CN101084881B

CN101084881B - Targeted quick-releasing effervescence preparation and preparation method thereof

Info

Publication number: CN101084881B
Application number: CN200710126505A
Authority: CN
Inventors: 叶红平; 孙萌; 朱作霖
Original assignee: HUAIBEI HUIKE PHARMACEUTICAL Co Ltd
Current assignee: HUAIBEI HUIKE PHARMACEUTICAL Co Ltd
Priority date: 2007-06-23
Filing date: 2007-06-23
Publication date: 2012-08-29
Anticipated expiration: 2027-06-23
Also published as: CN101084881A; WO2009000132A1

Abstract

The invention provides a new preparation method, especially relates to an effervescent preparation with targeting transfer, rapid action and good taste covering effect and its preparation method. The inventive product prepared by the method also has effects in regulating body pH value, reducing oxidization stress, and preventing disease such as tumour.

Description

Targeted quick-releasing effervescence preparation and preparation method thereof

Technical field

The present invention relates to a kind of new formulation method, more precisely relate to a kind of have targeted delivery, rapidly onset and have effervescent formulation of good screening function of odor and preparation method thereof.Use the present invention to disclose the product of formulation method preparation, also have regulating body pH value, reduce oxidative stress, prophylactic function.

Background technology

Effervescent tablet or effervescent granule have a lot of advantages, if can be in water disintegrate rapidly, active ingredient is discharged rapidly; Fully the remain valid physiologically active of composition improves the stability of bioactive substance, promotes the rapid absorption of human body to active ingredient; Be convenient to take, or the like.

Body acidification is disease patient and old people's a ubiquity phenomenon, and healthy person and teen-age body all are subalkaline.In sour environment; The generation of free radical is easier; The oxidative stress level of body is raise, and oxidative stress (OxidativeStress OS) is the main cause of various cell injury in the body; Be considered to cause diabetes and chronic complicating diseases of diabetes, the major reason of diseases such as pulmonary fibrosis, epilepsy, hypertension, atherosclerosis and corresponding cardiovascular disease, cancer, nephropathy change and parkinson disease.Though find that according to clinical evaluating result pathological changes not necessarily appears in acidic physique, a lot of patients such as cancer patient are acidic physique basically, keep body and are in the alkalescence state, are one of important means that reduces the oxidative stress level.

The Acidity of Aikalinity of food is not to confirm with mouthfeel, and the result that produced after the metabolism confirms but digested and assimilated in vivo by food.If the phosphate radical that is produced after the food metabolism, sulfate radical, chloride ion plasma are many, will cause body acidification, be acid food; If the sodium ion that is produced after the food metabolism, potassium ion, magnesium ion, calcium ion plasma are more, just be easy to cause the body alkalization, be basic food.Though mouthfeels such as citric acid are acid, the human body metabolism is translated into water and carbon dioxide, and it belongs to neutral food.This shows that another of effervescent tablet or effervescent granule provided the necessary alkaline matter of body by the advantage that the mankind have ignored, assisting to regulate body is alkalescence, reduces oxidative stress.

The advantage of comprehensive effervescent tablet or effervescent granule can find that this formulation method needing to be very suitable for the medicine of quick acting, and it is carsick to reduce body temperature, pain relieving, diarrhoea, blood pressure lowering, sleep, allergy and treatment during like fever, or the like.But because many medicines have very strong stimulation taste; Like ibuprofen (Ibuprofen), acetaminophen (Acetaminophen), hydrochloric acid Luo Pu Lamine (loperamide), reserpine (Reserpine), alprazolam (Alprazolam), diphenhydramine (diphenhydramine) and dimenhydrinate (Dimenhydrinate); Or the like, can't be with effervescent tablet or this formulation method of effervescent granule.Though many results of study have found the method for covering these medicine irritation tastes, before the present invention, also successfully these medication preparation are not become effervescent tablet and effervescent granule.Key issue is to exist three big problems, the one, reported to the medicine integument of these zest tastes when the preparation effervescent dosage form, in the presence of the solid acid alkaline agent, can occur breaking, and cause prepared effervescent screening function of odor not reach requirement; Its two, the sour agent content in traditional effervescent is very high, the pH value of water solution after water-soluble is all less than 5, the stripping of medicine is fast, does not reach requirement and cause prepared effervescent to hide function of odor; Its three, the packaging method of having reported all causes the release of effective ingredient slow, can't reach effervescent design quick acting purpose.

For example; U.S. Pat 5587179 has reported that use low melting point fatty acid ester or Cera Flava are as lapping; There is the pharmaceutical pack of stimulation taste to be rolled in high molecular fatty acid ester or the Cera Flava these; Because these low-melting fatty acid esters or Cera Flava just melt more than 30 ℃ in temperature, and discharge parcel medicine within it.This method can't thoroughly be avoided the stripping of medicine at normal temperatures; Hide function of odor and do not reach requirement; And medicine in vivo discharges slower, and said preparation does not possess target function, the medicine effervescent that uses this method to prepare; Its aqueous solution all occurs than the zest taste, as effervescent tablet or this formulation method of effervescent granule and unsuccessful.

Therefore this area presses for a kind of have targeted delivery, onset and have effervescent formulation of good screening function of odor and preparation method thereof rapidly.

Summary of the invention

One object of the present invention is to obtain a kind of effervescent, and it has targeted delivery, the rapid onset of ability and has good screening function of odor, also has regulating body pH value simultaneously, reduces oxidative stress, prophylactic function.

Another purpose of the present invention aims to provide a kind of formulation method of new invention effervescent.

Still a further object of the present invention aims to provide a kind of purposes of effervescent of the present invention.

First aspect present invention provides a kind of effervescent, comprises the effervescent substrate of effective dose, also comprises:

The active substance of treatment effective dose, and

The targeting h substance of effective dose, wherein said targeting h substance is the high molecular polymer coating material of the said active substance of covering, and said high molecular polymer coating material comprises the high molecular polymer that is only soluble in people and/or animal gastric pH environment;

Wherein said high molecular polymer accounts for said macromolecule coating material gross weight and is not less than 0.5 weight %.

In a preference, said active substance is selected from quick acting medicine or stomach medicine; Preferably, said quick acting medicine is selected from ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine or dimenhydrinate; Said stomach medicine is selected from Basic.

In a preference, said high molecular polymer is selected from functional group and is amino polymer;

Preferably; Said high molecular polymer is selected from polyethylene acetal diethyl amino yl acetate, IV gastric solubleness resin (Jiangsu JumpCan Medicines Co., Ltd.), aminoalkyl methacrylate copolymer or its combination; More preferably, the preferred Eudragit E of said aminoalkyl methacrylate copolymer polymer;

Preferably, said high molecular polymer accounts between the 0.5%-99.9% of said macromolecule coating material gross weight, more preferably between the 5%-95%.

In a preference, the part by weight of said effervescent substrate, active substance and targeting h substance is: effervescent substrate is 25-90%, and active substance is 0.01%-70%, and the targeting h substance is 0.5-74.9%, with the effervescent total weight;

More preferably, effervescent substrate is 25-90%, and active substance is 0.01%-50%, and the targeting h substance is 1-30%, with the effervescent total weight.

In a preference; Also comprise fatty acid glyceride in the said high molecular polymer coating material; Preferably monoglyceride; More preferably, said monoglyceride is selected from glyceryl monostearate, monopalmitin, single Olivanic Acid glyceride, single caprylin, single caprin, glyceryl monolaurate or its combination; Most preferably be selected from glyceryl monostearate;

And the weight ratio of said fatty acid glyceride and high molecular polymer is between 95: 5 to 35: 65; Preferably, (1～8): between 1.

In a preference, the sour agent in the said effervescent substrate and the molar ratio of alkaline agent are 1: (0.95～1.05);

Preferably, the alkaline agent of said effervescent substrate is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium glycine carbonate or its combination;

Preferably, the sour agent of said effervescent substrate is selected from citric acid, glycine citrate, monosodium citrate salt, malic acid, tartaric acid, fumaric acid or its combination.

The present invention provides a kind of formulation method of effervescent on the other hand, comprises the steps:

(a) mixture of the targeting h substance of the effervescent substrate of effective dose, the active substance of treating effective dose, effective dose is provided, and does not contain volatile organic solvent in the said mixture;

Wherein said targeting h substance is the high molecular polymer coating material of the said active substance of covering, and said high molecular polymer coating material comprises the high molecular polymer that is only soluble in people and/or animal gastric pH environment;

(b) said mixture is granulated, obtain said effervescent.

In a preference, the mixture of said step (a) obtains through following steps:

(i) granule of active substance is provided, said active substance is outside to cover said high molecular polymer coating material;

The granule of (ii) said step (i) mixes with said effervescent substrate, obtains the mixture of said step (a).

In a preference, also contain monoglyceride in the said high molecular polymer coating material in the step (i), and the weight ratio of said monoglyceride and high molecular polymer is between 95: 5 to 35: 65.

In a preference, the granule of the said active substance in the step (i) obtains through following method:

(I) the monoglyceride solution of high molecular polymer, the mixture of active substance are provided;

Preferably, the fineness of active substance is not more than 100 orders described in the step (I);

(II) mixture of said step (I) is granulated and is obtained the granule of the active substance in the step (i);

Preferably, said step (II) adopts the sprinkling granulation to granulate; More preferably, the method for granulating of step (II) comprises the steps: that the mixture of said step (I) was carrying out granulate 30 minutes～60 minutes through 40 ℃ ± 5 ℃ Celsius; Obtain the granule of the active substance in the step (i).

The present invention provides a kind of purposes of effervescent of the present invention on the other hand, and said effervescent is used for targeting and discharges medicine, makes the medicine quick acting or hide the zest taste of medicine.

The specific embodiment

The inventor is through extensive and deep research and design; Utilize the targeting h substance as coating material; Thereby the formulation method preparation that can utilize effervescent (for example effervescent tablet or effervescent granule) needs the medicine of quick acting; As it is carsick to reduce body temperature, pain relieving, diarrhoea, blood pressure lowering, sleep, allergy and treatment when having a fever, or the like.In a preferred implementation of the present invention, the inventor finds in coating, to add fatty acid glyceride can reach excellent especially effect.Accomplished the present invention on this basis.

As used herein, described " quick acting medicine " except as otherwise noted, refers to and in two hours, reaches the highest blood drug level, preferably reaches the medicine of high blood drug level in 30 minutes.Particularly for example at oral medicine Advil tablet, drink in the body after, blood drug level reached maximum concentration in the time of 101 minutes, this medicine generally is considered to the medicine of quick acting." quick acting medicine " of the present invention can be but to reduce body temperature, pain relieving, diarrhoea, blood pressure lowering, sleep, allergy or treatment when being not limited to be used to have a fever carsick; Or the like medicine; Also can be very strong tangy taste medicine, can be but be not limited to concrete example such as ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine or dimenhydrinate.

As used herein, described " stomach medicine " except as otherwise noted, is meant the medicine that reduces gastric acid or treatment gastritis.Can be but be not limited to Basic (bismuth subsalicylate).

As used herein, described " being only soluble in the high molecular polymer of people and/or animal gastric pH environment " is meant dissolving when these polymer are in the low pH environmental liquids that arrives stomach, and at the undissolved high molecular polymer of other internal milieu.For example meet the dissolved high molecular polymers of the digestion quick salify of fluid power below the pH5.0 such as gastric acid particularly.

As used herein, described " pharmaceutically acceptable carrier " is meant the carrier that is used to treat administration, and they itself are not necessary active component, and do not have undue toxicity after using.For example, excipient, filler, disintegrating agent, emulsifying agent, correctives, lubricant, binding agent, filler, coloring agent, flavoring agent, plasticizer, fat-soluble auxiliary substance, antioxidant etc.

As used herein, described " the effervescent substrate of effective dose " is meant that its consumption enough produces the carbon dioxide of complete disintegrate effervescent tablet and granule solid structure.Particularly for example, effervescent substrate accounts for 25～90 weight % of effervescent.

As used herein, described " the targeting h substance of effective dose " is meant that the consumption of targeting h substance can cover active substance and get final product.

As used herein, described " treatment effective dose " is meant people and/or animal produced function or amount active and that can be accepted by people and/or animal.Concrete consumption is decided according to employed concrete medicine, only otherwise goal of the invention of the present invention is produced restriction to get final product.

As used herein, described " covering ", except as otherwise noted, it comprises variously can reduce active substance and the surface area contacted mode of organism (comprising humans and animals), in for example active substance partly or entirely being wrapped in.Preferably all be wrapped to form coating material.

Below detail to various aspects of the present invention:

The targeting h substance

Targeting h substance of the present invention is for covering the high molecular polymer coating material of said active substance, and wherein said high molecular polymer comprises the high molecular polymer that is only soluble in people and/or animal gastric pH environment.

The characteristics of these high molecular polymers are to be only soluble in acid very high aqueous phase, and are not dissolved in the aqueous solution of any other pH.These characteristics guarantee that this product only dissolves in the relative very low pH environment in human stomach, product has at quick-dissolving targeted delivery effervescent tablet of gastric or effervescent granule.For example, be only soluble in stomach pH1～5, and be insoluble to other pH environment.

Preferably, the rate of release of said targeting h substance was weighed with the effectively the highest blood drug level time of reaching, and generally should be preferably lower than one hour less than two hours, desired result be between 30 minutes by one hour between.

More preferably, the high molecular polymer that the present invention selects for use be functional group be amino, humans and animals is not had the polymer of overt toxicity effect because amino under acid condition rapid salify, dissolving is fast.This base polymer includes but not limited to polyethylene acetal diethyl amino yl acetate (polyvinylacetal diethylaminoacetate), the IV gastric solubleness resin that Jiangsu JumpCan Medicines Co., Ltd. of China produces, aminoalkyl methacrylate copolymer.Use the product of the most commercial famous-brand and high-quality peculiar E (Eudragit E polymer now; Excellent peculiar E functional group is that uncle is amino; This material is met the quick salify dissolvings of the fluid power of digestion below the pH5.0 such as gastric acid; Effectively avoid position releases such as oral cavity, esophagus, but do not influence the dissolution time of medicine) and their mixture such as above-mentioned these high molecular polymers.

Can also comprise other additive in the high molecular polymer coating material of the present invention, the not special restriction of said additive, only otherwise goal of the invention of the present invention is produced restriction.For example fatty acid glyceride, various cellulose organic ester, amylose organic acid esters, derivative fibre have machine acid esters (like hydroxypropyl cellulose etc.), gelatin, Lac, keratin or its combination.Preferably, said additive can reduce fusing point to 42～100 ℃ of high molecular polymer.Fatty acid glyceride for example.

In a preferred implementation; We find; After adding a certain amount of fatty acid glyceride in the high molecular polymer in the high molecular polymer coating material; When being used for the coating material of drug ingredient with functional group for the mixture of amino polymer manufacture, the effervescent formulation of preparation has just possessed can be instant quickly at gastric, hides the excellent especially function of flavor effect.And after a certain amount of fatty acid glyceride is sneaked in use; The fusing point of gained mixture is lower than 100 ℃ Celsius; When for example mixture contained the EudragitE polymer of glyceryl monostearate (glyceryl monostearate) and 10 parts of 60 parts (weight ratios), the fusing point of mixture was lower than 90 ℃ Celsius.

After adding fatty acid glyceride, the effervescent tablet one of preparation is that the dissolution velocity at gastric reaches more quick-acting effects; The 2nd, when the preparation effervescent, reach the function that hides flavor better; Simultaneously; Need use volatile organic solvent to dissolve when using high molecular polymer separately; The use of volatile solvent causes complex manufacturing, is prone to a series of problems such as dissolvent residual is arranged in production safety problem and the product, but and the adding fatty acid glyceride solves the problems referred to above.

" fatty acid " in the said fatty acid glyceride is meant " Organic substance that contains a long hydrocarbon chain and a terminal carboxyl group "; Said long hydrocarbon chain is preferably C6～C30 hydrocarbon chain, is preferably that stearic acid, Palmic acid, Olivanic Acid are sad, capric acid, lauric acid or its combination.

The fatty acid glyceride that uses in the present invention can be monoglyceride, Diglyceride, triglyceride or its combination, preferably monoglyceride.Monoglyceride generally is a glyceryl monostearate; Monopalmitin (glycerylmonopalmitate); Single Olivanic Acid glyceride (glyceryl monooleate), single caprylin (glycerylmonocaprylate), single caprin (glyceryl monocaprate); Glyceryl monolaurate (glycerylmonolaurate), or its combination.Glyceryl monostearate commonly used.

The proportioning of high molecular polymer and fatty acid glyceride is selected according to following guiding theory: the fusing point of mixture will be lower than 100 ℃ Celsius, makes mixture be easy to fusing, and at high temperature rotten of the effective ingredient that prevents principal agent; Simultaneously, the fusing point of mixture is higher than 45 ℃ Celsius again, is dissolved in intravital other position to prevent prepared product.If because patient's fever, temperature might reach 42 ℃ Celsius in the body, under this temperature, heat fusing can take place and discharge medicine in the polymer of packaging medicine, influences the targeting ability of product.Preferably, the weight ratio of fatty acid glyceride and polymer is generally elected as between 95: 5 to 35: 65, and often selecting scope is (1～8): between 1.

The not special restriction of the consumption of targeting h substance is as long as make the targeting h substance can cover active substance.For example between the 0.5 weight %-74.9 weight %, be preferably 1-30%, particularly in the effervescent gross weight.

Said high molecular polymer consumption is: it accounts for said macromolecule coating material gross weight and is not less than 0.5%, preferably accounts between the 0.5%-99.9% that said high molecular polymer accounts for said macromolecule coating material gross weight, more preferably between the 5%-95%.

Active substance

Active substance of the present invention can be that very strong tangy taste medicine is arranged, can be but be not limited to like ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine and dimenhydrinate, or the like; Can also be the stomach medicine, can be but be not limited to Basic (bismuth subsalicylate).

The consumption of active substance is decided according to employed concrete medicine, only otherwise goal of the invention of the present invention is produced restriction to get final product.For example, active substance is 0.01%-50%, with the effervescent total weight.Example hydrochloric acid Luo Pu Lamine particularly, every single agent content is 2 milligrams; Basic, every single agent contains 500 milligrams of effective composition Basics or the like.

Effervescent substrate

Effervescent substrate in the effervescent of the present invention (for example effervescent granule or effervescent tablet) is made up of edible acid agent and the edible alkaline agent that can produce carbon dioxide.

The not special restriction of alkaline agent of the present invention, only otherwise goal of the invention of the present invention is produced restriction to get final product.For example; Mixed carbonate for potassium and sodium; Or mixed carbonic acid hydrogen salt; Or the salt-mixture of carbonate and bicarbonate, carbonate that is adopted and bicarbonate can be but be not limited to sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium glycine carbonate etc. that preferred alkaline agent is Carbon Dioxide hydrogen potassium and sodium bicarbonate.Among the present invention, the not special restriction of alkaline agent fineness, only otherwise it can for example be the 60-200 order particularly that goal of the invention of the present invention is produced restriction.The also not concrete restriction drying time of alkaline agent, only otherwise goal of the invention of the present invention is produced restriction to get final product, particularly for example: before the use, bicarbonate was at 60-80 ℃ of dry 2-4 hour; Carbonate was at 105-120 ℃ of dry 2-4 hour.

The not special restriction of sour agent of the present invention, only otherwise goal of the invention of the present invention is produced restriction to get final product.For example sour agent is the edible organic acid; Can be but be not limited to adopt one or more (for example two kinds) in citric acid, glycine citrate, monosodium citrate salt, malic acid, tartaric acid, the fumaric acid etc.; Fineness for example is the 60-200 order, should be at 105-110 ℃ of dry 2-4 hour before using.

Different with the ratio of soda acid agent in the commonly used effervescent; In the effervescent substrate of the present invention; The ratio of alkaline agent and sour agent is that perhaps the mole dosage of a little higher than sour agent of alkaline agent generally is higher than 0.1% near the mol ratio that equates; Be no more than 5%, be inappropriate for oral otherwise the alkali of prepared effervescent flavor is too big.

The not special restriction of the consumption of effervescent substrate of the present invention is as long as reach the effervescent effective dose.Said " effective dose " is meant that its consumption enough produces the carbon dioxide of complete disintegrate effervescent (for example effervescent tablet and granule) solid structure.Particularly for example, effervescent substrate accounts for 25～90 weight % of effervescent gross weight.

Effervescent

Effervescent of the present invention can be prepared into various suitable character, for example is tablet, granule.

Comprise the effervescent substrate of effective dose, the active substance of treatment effective dose in the effervescent of the present invention, the targeting h substance of effective dose.Particularly, its consumption can be between the consumption 0.5%-74.9% of effervescent substrate 25%-90% (weight ratio), active substance ten thousand/to 70%, targeting h substance (weight ratio), with the effervescent total weight.Preferably, effervescent substrate 25-90%, active substance are 0.01%-50%, and the targeting h substance is 1-30%, with the effervescent total weight.

Effervescent of the present invention can also contain pharmaceutically acceptable carrier.For example, corn starch (Corn starch) is as filler and disintegrating agent; Cellulose gum and pregelatinized Starch (Cellulose gel and pregelatinized starch) are as plasticizer and binding agent; Gelatin (Gelatin) is as emulsifying agent, binding agent and disintegrating agent; Glycerol (Glycerin) is as correctives; Hyprolose (Hydroxypropyl cellulose) is as water-dispersible material; Magnesium stearate or zinc (Magnesium/Zincstearate), Pulvis Talci (talc), silica flour (silica), and mineral oil (Mineral oil) etc. is as lubricant; Microcrystalline Cellulose (microcellulose) or carboxymethyl starch sodium etc. are as binding agent and disintegrating agent; Cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium) is as binding agent and disintegrating agent; Lactose (Lactose) is as filler and binding agent; Arabic gum (Acacia) is as emulsifying agent and binding agent; Stearic acid (Stearic acid) is as emulsifying agent and binding agent; Methylate hyprolose (Hydroxypropyl methylcellulose) as binding agent and disintegrating agent; Sorbitol (Sorbitol), sucralose (Sucralose), acesulfame potassium (Acesulfame potassium), and sucrose (Sugar) is as correctives; Polyethylene Glycol (Polyethylene glycol) is as filler, emulsifying agent and disintegrating agent; Degeneration food starch (Modifiedfood starch) is as filler and disintegrating agent; And Oleum Glycines (Soybean oil) and lecithin (Lecithin) etc. are as fat-soluble complementary material; Sorbitol is as binding agent, and titanium dioxide (Titanium dioxide) is used as coloring agent etc.Can also add Fructus Citri tangerinae in effervescent tablet or the effervescent granule in addition, Fructus Fragariae Ananssae, the flavoring agent of tastes such as Fructus Citri Limoniae (Flavors) is adjusted to the taste of inclination.

The not special restriction of the consumption of said pharmaceutically acceptable carrier, only otherwise goal of the invention of the present invention is produced restriction to get final product.For example the consumption of carboxymethyl starch sodium is 4%～8% particularly, with the effervescent total weight.

Formulation method

The formulation method of effervescent of the present invention; Comprise the steps: that (a) provides the mixture of the targeting h substance of the effervescent substrate of effective dose, the active substance of treating effective dose, effective dose; Wherein said targeting h substance is the high molecular polymer coating material of the said active substance of covering, and said high molecular polymer coating material comprises the high molecular polymer that is only soluble in people and/or animal gastric pH environment; (b) said mixture is granulated, obtain said effervescent.

In a preferred implementation of the present invention, the formulation method that uses among the present invention is the high molecular polymer that preparation earlier is used for packaging medicine.Above-mentioned melting point polymer is higher; When using them that drug microparticles is carried out coating; Need with an organic solvent dissolve them and be mixed with coating solution earlier; Traditionally with an organic solvent like chloroform, carbon tetrachloride, toluene and ethanol etc., but be to use above-mentioned volatile organic solvent to dissolve, the use of volatile solvent causes complex manufacturing, is prone to a series of problems such as dissolvent residual is arranged in production safety problem and the product.

Another characteristics of new production process are need not use volatile organic solvent.We find; In above-mentioned polymer, add a certain amount of fatty glyceride; The fusing point of gained mixture is lower than 100 ℃ Celsius; When for example mixture contained the Eudragit E polymer of glyceryl monostearate (glyceryl monostearate) and 10 parts of 60 parts (weight ratios), the fusing point of mixture was lower than 90 ℃ Celsius.Select the guiding theory of proportioning to be, the fusing point of mixture will be lower than 100 ℃ Celsius, makes mixture be easy to fusing, and at high temperature rotten of the effective ingredient that prevents principal agent; Simultaneously, the fusing point of mixture is higher than 45 ℃ Celsius again, is dissolved in intravital other position to prevent prepared product.If because patient's fever, temperature might reach 42 ℃ Celsius in the body, under this temperature, heat fusing can take place and discharge medicine in the polymer of packaging medicine, influences the targeting ability of product.The weight ratio of monoglyceride and polymer is generally elected as between 95: 5 to 35: 65, and often selecting scope is (1～8): between 1.

In a preferred implementation of the present invention; The preparation of polymeric blends generally uses monoglyceride to make solvent; At a certain temperature; High molecular polymer is dissolved in monoglyceride, yet adds the medicine that crushes (API) of required preparation again, and the fineness of medicine is generally less than 100 orders or thinner.Behind the mix homogeneously, the gained mixture directly is used for granulating in mixture.Traditional method of granulating all can be used in the granulation that is used for the high molecular polymer coated drugs in this invention through change seldom, the granulation (spray-granulation) that sprays commonly used among the present invention.The granule that makes generally carries out granulate at about 40 ℃ Celsius, gets required drug powder granule.The result finds, the packaging medicine granule of preparation carries out granulate through about 40 ℃ Celsius and surpasses more than 30 minutes, and is when the drug particles of parcel is used to prepare effervescent, to the screening effect of medicine irritation, better during than granulate not.

The excipient that can also contain other among the present invention, can be used as comprising of excipient following these: corn starch (Cornstarch) is as filler and disintegrating agent; Cellulose gum and pregelatinized Starch (Cellulose gel and pregelatinizedstarch) are as plasticizer and binding agent; Gelatin (Gelatin) is as emulsifying agent, binding agent and disintegrating agent; Glycerol (Glycerin) is as correctives; Hyprolose (Hydroxypropyl cellulose) is as water-dispersible material; Magnesium stearate or zinc (Magnesium/Zinc stearate), Pulvis Talci (talc), silica flour (silica), and mineral oil (Mineral oil) etc. is as lubricant; Microcrystalline Cellulose (microcellulose) is as binding agent and disintegrating agent; Cross-linked carboxymethyl cellulose sodium (Croscarmellose sodium) is as binding agent and disintegrating agent; Lactose (Lactose) is as filler and binding agent; Arabic gum (Acacia) is as emulsifying agent and binding agent; Stearic acid (Stearic acid) is as emulsifying agent and binding agent; Methylate hyprolose (Hydroxypropyl methylcellulose) as binding agent and disintegrating agent; Sorbitol (Sorbitol), sucralose (Sucralose), acesulfame potassium (Acesulfame potassium), and sucrose (Sugar) is as correctives; Polyethylene Glycol (Polyethylene glycol) is as filler, emulsifying agent and disintegrating agent; Degeneration food starch (Modifiedfood starch) is as filler and disintegrating agent; And Oleum Glycines (Soybean oil) and lecithin (Lecithin) etc. are as fat-soluble complementary material; Sorbitol is as binding agent, and titanium dioxide (Titanium dioxide) is used as coloring agent etc.Can also add Fructus Citri tangerinae in effervescent tablet or the effervescent granule in addition, Fructus Fragariae Ananssae, the flavoring agent of tastes such as Fructus Citri Limoniae (Flavors) is adjusted to the taste of inclination.

The production technology that effervescent among the present invention (effervescent granule or effervescent tablet) adopts can also comprise other step.If also contain other required coupling composition, lipid or fat-soluble complementary material and excipient in the formula for a product, then these compositions carry out independent mixing granulation.

The not special restriction of the preparation formulation method of effervescent of the present invention, only otherwise goal of the invention of the present invention is produced restriction to get final product.

For example, more than drug powder granule and other material particles of preparation, 15～25 ℃ of temperature, under the environment of relative humidity about 10% and the soda acid effervescent always mix, behind the mix homogeneously, process effervescent granule.

Above-mentioned effervescent granule under the environment of relative humidity about 10%, uses the punch die of 2～3 centimetres of diameters 15～25 ℃ of temperature, and compression moulding on tablet machine gets effervescent tablet.Every heavy 2.5～8 grams, preferred 3～6 grams.Packing.

Formulation method among the present invention generally makes with lubricator, add lubricant in lubricant comprises and add lubricant, in add lubricant and add the lubricant in the material before for the system granule; Add lubricant and be and add before the tabletting or in the tabletting process, be added in the mould.Lubricant adopts polyethylene glycol 6000, fumaric acid, adipic acid, leucine, vegetable oil, or in the mineral drug oil one or both, and leucine wherein, vegetable oil, or mineral drug oil can be and adds lubricant.

Preparation among the present invention generally also adds antioxidant; Antioxidant commonly used comprises vitamin C, vitamin E, thioctic acid, dibenzylatiooluene (dibutylhydroxyltoluene; BHT) and hydroxyl Fructus Foeniculi dibutyl ester (butylhydroxyanisol, BHA) etc.

Formulation products of the present invention can be adopted purgation and use: get effervescent tablet a slice and put in a small amount of pure water, all drank after the dissolving in about three minutes.Can adjust consumption and the number of times of every day according to concrete medicine situation and needs of patients.When the formulation products of preparation when being used for reducing body temperature rapidly, when being acetaminophen like effective composition, the then consumption of analogy acetaminophen and frequency of utilization; When the formulation products of preparation when being used for rapid antidiarrheal, when being hydrochloric acid Luo Pu Lamine like effective composition, the then consumption and the frequency of utilization of analogy hydrochloric acid Luo Pu Lamine; When the formulation products of preparation when being used for adjusting stomach upset rapidly, when being Basic like effective composition, the then consumption of analogy Basic and frequency of utilization; So analogize, the each consumption when treating concrete disease depends on multiple factor, comprises body weight, age, sex, inevitable medical symptom, disease weight, route of administration etc.

The invention has the advantages that:

(1) the present invention can be used to prepare effervescent tablet or the effervescent granule with very strong tangy taste medicine; Can be but be not limited to ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine and dimenhydrinate, or the like;

(2) formulation method of the present invention's announcement has been avoided using volatile organic solvent, has reduced medicine by the probability that organic solvent pollutes, and has reduced production stage;

(3) product of said preparation method preparation has good targeting ability; They only dissolve in the stomach; And can the dissolving at other position, these characteristics make the said preparation method also be particularly suitable for the preparation of stomach medicine, can be but are not limited to the oral agents of Basic (bismuthsubsalicylate).

Below in conjunction with specific embodiment, further set forth the present invention.Should be understood that these embodiment only to be used to the present invention is described and be not used in the restriction scope of the present invention.The experimental technique of unreceipted actual conditions in the following example is usually according to the normal condition or the condition of advising according to manufacturer.Unless otherwise indicated, otherwise all percentage ratio and umber by weight.

Only if definition separately, the same meaning that employed all specialties and scientific words and one skilled in the art are familiar with in the literary composition.In addition, any with the institute similar content of putting down in writing or the equalization method and material all can be applicable in the inventive method.The usefulness that preferable implementation method described in the literary composition and material only present a demonstration.

Embodiment 1

1, the drug particles powder of preparation high molecular polymer and glyceryl monostearate coating (also being coating material):

The glyceryl monostearate of 156 grams is under protection of nitrogen gas; In about 100 ℃ fusings Celsius, add the Eudragit E high molecular polymer of 26 grams then, under stirring high molecular polymer is dissolved fully after; The hydrochloric acid Luo Pu Lamine (also being loperamide) that in mixture, adds 19 grams; The granulation granulation is sprayed in the back use cooling that stirs, and the interior temperature control of spray dryer spray gun is at 80 ℃ Celsius, and the thick product of the granule of gained is under protection of nitrogen gas; Granulate under 40 ℃ the condition, 190 grams be wrapped in the drug particles powder in high molecular polymer and the glyceryl monostearate coating.

2, sour agent in the effervescent and alkaline agent drying for standby

Citric acid was at 105-110 ℃ of dry 2-4 hour, and sodium bicarbonate, potassium bicarbonate were pulverized then, sieved at 60-80 ℃ of dry 2-4 hour.

3, preparation flavoring agent and the prefabricated granule of other excipient

Required flavoring agent and other excipient in the effervescent; Sorbitol 860 grams, maltodextrin 21 grams, white titanium pigment 2 grams, Fructus Citri tangerinae flavor flavoring agent powder 162 grams, sucralose 2 grams, 10 gram antioxidant vitamin E (acetate) and acesulfame potassium 2 grams; Behind each component mix homogeneously; Mixing granulation in the high efficient mixed facility for granulating gets flavoring agent and good prefabricated granule 1036 grams of other excipient after the drying.

4, preparation effervescent granule

At temperature 15-25 ℃; Under the environment of relative humidity about 10%; Take by weighing the high molecular polymer and the drug particles powder (4.2%) of glyceryl monostearate coating of 10.6 grams that step 1 obtains, the exsiccant citric acid (41.6%) that 1042 gram steps 2 obtain, 756 restrain the exsiccant sodium bicarbonate (30.2%) that steps 2 obtain; The exsiccant potassium bicarbonate (6.9%) that 172 gram steps 2 obtain; Exsiccant flavoring agent and the prefabricated granule of other excipient (20%) that 500 gram steps 3 obtain add mineral oil 26 grams (1%) while stirring, get total batch mixing behind the mix homogeneously.This granule can directly be packed becomes effervescent granule, and every single agent contains 2 milligrams of effective composition hydrochloric acid Luo Pu Lamines.

5, effervescent tablet preparation

The total batch mixing of step 4 gained, at temperature 15-25 ℃, under the environment of relative humidity about 10%; Use the punch die of diameter 20-30 millimeter; Compression moulding on tablet machine, every heavy 5.0 grams, altogether about 500 flake products; Drying condition lower seal damp-prrof packing then, every contains 2 milligrams of effective composition hydrochloric acid Luo Pu Lamines.

Embodiment 2

1, the drug particles powder of preparation high molecular polymer and glyceryl monostearate coating:

The glyceryl monostearate of 780 grams is under protection of nitrogen gas; In about 100 ℃ fusings Celsius, add the Eudragit E high molecular polymer of 130 grams then, under stirring high molecular polymer is dissolved fully after; The ibuprofen that in mixture, adds 105 grams; The granulation granulation is sprayed in the back use cooling that stirs, and the interior temperature control of spray dryer spray gun is at 80 ℃ Celsius, and the thick product of the granule of gained is under protection of nitrogen gas; Granulate under 40 ℃ the condition, 965 grams be wrapped in the drug particles powder in high molecular polymer and the glyceryl monostearate coating.

2, sour agent in the effervescent and alkaline agent drying for standby

Citric acid was at 105-110 ℃ of dry 2-4 hour, and sodium bicarbonate and potassium bicarbonate were pulverized then, sieved at 60-80 ℃ of dry 2-4 hour.

3, preparation flavoring agent and the prefabricated granule of other excipient

Required flavoring agent and other excipient in the effervescent; Sorbitol 860 grams, maltodextrin 21 grams, zinc sulfate 12 grams; White titanium pigment 2 grams, Fructus Citri tangerinae flavor flavoring agent powder 162 grams, sucralose 2 grams, 10 gram antioxidant vitamin E (acetate) and acesulfame potassium 2 grams; Behind each component mix homogeneously, mixing granulation in the high efficient mixed facility for granulating gets flavoring agent and good prefabricated granule 1040 grams of other excipient after the drying.

4, preparation effervescent granule

At temperature 15-25 ℃, under the environment of relative humidity about 10%, take by weighing the high molecular polymer that obtains of step 1 of 965 grams and the drug particles powder of glyceryl monostearate coating; The exsiccant citric acid that 533 gram steps 2 obtain; The exsiccant sodium bicarbonate that 388 gram steps 2 obtain, the exsiccant potassium bicarbonate that 88 gram steps 2 obtain, exsiccant flavoring agent and the prefabricated granule of other excipient that 500 gram steps 3 obtain; Add mineral oil 26 grams while stirring, get total batch mixing behind the mix homogeneously.This granule can directly be packed becomes effervescent granule.

5, effervescent tablet preparation

The total batch mixing of step 4 gained of preparation granule, at temperature 15-25 ℃, under the environment of relative humidity about 10%; Use the punch die of diameter 20-30 millimeter; Compression moulding on tablet machine, every heavy 5.0 grams, altogether about 500 flake products; Drying condition lower seal damp-prrof packing then, every contains 200 milligrams of effective composition ibuprofen.

Embodiment 3

The glyceryl monostearate of 234 grams is under protection of nitrogen gas; In about 100 ℃ fusings Celsius, add the Eudragit E high molecular polymer of 39 grams then, under stirring high molecular polymer is dissolved fully after; The Basic that in mixture, adds 57 grams; The granulation granulation is sprayed in the back use cooling that stirs, and the interior temperature control of spray dryer spray gun is at 80 ℃ Celsius, and the thick product of the granule of gained is under protection of nitrogen gas; Granulate under 40 ℃ the condition, 320 grams be wrapped in the drug particles powder in high molecular polymer and the glyceryl monostearate coating material.

2, sour agent in the effervescent and alkaline agent drying for standby

3, preparation flavoring agent and the prefabricated granule of other excipient

Required flavoring agent and other excipient in the effervescent; Sorbitol 860 grams, maltodextrin 21 grams, zinc sulfate 12 grams; Cornstarch 2 grams, Fructus Citri tangerinae flavor flavoring agent powder 162 grams, sucralose 2 grams, 10 gram antioxidant vitamin E (acetate) and acesulfame potassium 2 grams; Behind each component mix homogeneously, mixing granulation in the high efficient mixed facility for granulating gets flavoring agent and good prefabricated granule 1039 grams of other excipient after the drying.

4, preparation effervescent granule

At temperature 15-25 ℃, under the environment of relative humidity about 10%, take by weighing the high molecular polymer of 320 grams and the drug particles powder of glyceryl monostearate coating; The exsiccant citric acid of 105 grams; The exsiccant sodium bicarbonate of 76 grams, the exsiccant potassium bicarbonate of 17 grams, exsiccant flavoring agent of 80 grams and the prefabricated granule of other excipient; Add mineral oil 10 grams while stirring, get total batch mixing behind the mix homogeneously.This granule can directly be packed becomes effervescent granule.

5, effervescent tablet preparation

The total batch mixing of step 4 gained of preparation granule, at temperature 15-25 ℃, under the environment of relative humidity about 10%; Use the punch die of diameter 20-30 millimeter; Compression moulding on tablet machine, every heavy 5.5 grams, altogether about 110 flake products; Drying condition lower seal damp-prrof packing then, every contains 500 milligrams of effective composition Basics.

The drug particles powder and the effervescent tablet of the single high molecular polymer coating material of embodiment 4 preparations:

Under the protection of nitrogen gas; At ambient temperature; The Eudragit E high molecular polymer of 26 grams is added in 200 milliliters the chloroform, stir down high molecular polymer is dissolved fully after, in mixture, add the 19 hydrochloric acid Luo Pu Lamines (also being loperamide) that restrain; The back use spray-drying process method that stirs is granulated, and gets the drug particles powder in the high molecular polymer coating material that is wrapped in of 43 grams.

The method that provides among all the other production stages and the embodiment 1 is identical, effervescent tablet A1.

Comparative Examples 1

Control sample

1, sour agent in the effervescent and alkaline agent drying for standby

2, prefabricated drug particles

2.1 restrain dry hydrochloric acid Luo Pu Lamine; With sorbitol 860 grams, maltodextrin 21 grams, Cornstarch 2 grams, Fructus Citri tangerinae flavor flavoring agent powder 162 grams, sucralose 2 grams, 10 gram antioxidant vitamin E (acetate) and acesulfame potassium 2 grams; Behind each component mix homogeneously; Mixing granulation in the high efficient mixed facility for granulating gets flavoring agent and good prefabricated granule 1036 grams of other excipient after the drying.

3, preparation effervescent granule

At temperature 15-25 ℃; Under the environment of relative humidity about 10%, take by weighing the exsiccant citric acid that 1042 gram steps 1 obtain, the exsiccant sodium bicarbonate that 756 gram steps 1 obtain; The exsiccant potassium bicarbonate that 172 gram steps 1 obtain; The exsiccant prefabricated drug particles that 500 gram steps 2 obtain adds mineral oil 26 grams while stirring, gets total batch mixing behind the mix homogeneously.This granule can directly be packed becomes effervescent granule.

4, effervescent tablet preparation:

The total batch mixing of step 3 gained of preparation granule, at temperature 15-25 ℃, under the environment of relative humidity about 10%; Use the punch die of diameter 20-30 millimeter; Compression moulding on tablet machine, every heavy 5.0 grams, altogether about 500 flake products; Drying condition lower seal damp-prrof packing then, every contains 2 milligrams of effective composition hydrochloric acid Luo Pu Lamines.

Embodiment 5 performance tests

Sensory test:

The effervescent tablet of getting embodiment 1～4, Comparative Examples 1 is dissolved in the drinking water, and every with about 150 milliliters water, and totally 20 healthy persons are participated in, and drink some respectively in mouth, tell then, come the zest and the tolerability of test water solution.

Test result is following:

The effervescent tablet aqueous solution of Comparative Examples 1 is all tested serious zest taste in 20 forces after preparation, 6 people think and can stand that 14 people think and can't stand.

The aqueous solution of the effervescent tablet A1 of embodiment 4 is after preparation, and 14 people do not test the zest taste, has 6 people to feel the zest taste, and 6 people all think and can stand; After 24 hours, have 11 people not test the zest taste, 9 people feel the zest taste, but 9 people all think and can stand.

And the effervescent tablet aqueous solution of embodiment 1～3 is not felt the zest taste after preparation; After 24 hours, still test less than any zest taste,

The result shows; In the novel formulation method that discloses among the present invention; Embodiments of the invention 1～4 have all reached very capable at the covering taste of coating packaging medicine of the effect, the particularly effervescent tablet of embodiment 1～3 that hide taste, also do not detect dissolving after 24 hours and discharge medicine.

Performance test embodiment 6

Pharmacokinetics difference:

The ibuprofen-effervescent sheet of getting embodiment 2 is dissolved in the drinking water, and every with about 150 milliliters water, contrasts the Advil tablet of buying on 200 milligrams the market.Totally 18 healthy persons are participated in test, every group 9 people, and after the mensuration user was taken and got in the body, blood ibuprofen pharmaceutical concentration is curve over time, and measuring the result is 9 people's meansigma methods.

Use the effervescent tablet aqueous solution of the embodiment of the invention 2, blood drug level just reaches maximum concentration in the time of 41 minutes after the tester drinks in the body; And the Advil tablet of buying on the market, blood drug level just reaches maximum concentration in the time of 101 minutes after the tester drinks in the body; And use the effervescent tablet aqueous solution of the embodiment of the invention 2, the highest blood drug level can reach 22 (μ g/ml); And the Advil tablet of buying on the market, the highest blood drug level has only 15 (μ g/ml).

In addition, hide the flavor test result and show, in the novel formulation method that discloses among the present invention, the covering taste of the medicine of coating parcel very capable do not detect dissolving yet and discharges medicine after 24 hours.

Embodiment 7

Prepare the not effervescent of drug:

1, sour agent in the effervescent and alkaline agent drying for standby

2, preparation flavoring agent and the prefabricated granule of other excipient

Required flavoring agent and other excipient in the effervescent; Sorbitol 860 grams, maltodextrin 21 grams, Cornstarch 2 grams, Fructus Citri tangerinae flavor flavoring agent powder 162 grams, sucralose 2 grams, 10 gram antioxidant vitamin E (acetate) and acesulfame potassium 2 grams; Behind each component mix homogeneously; Mixing granulation in the high efficient mixed facility for granulating gets flavoring agent and good prefabricated granule 1036 grams of other excipient after the drying.

3, preparation effervescent granule

At temperature 15-25 ℃; Under the environment of relative humidity about 10%, take by weighing the exsiccant citric acid of 1042 grams, the exsiccant sodium bicarbonate of 756 grams; The exsiccant potassium bicarbonate of 172 grams; Exsiccant flavoring agent of 500 grams and the prefabricated granule of other excipient add mineral oil 26 grams while stirring, get total batch mixing behind the mix homogeneously.This granule can directly be packed becomes effervescent granule.

4, effervescent tablet preparation

The total batch mixing of step 3 gained of preparation granule, at temperature 15-25 ℃, under the environment of relative humidity about 10%; Use the punch die of diameter 20-30 millimeter, compression moulding on tablet machine, every heavy 5.0 grams; Altogether about 500 flake products, drying condition lower seal damp-prrof packing then.

Embodiment 8

The antitumor action test

The effervescent tablet that makes with embodiment 7 carries out the antitumor action test, the inhibitory action of the effervescent tablet malignant mesothe growth of the no any ingredient of test.Every effervescent tablet uses the dissolving of 100 ml distilled waters, uses the clear liquid after filtering to handle cell.

The normal optimum mesothelial cell of test contrast, the growth of cell is adopted the terminal point enzyme labeled immunoassay to attach algoscopy (ELISA, enzyme-linked immunosorbent assay) colorimetric reagent box and is measured through measuring the synthetic detection of DNA.Two kinds of cells are planted obstructed 24-hole culture plate simultaneously, and every hole kind goes into 10 ⁵Cell; Every hole adds and the isopyknic effervescent tablet clear liquid of Cell sap; In 37 ℃ incubator, hatched 24,48 and 72 hours; In the 5-bromo-2-deoxyuridine of 2 μ M, hatched 2 hours in 37 ℃ the incubator then, use FixDenat liquid in 37 ℃ incubator, to hatch 30 minutes subsequently cell fixation.

Above-mentioned cell is hatched 90 fens kinds again under the effect of anti-5-bromo-2-deoxyuridine antibody, and then hatches the sulphuric acid stopped reaction of back adding 30 minutes (after adding tetramethyl benzidine Tetramethylbenzidine) 1M, measures the absorbance at 450nm place.

The blank of test does not use effervescent tablet, uses distilled water, and the growth of cell uses blank to calculate relative value as radix.

	24 hours	48 hours	72 hours
				Malignant mesothe	92％	81％	70％
Optimum mesothelial cell	96％	101％	94％

The result shows that in the novel formulation method that discloses among the present invention, the effervescent prescription of drug does not have the ability of certain inhibition growth of tumour cell, and to not influence of Normocellular growth.

All documents in that the present invention mentions are all quoted as a reference in this application, are just quoted such as a reference separately as each piece document.Should be understood that in addition after having read above-mentioned teachings of the present invention, those skilled in the art can do various changes or modification to the present invention, these equivalent form of values fall within the application's appended claims institute restricted portion equally.

Industrial applicability

The major advantage of effervescent of the present invention and formulation method thereof is:

First; Method of the present invention can be used for preparing effervescent tablet or the effervescent granule with very strong tangy taste medicine; Can be but be not limited to ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine and dimenhydrinate, or the like;

The second, the formulation method that the present invention discloses has been avoided using volatile organic solvent, has reduced medicine by the probability that organic solvent pollutes, and has reduced production stage;

The 3rd, effervescent product of the present invention has good targeting ability, and they only dissolve in the stomach, and can be in other position dissolving.

Claims

1. an effervescent is characterized in that, with the effervescent total weight: comprise the effervescent substrate of 25-90%, the active substance of 0.01-70%, the targeting h substance of 0.5-74.9%;

Described effervescent substrate is made up of edible acid agent and the edible alkaline agent that can produce carbon dioxide, and the molar ratio of sour agent and alkaline agent is 1: (0.95～1.05); The alkaline agent of said effervescent substrate is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium glycine carbonate or its combination; The sour agent of said effervescent substrate is selected from citric acid, glycine citrate, monosodium citrate salt, malic acid, tartaric acid, fumaric acid or its combination;

Described active substance is selected from quick acting medicine or stomach medicine; Said quick acting medicine is selected from ibuprofen, acetaminophen, hydrochloric acid Luo Pu Lamine, reserpine, alprazolam, diphenhydramine or dimenhydrinate; Said stomach medicine is selected from Basic;

Described targeting h substance is for covering the high molecular polymer coating material of said active substance; And said high molecular polymer coating material comprises the high molecular polymer that is only soluble in people and/or animal gastric pH environment, and wherein said high molecular polymer accounts for said macromolecule coating material gross weight and is not less than 0.5 weight %; Said high molecular polymer selects Eudragit E polymer;

Also comprise glyceryl monostearate in the said high molecular polymer coating material, and the weight ratio of said glyceryl monostearate and high molecular polymer is between 95: 5 to 35: 65;

The method for preparing of described effervescent comprises the steps:

(a) the drug particles powder of preparation active substance:

The fusing glyceryl monostearate adds above-mentioned targeting h substance, and stirring and dissolving adds above-mentioned active substance, granulates, and obtains the drug particles powder;

(b) drug particles powder that obtains step (a) and above-mentioned effervescent substrate and flavoring agent and mixed with excipients are even, obtain the effervescent granule.

2. effervescent as claimed in claim 1 is characterized in that, with the effervescent total weight: comprise the effervescent substrate of 25-90%, the active substance of 0.01-50%, the targeting h substance of 1-30%.

3. effervescent as claimed in claim 1 is characterized in that, said high molecular polymer accounts between the 0.5%-99.9% of said macromolecule coating material gross weight.

4. effervescent as claimed in claim 1 is characterized in that, said high molecular polymer accounts between the 5%-95% of said macromolecule coating material gross weight.

5. effervescent as claimed in claim 1 is characterized in that the weight ratio of said glyceryl monostearate and high molecular polymer is (1～8): between 1.

6. effervescent as claimed in claim 1 is characterized in that, the particle powder of the said active substance in the step (a) obtains through following method:

(I) the glyceryl monostearate solution of high molecular polymer, the mixture of active substance are provided;

(II) mixture of said step (I) is granulated and is obtained the granule of the active substance in the step (a).

7. effervescent as claimed in claim 6 is characterized in that, the fineness of active substance is not more than 100 orders described in the step (I).

8. effervescent as claimed in claim 6 is characterized in that, said step (II) adopts the sprinkling granulation to granulate.

9. effervescent as claimed in claim 8 is characterized in that, the method for granulating of step (II) comprises the steps: that the mixture of said step (I) was carrying out granulate 30 minutes～60 minutes through 40 ℃ ± 5 ℃ Celsius; Obtain the granule of the active substance in the step (a).

10. the purposes of an effervescent as claimed in claim 1 is characterized in that, said effervescent discharges medicine at the preparation targeting, make the medicine quick acting or hide the application in the medicine of zest taste of medicine.