount of magnesium hydroxide is up to 165mg, and amount only have famotidine 10mg, and the chemical stability of famotidine is relatively sensitive, therefore, and preparing should There is many technical difficulties in compound chewable tablets.

Therefore, the famotidine with advantageous property/calcium carbonate/magnesium hydroxide compound preparation is still expected for example in this area Its chewable tablets, for example, especially expect that this chewable tablets not only has excellent preparation performance but also with excellent stability.

The content of the invention

It is an object of the invention to provide a kind of famotidine with advantageous property/calcium carbonate/magnesium hydroxide compound system Agent such as its chewable tablets, for example, especially expect that this chewable tablets has excellent preparation performance and/or with excellent stability. It has been found, unexpectedly, the famotidine with feature of present invention/calcium carbonate/magnesium hydroxide compound chewable tablets have it is excellent Good preparation performance and/or with excellent stability, the present invention is accomplished based on this discovery.

Therefore, first aspect present invention provides a kind of famotidine calcium and magnesium chewable tablets, wherein including famotidine, carbonic acid Calcium, magnesium hydroxide.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein not replaced comprising method The parts by weight of fourth 10, the parts by weight of calcium carbonate 750~850 (such as 780~820 parts by weight, e.g., from about 800 parts by weight), magnesium hydroxide 150~180 parts by weight (such as 155~175 parts by weight, e.g., from about 165 parts by weight).

Wrapped in the famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, its every tablet 2-25mg containing famotidine, such as comprising famotidine 5-20mg, such as comprising famotidine 5-15mg, for example, do not replace comprising method Fourth 5mg, 10mg, 15mg.

According to a first aspect of the present invention any embodiment provide famotidine calcium and magnesium chewable tablets, wherein also comprising times he Cyclodextrin.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, relative to every 10 weight Part famotidine for, wherein the amount of betadex be 10~100 parts by weight, such as 20~80 parts by weight, such as 30~ 70 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the method is not replaced Fourth is that the form of inclusion compound is made in advance with betadex to be added in the chewable tablets.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the inclusion compound Prepared according to following method：Purified water (its weight is 4-8 times of betadex) is heated to 85 ± 5 DEG C, addition Betadex, stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, famotidine is added, stirring makes whole dissolvings； It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then 1-3% (w/v) propane diols is added into the decoction under agitation；Then after It is continuous to be cooled to room temperature, it is transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerates 16-20 hours；After decoction separates out crystallization, crystallization is isolated, in temperature Dried at 70 ± 5 DEG C of degree to moisture and be less than 5%, then crushed, produced with the pulverizer equipped with 0.4mm apertures sieve.In this hair In the inclusion compound of the bright various batches prepared, according to Ma Mingxin etc. document, (Ma Mingxin determines profit etc., gas chromatography for it The content of propane diols in good fortune mycin sodium injection, Pharmaceutical Analysis magazine, the 10th phase in 2013) in gas chromatography determine, knot Fruit shows that these inclusion compounds are not detected by remnants propane diols, i.e., in end-product chewable tablets of the present invention, do not include substantially Propane diols.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein also including pharmacy Acceptable auxiliary material (referring to the auxiliary material in addition to betadex described above).

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes diluent.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the diluent Example be such as, but not limited to sucrose, mannitol, lactose, fructose, sorbierite etc. and combinations thereof.Due to these diluents generally and The large usage quantity of speech in tablets, although their some kinds have sweet taste and can used sometimes as flavor enhancement, at this Because substantial amounts of active constituents of medicine is present in invention, seasoning effect of these diluents in prescription be not obvious, therefore this Field generally classifies them as diluent rather than is classified as flavor enhancement.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the diluent Consumption in the chewable tablets is so that the piece of the chewable tablet every is focused in the range of 800~3000mg, such as 800~ In the range of 2500mg, such as in the range of 800~2000mg.Now, the base of each of which function is realized in the other auxiliary materials of guarantee On plinth, the consumption of diluent is generally that by preparation shaping, and therefore, typically, the consumption of diluent is can With what is be not particularly limited, active component and piece particularly in every are determined again in the case that.In an embodiment In, consumption of the diluent in the chewable tablets is 0.5~3 times of weight of calcium carbonate, particularly 0.5~2 times.

Furthermore, it is contemplated that the present invention is to the substantial contribution of prior art and does not lie in selection and the consumption of diluent, therefore When diluent of the present invention using combination, the portfolio ratio of these diluents need not be simultaneously particularly limited.

In the presence of a diluent, the shaping of tablet can be achieved on, such as because supplementary material has necessarily Caking property and the wetting granulation that can directly add water, particle has certain mobility and can be not added with lubricant tabletting in itself.That is, root According to the present invention, above-mentioned three kinds of raw materials and cyclodextrin and diluent are used, you can the chewable tablet of the present invention is made.People is gone out Expect ground to find, the tablet prepared is handled by the inventive method, even if without other auxiliary materials, these tablets have been in Existing unique pharmaceutical properties are for example with unique stability.

Certainly, in order to assign tablet other premium properties, added into tablet other auxiliary materials be still can be with acceptable.

Especially, chewable tablets of the present invention can be prepared by wet granule compression tablet method.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes flavor enhancement.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes adhesive.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes lubricant.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes colouring agent.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving is to be selected from following one or more：Diluent, flavor enhancement, colouring agent, adhesive, lubricant and combinations thereof.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the pharmacy can The auxiliary material of receiving includes：Diluent, flavor enhancement, colouring agent, adhesive, lubricant and combinations thereof.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the flavor enhancement Example be such as, but not limited to sweetener, essence and combinations thereof.In one embodiment, the example of the sweetener for example but It is not limited to Sucralose, saccharin sodium etc. and combinations thereof.In one embodiment, the example of essence is such as, but not limited to ice-cold sweet tea Orange powdered flavor, peppermint powdered flavor and combinations thereof.The famotidine that any embodiment is provided according to a first aspect of the present invention Calcium and magnesium chewable tablets, for the famotidine of every 10 parts by weight, wherein the amount of flavor enhancement be 1~15 parts by weight, such as 2~ 12 parts by weight, such as 3~8 parts by weight, such as 4~6 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the colouring agent It is aluminum lake.In one embodiment, the aluminum lake is Ponceau 4R aluminum lake.It is any according to a first aspect of the present invention to implement The famotidine calcium and magnesium chewable tablets that scheme is provided, for the famotidine of every 10 parts by weight, the amount of wherein colouring agent is 0.1~1 parts by weight, such as 0.2~0.75 parts by weight, such as 0.3~0.7 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein described adhesive Such as, but not limited to PVP, hydroxypropyl methyl cellulose, starch etc. and combinations thereof.They are configured to the water-soluble of suitable concentration Liquid is preferred, and the aqueous solution for being for example configured to 2-8% is used.Certainly, being directly also as wetting agent wet granular using water can Capable.Typically, the consumption of bonder is by empirically determined, that is, to reach the degree that suitable wet granular is made.Allusion quotation Type, the adhesive of mentioned kind counts amount in tablets as 0.5~5% using dry weight, and such as 1~3%.Or, it is typical on Amount of the adhesive of species in terms of dry weight in tablets is stated, for the famotidine of every 10 parts by weight, in an amount of from 10~ 50 parts by weight, such as 10~40 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein adhesive includes PVP.In one embodiment, described PVP is PVP K-30,30 POVIDONE K 30 BP/USP -15 or 30 POVIDONE K 30 BP/USP -60.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the PVP It is to be added as the consumption of adhesive.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the PVP It is to be configured to after the solution of concentration 2~8% as the consumption of adhesive add with water.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein the lubricant Such as, but not limited to silica, magnesium stearate, stearic acid, talcum powder etc. and combinations thereof.It is any according to a first aspect of the present invention The famotidine calcium and magnesium chewable tablets that embodiment is provided, for the famotidine of every 10 parts by weight, wherein lubricant Measure as 10~50 parts by weight, such as 10~40 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, wherein including：

The parts by weight of famotidine 10,

The parts by weight of calcium carbonate 750~850 (such as 780~820 parts by weight, e.g., from about 800 parts by weight),

The parts by weight of magnesium hydroxide 150~180 (such as 155~175 parts by weight, e.g., from about 165 parts by weight),

The parts by weight of betadex 10~100 (such as 20~80 parts by weight, such as 30~70 parts by weight),

Its amount of diluent be weight of calcium carbonate 0.5~3 times (such as 0.5~2 times),

The parts by weight of flavor enhancement 1~15, such as 2~12 parts by weight, such as 3~8 parts by weight, such as 4~6 parts by weight,

The parts by weight of colouring agent 0.1~1, such as 0.2~0.75 parts by weight, such as 0.3~0.7 parts by weight,

The parts by weight of adhesive 10~50, such as 10~40 parts by weight,

The parts by weight of lubricant 10~50, such as 10~40 parts by weight.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, it is packing bar Under part, be placed in 40 DEG C, place 6 months under the conditions of lucifuge, the famotidine calcium and magnesium chewable tablets at June relative to 0 month when phase Residual content (%) when being June to content (%) is more than 95%, for example, 95%~102%, for example, 96%~101%.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, it is packing bar Under part, 40 DEG C being placed in, being placed 6 months under the conditions of lucifuge, famotidine calcium and magnesium chewable tablets impurity C at June increases percentage amounts (%) is less than 75%, for example, 20~100%, for example, 20~80%, for example, 20~60%.

The famotidine calcium and magnesium chewable tablets that any embodiment is provided according to a first aspect of the present invention, it is by routine Wet granule compression tablet mode is prepared.For example, it is prepared by the method comprised the following steps：

(1) adhesive is configured to the solution that concentration is 2~8%, it is standby；

(2) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide and other solid materials are distinguished into powder It is broken, cross 120 mesh sieves；

(3) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide are well mixed, add optional dilution Agent, flavor enhancement, colouring agent are well mixed, and wet granulation is carried out to mixed-powder material with binder solution obtained by step (1), will Gained wet granular is transferred in air dry oven, 60~80 DEG C of dryings 2~4 hours, and whole grain obtains dry particl；

(4) it is dry particl obtained by step (3) is uniform with mix lubricant, mixed particle eventually is obtained, it is tabletted, obtain method not For fourth calcium and magnesium chewable tablets.

Further, second aspect of the present invention provides a kind of method for preparing famotidine calcium and magnesium chewable tablets.

The method that any embodiment is provided according to a second aspect of the present invention, wherein in the famotidine calcium and magnesium chewable tablets Include famotidine, calcium carbonate, magnesium hydroxide.

The method that any embodiment is provided according to a second aspect of the present invention, wherein in the famotidine calcium and magnesium chewable tablets Include the parts by weight of famotidine 10, the parts by weight of calcium carbonate 750~850 (such as 780~820 parts by weight, e.g., from about 800 weight Part), the parts by weight of magnesium hydroxide 150~180 (such as 155~175 parts by weight, e.g., from about 165 parts by weight).

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets is every Famotidine 2-25mg is included in grain tablet, such as comprising famotidine 5-20mg, for example comprising famotidine 5-15mg, for example Include famotidine 5mg, 10mg, 15mg.

The method that any embodiment is provided according to a second aspect of the present invention, wherein in the famotidine calcium and magnesium chewable tablets Also include betadex.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, for the famotidine of every 10 parts by weight, wherein the amount of betadex be 10~100 parts by weight, such as 20~ 80 parts by weight, such as 30~70 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the famotidine is that the form of inclusion compound is made in advance with betadex to be added in the chewable tablets.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, wherein the inclusion compound is prepared according to following method：Purified water (its weight is 4-8 times of betadex) is added Heat adds betadex to 85 ± 5 DEG C, and stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, addition method is not replaced Fourth, stirring makes whole dissolvings；It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then into the decoction add 1-3% under agitation (w/v) propane diols；Then proceed to be cooled to room temperature, be transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerate 16-20 hours；Treat that decoction separates out crystallization Afterwards, crystallization is isolated, is dried at 70 ± 5 DEG C of temperature to moisture and is less than 5%, then with the crushing equipped with 0.4mm apertures sieve Machine is crushed, and is produced.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, in addition to pharmaceutically acceptable auxiliary material (referring to the auxiliary material in addition to betadex described above).

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes diluent.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the example of the diluent is such as, but not limited to sucrose, mannitol, lactose, fructose, sorbierite etc. and combinations thereof.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, consumption of the diluent in the chewable tablets is so that the piece of the chewable tablet every is focused in the range of 800~3000mg, for example In the range of 800~2500mg, such as in the range of 800~2000mg.Now, each of which work(is realized in the other auxiliary materials of guarantee On the basis of energy, the consumption of diluent is generally that by preparation shaping, therefore, typically, the use of diluent Amount can be not particularly limited, the active component and piece particularly in every are determined again in the case that.In a reality Apply in scheme, consumption of the diluent in the chewable tablets is 0.5~3 times of weight of calcium carbonate, particularly 0.5~2 times.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets is Prepared by wet granule compression tablet method.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes flavor enhancement.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes adhesive.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes lubricant.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes colouring agent.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material is to be selected from following one or more：Diluent, flavor enhancement, colouring agent, adhesive, profit Lubrication prescription and combinations thereof.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the pharmaceutically acceptable auxiliary material includes：Diluent, flavor enhancement, colouring agent, adhesive, lubricant and combinations thereof.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the example of the flavor enhancement is such as, but not limited to sweetener, essence and combinations thereof.In one embodiment, the sweet taste The example of agent is such as, but not limited to Sucralose, saccharin sodium etc. and combinations thereof.In one embodiment, the example of essence is for example But it is not limited to ice-cold sweet orange powdered flavor, peppermint powdered flavor and combinations thereof.Any embodiment according to a first aspect of the present invention The famotidine calcium and magnesium chewable tablets of offer, for the famotidine of every 10 parts by weight, wherein the amount of flavor enhancement is 1~15 Parts by weight, such as 2~12 parts by weight, such as 3~8 parts by weight, such as 4~6 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the colouring agent is aluminum lake.In one embodiment, the aluminum lake is Ponceau 4R aluminum lake.According to the present invention the The famotidine calcium and magnesium chewable tablets that one side any embodiment is provided, for the famotidine of every 10 parts by weight, its The amount of middle colouring agent is 0.1~1 parts by weight, such as such as 0.2~0.75 parts by weight, 0.3~0.7 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, described adhesive is such as, but not limited to PVP, hydroxypropyl methyl cellulose, starch etc. and combinations thereof.They are configured to The aqueous solution of suitable concentration is preferred, and the aqueous solution for being for example configured to 2-8% is used.Certainly, wetting agent is directly used as using water Wet granular processed is also feasible.Typically, the consumption of bonder is by empirically determined, that is, to reach and suitable wet granular is made Degree.Typically, the adhesive of mentioned kind counts amount in tablets as 0.5~5% using dry weight, and such as 1~3%. Or, the amount of the adhesive of typical mentioned kind in terms of dry weight in tablets, relative to every 10 parts by weight famotidine and Speech, in an amount of from 10~50 parts by weight, such as 10~40 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, adhesive includes PVP.In one embodiment, described PVP is PVP K-30,30 POVIDONE K 30 BP/USP -15 or poly- Tie up ketone K-60.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the PVP is added as the consumption of adhesive.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the PVP is to be configured to after the solution of concentration 2~8% as the consumption of adhesive add with water.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets In, the lubricant is such as, but not limited to silica, magnesium stearate, stearic acid, talcum powder etc. and combinations thereof.According to the present invention The method that second aspect any embodiment is provided, wherein in the famotidine calcium and magnesium chewable tablets, relative to every 10 parts by weight Famotidine for, wherein the amount of lubricant be 10~50 parts by weight, such as 10~40 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein in the famotidine calcium and magnesium chewable tablets Comprising：

The parts by weight of famotidine 10,

The parts by weight of adhesive 10~50, such as 10~40 parts by weight,

The parts by weight of lubricant 10~50, such as 10~40 parts by weight.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets exists Under the conditions of packing, be placed in 40 DEG C, place 6 months under the conditions of lucifuge, the famotidine calcium and magnesium chewable tablets at June relative to Residual content (%) during relative amount (%) June at 0 month is more than 95%, for example, 95%~102%, for example, 96% ~101%.

The method that any embodiment is provided according to a second aspect of the present invention, wherein the famotidine calcium and magnesium chewable tablets exists Under the conditions of packing, 40 DEG C are placed in, place 6 months under the conditions of lucifuge, famotidine calcium and magnesium chewable tablets impurity C at June Increase percentage amounts (%) and be less than 75%, for example, 20~100%, for example, 20~80%, for example, 20~60%.

The method that any embodiment is provided according to a second aspect of the present invention, it is conventional wet granule compression tablet technique.

The method that any embodiment is provided according to a second aspect of the present invention, it comprises the following steps：

In the step of above-mentioned preparation method of the invention, although specific steps that it is described are in some details or language The step of described in preparation example in description with following detailed description part, is otherwise varied, however, people in the art Member can summarize approach described above step completely according to the detailed disclosure of full text of the present invention.

Any embodiment of the either side of the present invention, can be combined with other embodiments, as long as they are not Contradiction occurs.In addition, in any embodiment of either side of the present invention, any technical characteristic goes for other realities The technical characteristic in scheme is applied, as long as they are not in contradiction.The invention will be further described below.

All documents recited in the present invention, their full content is incorporated herein by reference, and if these are literary Offer expressed implication with it is of the invention inconsistent when, be defined by the statement of the present invention.In addition, the various terms that use of the present invention and Phrase has well known to a person skilled in the art general sense, nonetheless, the present invention remain desirable at this to these terms and Phrase is described in more detail and explained that the term and phrase referred to is if any inconsistent with common art-recognized meanings, with institute's table of the present invention The implication stated is defined.

In the present invention, famotidine calcium and magnesium chewable tablets of the invention be also referred to as compound famotidine chewing tablet or its Its similar appellation.

Main composition famotidine contained by this product famotidine calcium and magnesium chewable tablets, is gone out after Cimetidine and ranitidine Existing third generation H₂Receptor antagonist, its action intensity is bigger than Cimetidine 32 times, bigger than ranitidine 9 times, action time It is longer than Cimetidine and ranitidine by 1/3.Famotidine energy blocking histamine and the H on parietal cell film₂Acceptor is combined, so that agent Suppress basal gastric acid secretion and the hydrochloric acid in gastric juice stimulated by food, pentagastrin, histamine, insulin and caffeine to amount correlation Secretion.Take after 20,40mg famotidines in the evening, and the secretion of hydrochloric acid in gastric juice is suppressed 86% and 94% respectively, takes 20,40mg mornings After famotidine 3~5 hours, the secretion of hydrochloric acid in gastric juice is suppressed after 76% and 84%, 8~10 hours as 25% and 30% respectively. In this product, famotidine Sustainable Control acid was up to 12 hours.

Every calcium carbonate of this product and magnesium hydroxide, both compositions can neutralize hydrochloric acid in gastric juice, to gastric acid secretion without directly suppression Effect, mainly eliminates the feedback suppression that hydrochloric acid in gastric juice is secreted to parietal cell, specific mechanism of action is by improving hydrochloric acid in gastric juice pH：1、 Neutralize H⁺, reduce H⁺To the back diffusion of gastric mucosa；2nd, the activity of gastric juice pH, reduction hydrochloric acid in gastric juice and pepsin is improved.

Hydrogen-oxygen typically shares to eliminate the hypocatharsis effect of magnesium for magnesium and with calcium carbonate.

Given in the healthy volunteer's compound famotidine chewing tablet single dose carried out to famotidine calcium and magnesium chewable tablets of the present invention In the pharmacokinetics test of medicine, determine compound famotidine chewing tablet main component famotidine through when blood concentration, calculate Famotidine main pharmacokinetic parameter, understands absorption of the famotidine in human body, distribution, depletion role, is compound method For the clinical trial phase of fourth chewable tablets II provide safely, effectively, rational testing program.

Healthy volunteer 10, men and women half and half, once took compound famotidine on an empty stomach respectively at experiment morning on the same day and chews Piece 2, in before medicine and taking ulnar vein blood 4ml within 0.5,1.0,1.5,2,2.5,3,3.5,4,6,8,10,12,15 hours after medicine, puts In heparinized tubes, 3000 revs/min centrifuge 10 minutes, take blood plasma point double in the standby survey of -20 DEG C of storages.Famotidine blood concentration Degree-time data warp《DAS practicality pharmacokinetics calculation procedures》Processing, obtains the pharmacokinetic parameter of famotidine.As a result It has been shown that, famotidine main pharmacokinetic parameter t_1/2For 4.013 ± 0.332h, Tmax is 1.950 ± 0.284h, and Cmax is 63.597 ± 17.703 μ g/ml, AUC_0~15For 327.837 ± 73.647 μ g/mlh, AUC_0~∞For 394.937 ± 75.533 μ G/mlh, Ke are 0.174 ± 0.016h^-1, MRT is 6.552 ± 0.635h.Show that method is not replaced in compound famotidine chewing tablet The oral about 2h of fourth reaches blood concentration peak value, mean elimination half life 4h, basically identical with document report.Other compositions not shadow in preparation Ring its physiological disposition.

In the multiple center clinical study carried out to famotidine calcium and magnesium chewable tablets of the present invention, compound famotidine have rated Chewable tablets is alleviated caused by acid-related disease (peptic ulcer, GERD, reflux esophagitis, chronic gastritis etc.) The clinical efficacy and its security of the symptoms such as heartburn, acid reflux, stomachache, and compared with famotidine tablets.

Main validity evaluation index includes：Clinical symptoms total score, paresthesia alleviateding time after first dose.Symptom is delayed after first dose The time of the symptom complete incidence graph such as heartburn, sour regurgitation after solution time=medication (first dose) medication in first day, blocked according to Patients Diary and remembered Record judges.

Administrated method：The whole course for the treatment of is 7 days.First famotidine simulation piece 1 when test group has symptom for first day, after Take compound famotidine chewing tablet 1, second day and take medicine (method of administration and dosage are ibid) when then having within several days symptom, If asymptomatic, preceding medication is slept.First famotidine piece 1 when control group has symptom for first day, after take compound method and do not replace Fourth chewable tablets is simulated piece 1, second day and taken medicine (method of administration and dosage are ibid) when then having within several days symptom, if without disease Shape, then sleep preceding medication.

As a result show, compound famotidine chewing tablet of the invention for sour regurgitation, hydrochloric acid in gastric juice, heartburn (heartburn), stomachache, Effective percentage is up to more than 95% in terms of gasteremphraxis, belch and other treatment or prevention having a stomach upset, and adverse reaction rate is extremely low.

Embodiment

The present invention can be further described by the following examples, however, the scope of the present invention is not limited In following embodiments.One of skill in the art, can be with it is understood that on the premise of without departing substantially from the spirit and scope of the present invention Various change and modification are carried out to the present invention.The present invention carries out general to the material and test method that are arrived used in experiment And/or specific description.Although for realize many materials used in the object of the invention and operating method be it is known in the art that But the present invention is still described in detail as far as possible herein.

Hereafter preparation process is for the purpose of citing, and the comparability based on each citing and make some specific description, Those skilled in the art can therefrom summarize the method that the present invention prepares product that obtains according to existing knowledge completely.Prepare below Various chewing tablet compositions in, if not otherwise indicated, total dosage of every batch is to contain famotidine in 50,000 amounts, every 10mg (realizes the compacting of other specification tablets, such as with small rule easily by the specification of adjustment plunger die for tabletting press in preparation industry Lattice punch die or big specification punch die suppress the tablet of 5mg or 15mg specifications).When listing formula and preparation process, for various Agent, formula and preparation method are illustrated with the composition in every 1.In the example for preparing composition below, if not otherwise indicated, various materials Crushed and can be by 120 mesh sieve using preceding.

First, method of testing

Famotidine assay in test case 1, tablet

According to the D high effective liquid chromatography for measuring of two annex of Chinese Pharmacopoeia 2010 edition V；

Chromatographic condition and system suitability：It is filler with octadecylsilane chemically bonded silica；With sodium heptanesulfonate Solution (taking sodium heptanesulfonate 2.0g, after the 900ml that adds water dissolvings, adjust pH value to 3.9 with glacial acetic acid, add water to 1000ml)-second Nitrile-methanol (25:6:1) it is mobile phase；Detection wavelength is 254nm；Number of theoretical plate is calculated by famotidine peak to be not less than 2000；

Determination method：The sample that weight differential of learning from else's experience is determined, finely ground, precision is weighed (is approximately equivalent to famotidine in right amount 10mg), put in 50ml measuring bottles, plus appropriate methanol, shaking dissolves famotidine, and is shaken up with methanol dilution to scale, filters Cross, precision measures subsequent filtrate 1ml, put in 10ml measuring bottles, scale is diluted to mobile phase, shake up, filter, it is molten as test sample Liquid, measures 20 μ l injection liquid chromatographs, records chromatogram；Another 80 DEG C of phosphorus pentoxide of learning from else's experience is dried under reduced pressure the method for 4 hours not It is appropriate for fourth reference substance, it is measured in the same method；By external standard method with calculated by peak area, the famotidine (C in every₈H₁₅N₇O₂S₃) content.

Famotidine Determination of Content Uniformity in test case 2, tablet

According to the famotidine in the tablet of method and above-mentioned test case 1 shown in two annex X E of Chinese Pharmacopoeia 2010 edition Content determination, determines the famotidine uniformity of dosage units in each preparation-obtained compound famotidine chewing tablet of experiment. Generally speaking, States Pharmacopoeia specifications, A+1.80S≤15.0 item are qualified, and uniformity of dosage units is better if A+1.80S values are smaller；If A +1.80S>15.0 it is then unqualified.When certain A+1.80S is close to 15.0, show that preparation process is dangerous and is to have much room for improvement 's.

Specific impurities inspection in test case 3, tablet

According to having in American Pharmacopeia 35 editions (USP35) contained famotidine tablets (Famotidine Tablets) of page 3153 Related compounds (Related compounds) detection method checked, especially severe to relative retention time therein about 0.8 at Impurity C be 3- [2- (diaminomethyleneamino) -1,3-thiazoles -4- ylmethylthios]-N- sulfamoyls-propionamide, English Literary fame：3-[2-(diaminomethyleneamino)-1,3-thiazol-4-ylmethylthio]-N-sulfamoyl- Propanamide, it has been found that this impurity easily increases and typically especially needs what is paid close attention in the formulation.

The preparation of inclusion compound 1：Purified water 6 times of betadex (its weight be) is heated to 85 ± 5 DEG C, him is added times Cyclodextrin, stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, famotidine is added (in an amount of from betadex 1/5), stirring makes whole dissolvings；It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then into the decoction add 2% under agitation (w/v) propane diols；Then proceed to be cooled to room temperature, be transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerate 18 hours；After decoction separates out crystallization, Crystallization is isolated, is dried at 70 ± 5 DEG C of temperature to moisture and is less than 5%, then with the pulverizer powder equipped with 0.4mm apertures sieve It is broken, produce.

The preparation of inclusion compound 2：Purified water 4 times of betadex (its weight be) is heated to 85 ± 5 DEG C, him is added times Cyclodextrin, stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, famotidine is added (in an amount of from betadex 1/3), stirring makes whole dissolvings；It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then into the decoction add 3% under agitation (w/v) propane diols；Then proceed to be cooled to room temperature, be transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerate 16 hours；After decoction separates out crystallization, Crystallization is isolated, is dried at 70 ± 5 DEG C of temperature to moisture and is less than 5%, then with the pulverizer powder equipped with 0.4mm apertures sieve It is broken, produce.

The preparation of inclusion compound 3：Purified water 8 times of betadex (its weight be) is heated to 85 ± 5 DEG C, him is added times Cyclodextrin, stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, famotidine is added (in an amount of from betadex 1/7), stirring makes whole dissolvings；It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then into the decoction add 1% under agitation (w/v) propane diols；Then proceed to be cooled to room temperature, be transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerate 20 hours；After decoction separates out crystallization, Crystallization is isolated, is dried at 70 ± 5 DEG C of temperature to moisture and is less than 5%, then with the pulverizer powder equipped with 0.4mm apertures sieve It is broken, produce.

The preparation of inclusion compound 4,5,6：Respectively refer to above-mentioned inclusion compound 1, inclusion compound 2, the preparation method of inclusion compound 3, it is different only It is, without propane diols, to respectively obtain inclusion compound 4, inclusion compound 5, inclusion compound 6.

The preparation (#473) of inclusion compound 7：

Famotidine 10g

Beta-schardinger dextrin 10g

Pure water 250ml

Preparation method：200ml purified waters are heated to 90 DEG C or so, water-bath insulation adds beta-schardinger dextrin 40g and constantly stirred Mix, water-bath is incubated between cooling to 75-78 DEG C after being completely dissolved, add famotidine 10g, stirring is to being completely dissolved, Ran Houbao Temperature stirring 1 hour, then naturally cools to room temperature to 12 hours, suction filtration is dried about 4 hours in 50 DEG C, is taken out simultaneously while stirring 50 mesh sieves are crossed, does in the proper way and does not replace butyl- Benexate Hydrochloride.

Differential thermal analysis and infrared scan analysis are carried out to above inclusion compound 1-7,7 kinds of inclusion compounds are in following result：

1) differential thermal analysis result is shown：Famotidine occurs endothermic peak at 160 DEG C or so, and beta-schardinger dextrin is at 50 DEG C -120 DEG C There is obvious endothermic peak, the reason for be due to dehydration：Famotidine and beta-schardinger dextrin physical mixture have concurrently famotidine, β- The characteristic absorption peak of cyclodextrin：Famotidine-Benexate Hydrochloride almost disappears in 160 DEG C or so of endothermic peak, Er Qie Endothermic peak between 50 DEG C -120 DEG C also becomes gentle, it was demonstrated that famotidine is by beta-cyclodextrin inclusion compound.

2) infrared scan analysis result is shown：Famotidine and beta-schardinger dextrin (1mol：1mol) physical mixture and method be not For fourth, beta-schardinger dextrin characteristic peak without significantly different, but the figure ratio of famotidine-Benexate Hydrochloride and physical mixture Compared with：Significantly be subjected to displacement in 1500-l650cm-1 C-N characteristic peaks, show guanidine radicals nitrogen in famotidine molecular structure and Thiazole nitrogen and the hydroxy combining in beta-schardinger dextrin molecule cavity, therefore famotidine forms inclusion compound with beta-schardinger dextrin.

Assemble thing preparation：Above-mentioned inclusion compound 1~7 seven sample is taken, it is well mixed to (method is not replaced with magnesium hydroxide respectively Fourth and the weight of magnesium hydroxide ratio are 10: 165), obtain seven kinds of compositions and be designated as assembling thing 1~7 that (inclusion compound is numbered and group respectively It is consistent with thing numbering).

Test example 1：Above-mentioned inclusion compound 1~7 is taken respectively and thing 1~7 is assembled, and is placed in 40 DEG C, 6 are placed under the conditions of lucifuge Month, the content for respectively assembling thing impurity C (relative to famotidine) at 0 month and during in June is determined, and each group is calculated as follows Increase percentage amounts (%) with impurity C in thing：

Impurity C increase percentage amounts (%)=[(- 0 month impurity C content of impurity C content in June) 0 month impurity C content of ÷)] × 100%

As a result：The impurity C increase percentage amounts (%) of inclusion compound 1~7 seven sample are respectively less than 20%, and it is steady to show them Fixed；The impurity C increase percentage amounts (%) of thing 4~7 four are assembled in the range of 142~188%；Assemble the three's of thing 1~3 Impurity C increase percentage amounts (%) are in the range of 23~41%.This shows different inclusion compounds when being combined with magnesium hydroxide miscellaneous Different results are presented in terms of the stability that matter C is characterized.

Embodiment part prepared by chewable tablet

Embodiment 1：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 1,

Calcium carbonate 800mg,

Magnesium hydroxide 165mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 400mg,

Sucrose 400mg,

Sucralose 3mg,

Ice-cold sweet orange powdered flavor 1mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.5mg,

PVP K-30,20mg (5% solution),

Magnesium stearate 15mg,

Silica 1 0mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

(3) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide are well mixed, add diluent, seasoning Agent, colouring agent are well mixed, and wet granulation is carried out to mixed-powder material with binder solution obtained by step (1), and gained is wet Particle is transferred in air dry oven, 70 DEG C of dryings 3 hours, and whole grain obtains dry particl；

Embodiment 2：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 2,

Calcium carbonate 800mg,

Magnesium hydroxide 165mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 400mg,

Sucrose 400mg,

Sucralose 3mg,

Ice-cold sweet orange powdered flavor 1mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.5mg,

PVP K-30,20mg (5% solution),

Magnesium stearate 15mg,

Silica 1 0mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

(3) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide are well mixed, add diluent, seasoning Agent, colouring agent are well mixed, and wet granulation is carried out to mixed-powder material with binder solution obtained by step (1), and gained is wet Particle is transferred in air dry oven, 60 DEG C of dryings 4 hours, and whole grain obtains dry particl；

Embodiment 3：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 3,

Calcium carbonate 800mg,

Magnesium hydroxide 165mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 400mg,

Sucrose 400mg,

Sucralose 3mg,

Ice-cold sweet orange powdered flavor 1mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.5mg,

PVP K-30,20mg (5% solution),

Magnesium stearate 15mg,

Silica 1 0mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

(3) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide are well mixed, add diluent, seasoning Agent, colouring agent are well mixed, and wet granulation is carried out to mixed-powder material with binder solution obtained by step (1), and gained is wet Particle is transferred in air dry oven, 80 DEG C of dryings 2 hours, and whole grain obtains dry particl；

Embodiment 4：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 1,

Calcium carbonate 750mg,

Magnesium hydroxide 180mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 600mg,

Sucrose 900mg,

Sucralose 5mg,

Ice-cold sweet orange powdered flavor 2mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.7mg,

PVP K-30,10mg (5% solution),

Magnesium stearate 5mg,

Silica 5mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

Embodiment 5：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 1,

Calcium carbonate 850mg,

Magnesium hydroxide 150mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 200mg,

Sucrose 225mg,

Sucralose 3mg,

Ponceau 4R aluminum lake 0.3mg,

30 POVIDONE K 30 BP/USP -60,40mg (5% solution),

Magnesium stearate 20mg,

Silica 20mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

Embodiment 6：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 2,

Calcium carbonate 800mg,

Magnesium hydroxide 165mg,

Betadex (feeds intake) in inclusion compound form,

Lactose 400mg,

Sucrose 400mg,

Saccharin sodium 3mg,

Ice-cold sweet orange powdered flavor 2mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.5mg,

30 POVIDONE K 30 BP/USP -15,20mg (8% solution),

Magnesium stearate 15mg,

Silica 1 0mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

Embodiment 7：Prepare famotidine calcium and magnesium chewable tablets

Prescription：

Famotidine 10mg (is fed intake) with inclusion compound 3,

Calcium carbonate 800mg,

Magnesium hydroxide 165mg,

Betadex (feeds intake) in inclusion compound form,

Mannitol 400mg,

Sucrose 400mg,

Sucralose 3mg,

Peppermint powdered flavor 1mg,

Ponceau 4R aluminum lake 0.5mg,

Hydroxypropyl methyl cellulose, 20mg (2% solution),

Stearic acid 15mg,

Talcum powder 10mg.

Preparation method：

(1) adhesive is configured to solution, it is standby；

Embodiment 8：Prepare famotidine calcium and magnesium chewable tablets

The preparation of chewable tablets is carried out according to the formula of embodiment 1, different is only by famotidine betadex therein Inclusion compound replaces with inclusion compound 4, inclusion compound 5, inclusion compound 6, inclusion compound 7 respectively, obtain four batches of chewable tablets be designated as respectively Ex81, Ex82、Ex83、Ex84。

Embodiment 9：According to CN1456160A specifications page 1 its composition of compound famotidine dispersible tabletses " one, " with And the technique one of page 2 its " two, the preparation technology of compound famotidine dispersible tabletses " prepares tablet (in last tabletting, with every Piece 10mg containing famotidine amount tabletting), thus obtained tablet is designated as Ex91；According to CN1634045A specifications embodiment 5 Formula and preparation method prepare tablet, and coating famotidine used is obtained according to the formula and preparation method of embodiment 1 therein, thus obtained Tablet is designated as Ex92；Tablet is prepared (in last tabletting, with every according to the formula and preparation method of CN1768744A specifications embodiment 1 Piece 10mg containing famotidine amount tabletting), thus obtained tablet is designated as Ex93.

Test example 2：Investigate the stability of Tablets

The various tablet samples that above example 1-9 is prepared, are packed using aluminum-plastic composite membrane generation, are placed in 40 DEG C, place that (in the present invention, such a high-temperature treatment mode for its reserve temperature can claim in 6 months under the conditions of lucifuge For high temperature June, 40 DEG C of June, high temperature disposal in June, 40 DEG C of disposal in June etc.), using containing described in the present invention above method of testing part Determination method and determination of foreign matter method are measured, these samples (0 month), rear (June) impurity C content before disposal is determined, and calculate impurity C Increase percentage amounts (%).As a result：Whole tablets that embodiment 1-7 is prepared, its impurity C increase percentage amounts (%) 25~ In the range of 56%；Whole tablets that embodiment 8-9 is prepared, its impurity C increase percentage amounts (%) are in 184~276% models In enclosing.

Test example 3：Investigate the performance of Tablets

The Pharmacopoeia of People's Republic of China enlarged edition of version second page 253 in 2010 has recorded the method with inventive formulation not For fourth calcium and magnesium chewable tablets, detailed regulation has been carried out to every quality requirement of the chewable tablets in the pharmacopeia.The present inventor is shone should Official method, whole chewable tablets that measure example 1 above -7 of the present invention is prepared are detected, as a result show seven chewings Every testing result of piece sample meets the regulation of the standard.In addition, by example 1 above -7 of the present invention prepare it is complete Portion's chewable tablets is placed in 40 DEG C, placed 6 months under the conditions of lucifuge, determines whole chewable tablets according to the official method at 6 months, as a result Show that the tablet of this seven batches is still conforming to standard regulation after high-temperature treatment；For example, all the tablet of seven batches exists Under the conditions of packing, be placed in 40 DEG C, place 6 months under the conditions of lucifuge, the famotidine calcium and magnesium chewable tablets at June relative to Residual content (%) during relative amount (%) June at 0 month is in the range of 96%~101%.In addition, by the present invention Whole chewable tablets that literary embodiment 1-7 is prepared are placed 24 months under the conditions of being placed in room temperature (20~25 DEG C), lucifuge, at 24 Month when determine whole chewable tablets according to the official method, as a result show the tablets of this seven batches after being placed for a long time through normal temperature still Meet standard regulation.

The spirit of the present invention is elaborated above by present pre-ferred embodiments.Those skilled in the art manage Solution, every any modification, equivalent variations and modification substantially made according to the technology of the present invention to above example, all falls within this hair In bright protection domain.

Claims

1. famotidine calcium and magnesium chewable tablets, wherein including the parts by weight of famotidine 10, the parts by weight of calcium carbonate 750 ~ 850, hydroxide The parts by weight of magnesium 150 ~ 180, the parts by weight of betadex 20 ~ 80；The famotidine is that inclusion is made in advance with betadex The form of thing is added in the chewable tablets, and the inclusion compound is prepared according to following method：Purified water is heated to 85 ± 5 DEG C, betadex is added, stirring makes whole dissolvings；70 ± 5 DEG C are cooled to, stops cooling, famotidine is added, stirs Mixing makes whole dissolvings；It is cooled to 60 ± 2 DEG C again, insulated and stirred 1 hour, then 1-3% (w/v) is added into the decoction under agitation Propane diols；Then proceed to be cooled to room temperature, be transferred in 0 ± 2 DEG C of refrigerator-freezer and refrigerate 16-20 hours；After decoction separates out crystallization, point Crystallization is separated out, is dried at 70 ± 5 DEG C of temperature to moisture and is less than 5%, is then crushed with the pulverizer equipped with 0.4mm apertures sieve, Produce.

2. famotidine calcium and magnesium chewable tablets according to claim 1, wherein comprising the parts by weight of famotidine 10, calcium carbonate 780 ~ 820 parts by weight, the parts by weight of magnesium hydroxide 155 ~ 175.

3. famotidine calcium and magnesium chewable tablets according to claim 1, wherein including the parts by weight of famotidine 10, the weight of calcium carbonate 800 Measure part, the parts by weight of magnesium hydroxide 165.

4. famotidine 2-25mg is included in famotidine calcium and magnesium chewable tablets according to claim 1, its every tablet.

5. famotidine calcium and magnesium chewable tablets according to claim 1, for the famotidine of every 10 parts by weight, wherein times The amount of his cyclodextrin is 30 ~ 70 parts by weight.

6. famotidine calcium and magnesium chewable tablets according to claim 1, prepares the weight of purified water used during the inclusion compound for again 4-8 times of his cyclodextrin.

7. famotidine calcium and magnesium chewable tablets according to claim 1, wherein also including the medicine in addition to the betadex Learn acceptable auxiliary material.

8. famotidine calcium and magnesium chewable tablets according to claim 7, wherein the pharmaceutically acceptable auxiliary material includes diluent.

9. famotidine calcium and magnesium chewable tablets according to claim 8, wherein the diluent is selected from sucrose, mannitol, lactose, fruit Sugar, sorbierite and combinations thereof.

10. famotidine calcium and magnesium chewable tablets according to claim 8, wherein consumption of the diluent in the chewable tablets is to make The piece for obtaining the chewable tablet every is focused in the range of 800 ~ 2000mg.

11. famotidine calcium and magnesium chewable tablets according to claim 8, consumption of the diluent in the chewable tablets is calcium carbonate 0.5 ~ 2 times of weight.

12. famotidine calcium and magnesium chewable tablets according to claim 1, it is prepared by wet granule compression tablet method.

13. famotidine calcium and magnesium chewable tablets according to claim 7, the pharmaceutically acceptable auxiliary material includes flavor enhancement.

14. famotidine calcium and magnesium chewable tablets according to claim 7, the pharmaceutically acceptable auxiliary material includes adhesive.

15. famotidine calcium and magnesium chewable tablets according to claim 7, the pharmaceutically acceptable auxiliary material includes lubricant.

16. famotidine calcium and magnesium chewable tablets according to claim 7, the pharmaceutically acceptable auxiliary material includes colouring agent.

17. famotidine calcium and magnesium chewable tablets according to claim 13, the flavor enhancement is selected from sweetener, essence and combinations thereof.

18. famotidine calcium and magnesium chewable tablets according to claim 17, the sweetener is selected from Sucralose, saccharin sodium and its group Close.

19. famotidine calcium and magnesium chewable tablets according to claim 13, for the famotidine of every 10 parts by weight, wherein The amount of flavor enhancement is 3 ~ 8 parts by weight.

20. famotidine calcium and magnesium chewable tablets according to claim 16, the colouring agent is aluminum lake.

21. famotidine calcium and magnesium chewable tablets according to claim 16, for the famotidine of every 10 parts by weight, wherein The amount of colouring agent is 0.3 ~ 0.7 parts by weight.

22. famotidine calcium and magnesium chewable tablets according to claim 14, described adhesive is selected from PVP, hydroxypropyl methyl fiber Element, starch and combinations thereof.

23. famotidine calcium and magnesium chewable tablets according to claim 14, amount of the described adhesive in terms of dry weight in tablets, relatively For the famotidine of every 10 parts by weight, in an amount of from 10 ~ 40 parts by weight.

24. famotidine calcium and magnesium chewable tablets according to claim 22, described PVP be PVP K-30,30 POVIDONE K 30 BP/USP- 15 or 30 POVIDONE K 30 BP/USP -60.

25. famotidine calcium and magnesium chewable tablets according to claim 22, wherein the PVP is that concentration 2 ~ 8% is configured to water Solution after as adhesive consumption add.

26. famotidine calcium and magnesium chewable tablets according to claim 15, the lubricant is selected from silica, magnesium stearate, hard Resin acid, talcum powder and combinations thereof.

27. famotidine calcium and magnesium chewable tablets according to claim 15, for the famotidine of every 10 parts by weight, wherein The amount of lubricant is 10 ~ 40 parts by weight.

28. famotidine calcium and magnesium chewable tablets according to claim 1, wherein including：

The parts by weight of famotidine 10,

The parts by weight of calcium carbonate 780 ~ 820,

The parts by weight of magnesium hydroxide 155 ~ 175,

The parts by weight of betadex 20 ~ 80,

Diluent, its amount is 0.5 ~ 2 times of weight of calcium carbonate,

The parts by weight of flavor enhancement 3 ~ 8,

The parts by weight of colouring agent 0.3 ~ 0.7,

The parts by weight of adhesive 10 ~ 40,

The parts by weight of lubricant 10 ~ 40；

It is prepared by the method comprised the following steps：

(1) adhesive is configured to the solution that concentration is 2 ~ 8%, it is standby；

(2) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide and other solid materials are crushed respectively, mistake 120 mesh sieves；

(3) famotidine betadex inclusion compound, calcium carbonate, magnesium hydroxide are well mixed, add diluent, flavor enhancement, Colouring agent is well mixed, and wet granulation is carried out to mixed-powder material with binder solution obtained by step (1), by gained wet granular It is transferred in air dry oven, 60 ~ 80^oC is dried 2 ~ 4 hours, and whole grain obtains dry particl；

(4) it is dry particl obtained by step (3) is uniform with mix lubricant, mixed particle eventually is obtained, it is tabletted, obtain famotidine Calcium and magnesium chewable tablets.