CN1795856A - Medicinal preparation of containing Tenatoprazole and preparation method - Google Patents

Abstract

A medicine in the form of micropill containing tytolazole is composed of the inertial core prepared from tytolazole and one or more excipients, the isolating layer and the enteric layer. Its advantages are high biologic utilization rate, less irritation to stomach and intestine, and zero-class release speed.

Description

A kind of pharmaceutical preparation and preparation method that contains Tenatoprazole

Technical field

The present invention relates to contain the pharmaceutical preparation and the preparation method of Tenatoprazole, relate in particular to a kind of oral drug preparation that contains the enteric coated-pellet form of Tenatoprazole.

Background technology

H ⁺/ K ⁺-atpase inhibitor, promptly proton pump inhibitor (PPI) is the excretory medicine of the novel gastric acid inhibitory of a class.H ⁺/ K ⁺-ATP enzyme (proton pump) is positioned on the tubulovesicle and secretion periosteum of parietal cell, participates in last link of gastric acid secretion, suppresses the activity of this enzyme, can suppress the gastric acid secretion that various factors causes.Tenatoprazole is a kind of novel proton pump inhibitor, and significantly the secretion of gastric acid inhibitory also has inhibitory action to helicobacter pylori simultaneously.Its mechanism of action also is to act on the gastric mucosa parietal cell by the special opposite sex, reduces H in the parietal cell ⁺/ K ⁺-atpase activity, gastric acid inhibitory is secreted, and helicobacter pylori is had unique antibacterial activity.Proton pump inhibitor is mainly used in treatment gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Eillison syndrome etc. and gastric acid secretion imbalance diseases associated.This class medicine is than histamine H ₂-receptor antagonist and the excretory medicine of other gastric acid inhibitory have obvious superiority.The oral post-absorption of this medicine is rapid, and absorption region is directly proportional with dosage, and toleration and safety are good.Curative effect is than at present clinical widely used like product omeprazole is strong 7 times, and physical and chemical quality is stable, is the kind of tool potentiality in the like product of having developed.The proton pump preparation of existing approved listing has omeprazole (listing in 1988), lansoprazole (listing in 1992), dissolves appropriate draw azoles (listing in 1994) and rabeprazole (1998) listing.The gastric acid secretion of the inhibition pylorus ligation rat of Tenatoprazole dose dependent, ED50 is 3.0mg/kg.It blocks Gaster Sus domestica liquid H ⁺/ K ⁺The effect and the omeprazole of-ATP enzyme physiologically active and gastric motility almost equal (IC50=6.2/4.2mg/kg P.O.).Animal experiment shows: oral Tenatoprazole 0.2mg/kg 7 days is than omeprazole and the more effective gastric acid inhibitory secretion of lansoprazole, reaches greatest treatment efficacy after the administration 3～4 times.The oral Tenatoprazole 0.3mg/kg of stomach basket pipe rat, the persistent period that gastric acid secretion reduces is longer than omeprazole (0.6mg/kg) and lansoprazole (0.9mg/kg).Tenatoprazole, omeprazole and lansoprazole suppress H in the isolated test that dog stomach microsome carries out ⁺/ K ⁺The IC50 of-ATP enzyme is respectively 8.6,8.8 and 9.9umol/L.Numerous tests show that Tenatoprazole suppresses H ⁺/ K ⁺The activity of-ATP enzyme is better than omeprazole and lansoprazole.

Have now found that aspect stable, Tenatoprazole stability is much better than omeprazole.Domestic to having made mensuration from 34 omeprazole stability of formulation of 13 countries such as Portugal, Brazil, India, China.The result shows to have only 6 products (18%) to present the stability of good physics and chemistry at duration of test.27 products (79%) relatively poor (containing middle home made article), tangible chemolysis has appearred in its active component, and also corresponding appearance such as physical property such as color and dissolution etc. changes.And show a result of the test that is intended to the stability of more various proton pump inhibitors, under 60 ℃, the condition of relative humidity 75%, investigate 8 days, omeprazole decomposes only remaining 3% effective ingredient of back, and these data of Tenatoprazole are 77%, illustrate that Tenatoprazole stability is much better than omeprazole.

Tenatoprazole is a kind of potent gastric acid secretion inhibitor, and its chemical name is 5-methoxyl group-2-(4-methoxyl group-3,5-lutidines-2-methylsulfinyl), imidazo (4, a 5-b) pyridine (Tenatoprazole), and its chemical structure of general formula is as follows:

Clinical research shows that Tenatoprazole is subjected to the new generation product of antiulcer drug proton pump inhibitor, and it is evident in efficacy, obviously is better than other products, and side effect is small and light, and it is the secretion of gastric acid inhibitory obviously, simultaneously helicobacter pylori is also had inhibitory action.The oral post-absorption of this medicine is rapid, and absorption region is directly proportional with dosage, and toleration and safety are good.Curative effect is than at present clinical widely used like product Ao Nuola azoles (commodity be called losec) is strong 7 times, and physicochemical property stablizes, and is the kind of tool potentiality in the like product of having developed.

Yet, though with regard to Tenatoprazole itself, though being better than other, its stability draws azole drug, but, it still is a kind of unsettled medicine, and general formulation such as tablet are under acid condition, and medicine decomposes fast, cause losing and the increase of impurity of effective ingredient, make medicine can not reach ideal therapeutic effect.There is report that omeprazole is made enteric coated micropill, and prescription is optimized, effectively solved the problem of omeprazole, strengthened stability, and improved bioavailability adjuvant compatibility difference.But the Tenatoprazole and the adjuvant compatibility are very poor, can with most of adjuvants reactions, this has increased this special dosage form of difficulty, especially pellet preparations that Tenatoprazole is made various dosage forms again.

In addition, Tenatoprazole is an insoluble drug, and the stripping of this type of medicine and bioavailability are relatively poor usually, and medicine is difficult for being absorbed by the body.

At present, to studies show that of micropill dosage form, the influence that the transhipment unable to take food thing of micropill in gastrointestinal tract carried the rhythm and pace of moving things, diameter is less than the piller of 2mm, even when sphincter of pylorus is closed, still can pass through pylorus, so piller absorbs the influence that generally is not subjected to gastric emptying at gastrointestinal.

The drug release behavior of pellet is a summation of forming each piller drug release behavior of a dosage, error or the defective unlikely drug release behavior to whole preparation of indivedual pillers in preparation produces and has a strong impact on, and therefore is being better than other dosage forms aspect the repeatability of release rule, the concordance.Absorption that there are some researches show enteric coated tablet is subjected to food effect big, and enteric coated micropill is subjected to the influence of food not obvious.

The piller of several different rate of releasing drug can be made capsule on demand, can make blood drug level reach therapeutic effect rapidly behind the clothes, can keep longer action time again, so plasma concentration curve is steady, and repeatability is arranged, and adverse reaction rate is low.How Tenatoprazole is cooperated with suitable dressing, preparation becomes oral pellet, is the problem that is worth people to pay close attention to.

Summary of the invention

The purpose of this invention is to provide a kind of pharmaceutical preparation and preparation method that contains Tenatoprazole, to overcome the defective that existing preparation exists.

The pharmaceutical preparation that contains Tenatoprazole of the present invention is a kind of enteric coated-pellet preparation, comprises nuclear core, sealing coat and enteric layer, preferably also is provided with outermost layer outside enteric layer.

Said nuclear core comprises the inert core may that Tenatoprazole and one or more pharmaceutical excipients are formed, and it is outer or/and mix in the inert core may that Tenatoprazole is coated on one or more pharmaceutical excipients; Sealing coat is coated on outside the nuclear core, and enteric layer is coated on outside the sealing coat;

Wherein, in the weight of product:

Nuclear core 10%～70%

Medicine 3%～35%.

Sealing coat 1%～40%

Enteric layer 5%～45%

Preferably:

Nuclear core 20%～45%

Medicine 3%～20%.

Sealing coat 2%～20%

Enteric layer 20%～40%.

As being enclosed with outermost layer, outermost weight is 0.1～10% of product weight.

Described inert core may is commonly used in the pharmaceutical field, all can buy easily in all industrial countries.Most preferred inert core may is to be prepared by starch that is used for confection or drug manufacture or sucrose, or adopts any other pharmaceutical excipient, and described excipient comprises for example microcrystalline Cellulose, plant gum, wax etc.The principal character of inert core may is, with respect to other excipient in Tenatoprazole and the micropill and will to take for the patient of this micropill be inert.

The size of nuclear core depends on the required size of micropill to be produced.Usually, this nuclear core can be as small as 0.1mm, or greatly to 2mm.Preferred nuclear core is about 0.3 to about 0.8mm, so as finally to obtain required preferred size, diameter is the micropill of about 0.5mm～1.5mm.

The amount of used nuclear core depends on weight and the thickness that adds layer.Usually, the weight of nuclear core accounts for the about 10%～70% of product, more preferably examines core and accounts for about 20%～45% of product.

When producing micropill, usually Tenatoprazole is coated on the nuclear core so that final drug level is about 10%～35% of a product weight with inert core may.Certainly, the amount of Tenatoprazole depends on required drug dose and the required micropill amount of user.The dosage of Tenatoprazole is 5mg to 40mg, and preferred 7.5mg to 20mg, the constant of micropill are the amounts of gelatine capsule of packing into usually.By the volume of comparison gelatine capsule and required dosage, the concentration range that the pharmacists can determine Tenatoprazole in the product of the present invention is about 10% to about 35%.

Should also be noted that the particle diameter of Tenatoprazole.Suggestion by grinding or additive method is brought down below about 10 μ m with the particle diameter of Tenatoprazole, was generally 1～10 μ m before being used for product of the present invention and method.The present invention is wrapped in the Tenatoprazole bag on the inert core may, thereby can improve the stability of Tenatoprazole;

Said sealing coat is to comprise by polymeric material and as the fine-powder solid pharmaceutical excipients of filler forming, polymeric material is selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl cellulose etc. to increase the adhesion and the bonding force of sealing coat, the fine-powder solid pharmaceutical excipients is selected from thin powder Talcum, silicon dioxide etc. and is used as drug excipient widely, can add easily in the case to fill separate layer and to make it smooth, with smoothness and the solidness that increases this sealing coat.

Have now found that when adding pharmaceutically useful non-reducing sugar in sealing coat, micropill is to the beat all obvious increase of the resistivity of acid condition.Therefore, these sugar can be added in the sealing coat that is coated on nuclear cores, contain the amount that sugared sealing coat can be reduced to the required enteric polymer of the acidproof level that reaches given.Therefore can obviously reduce the cost of institute's formulated product.Use more a spot of enteric polymer to have reduced cost of material and process time, and reduced can with the amount of the polymer of Tenatoprazole reaction.To interactional inhibitory action between nuclear core/enteric layer is mechanical.Said non-reducing sugar preferably sucrose, trehalose, lactose or its mixture, its addition are 0～10% of product weight;

Also can add optical screen barrier material in the sealing coat, as titanium dioxide, ferrum oxide etc., make it opaque and play the effect of optical screen barrier, the addition of optical screen barrier material is 0.1～10% of a product weight;

Usually, in the weight of final products, when using sugar, the content of sugar is about 0～10% in the sealing coat, and the content of polymeric material is about 0.1～5%, and filler such as talcous content are about 5%～15%.

Must the parcel sealing coat between nuclear core that contains Tenatoprazole and enteric layer.The function of sealing coat is that the coating for enteric layer provides slick substrate, prolongs the time of micropill opposing acid condition, and the interaction between the enteric polymer improves stability in medicine and the enteric layer by suppressing;

The smooth function of sealing coat is pure machinery, its objective is the coating that improves enteric layer, avoids projection and the irregular point that approaches that forms on enteric layer because of the nuclear core.Therefore, make smooth more regularly more if will examine core, the required material of sealing coat is just few more, and the nuclear core of and preparation superfine when the granule of Tenatoprazole very when spherical, just can not need the smooth features of sealing coat near real fully.

Said enteric layer is to comprise preparing with the enteric polymer and the plasticizer of Tenatoprazole compatibility;

Preferred enteric polymer is an acrylic resin.It can obtain from German Romo Co.,Ltd, and commodity are called EUDRAGIT.This product has L30D-55 and L100D-55, but estimates also can use other rank.L30D-55 preferably.

The particle mean size of enteric polymer is about 1 μ m～5 μ m, preferred 1 μ m～3 μ m.

Under the situation of L30D-55, preferred plasticizer is a triethyl citrate, and its consumption is about 15%-30% of enteric polymer amount.

When needing, in above-mentioned enteric polymer and plasticizer, can also add one or more pharmaceutically acceptable carriers, described carrier comprises diluent, filler, binding agent, wetting agent, disintegrating agent, absorption enhancer, surfactant, absorption carrier, lubricant, plasticizer of pharmaceutical field routine etc., can also add flavouring agent, sweeting agent, pH regulator agent etc. in case of necessity.For example, can regulate the pH value to 5.4 of enteric liquid usually with magnesium hydroxide; Can with Pulvis Talci with the thickness that increases layer, make that it is firm, reduce electrostatic charge and prevent the coating solution adhesion, about 1% to about 10% the above-mentioned solid that can be end product with content adds in the enteric polymer mixture, and the content of enteric polymer itself is generally about 5%～45%, more preferably about 20%～40% of product weight.

Said outermost layer is not all to need in each case, but but outermost layer can improve the outward appearance of product and processing, storage and the machining characteristic of product usually, can bring other benefits in addition.Outermost material is selected from antistatic composition; as Pulvis Talci or silicon dioxide, wax; as Cera Flava or polymeric material; as hydroxypropyl methylcellulose or polyvinylpyrrolidone etc.; also can have opacifier, solubilizing agent or coloring agent in the polymeric material; preferred opaque trickle coloring agent such as redness or the yellow iron oxide of adopting, outermost layer can dissolve rapidly under one's belt, exposes enteric layer protection Tenatoprazole.Outermost parcel amount is 0.1～10% of a product weight, and the amount when adopting static composition or wax is 0.1～1%; Amount when adopting polymeric material is 2%～10%.

The preferred Tenatoprazole of preparation of the present invention, but it will be understood by those skilled in the art that the form of other Tenatoprazole salt of use can reach beneficial effect of the present invention equally.

In present specification, except as otherwise noted, expression waies such as all percentage ratios, ratio, ratio all are unit with weight.The weight of product is meant the dried forms behind the water of having removed dissolving or having disperseed multiple composition.

The preparation method of preparation of the present invention comprises the steps:

(1) preparation of nuclear core:

Inert core may is moistening with binding agent, add the Tenatoprazole powder, then with the mixture drying.Or Tenatoprazole directly is dissolved in the binding agent, be sprayed on the inert core may, then with the mixture drying, suitable device is a usual means.

Said binding agent is selected from a kind of or its mixture in hypromellose, hyprolose or the polyvinylpyrrolidone;

Should also be noted that the particle diameter of Tenatoprazole.Suggestion before being used for product of the present invention and method by grinding or additive method is brought down below about 10 μ m with the particle diameter of Tenatoprazole.

In fact, in many steps of the inventive method, all used this device, therefore will carry out detailed discussion it.Usually, this method to the used similar conventional coating pan of sweet tablet method in carry out.We can use this method preparation nuclear core, but the air-flow efficient and the drying capacity of this device are lower, thereby have limited coating speed, therefore, just must prolong process time in order to reduce agglomeration as much as possible.We can also prepare product of the present invention with fluidized bed plant (using rotary processing equipment) or rotating plate device.Rotating plate device is that the cylinder of rotatable platform is formed by the bottom generally.By being made, granule friction between the fixation wall of cylinder and rotation bottom treats that coated granules produces motion.Available warm air drying granule, when using fluid bed, can be on material spraying liquid and balance dry rate.

When preparing powder coating, inert core may is kept certain viscosity, treat adherent powder (being Tenatoprazole under this situation of the present invention) and make on its inert core may that sticks to viscosity to wherein adding continuously or periodically.After having coated whole Tenatoprazoles, stop spraying and make granule dry in air flow.As needs, can also in Tenatoprazole, add some inert powders.Also other adjuvants can be added on the layer with Tenatoprazole.Add these adjuvants with the need so as in the coating process fluidizer, increase the clothing film toughness, reduce electrostatic charge, help wholely to assemble and form slick surface.Can use inert substance such as Pulvis Talci, PEG6000, Kaolin and titanium dioxide, lubricant such as magnesium stearate, fine silicon dioxide, crosslinked ketopyrrolidine (crospovidone) and non-reducing sugar such as sucrose also can add pH regulator agent such as sodium hydrogen phosphate, magnesium oxide and wait the stable and dissolving that keeps medicine.Described amount of substance is a product 1 ‰ to about 20%, and described adjuvant should be particle diameter and is lower than 50 μ m fine graineds, to form slick surface;

Or drug excipient is sprayed on the inert core may, then Tenatoprazole being sticked on the inert core may, described excipient is clamminess when moistening, can form very fine and close film after the drying.Pharmacy man knows and often uses many such materials, and wherein major part is a polymer.Described polymer preferably includes hydroxypropyl emthylcellulose, hydroxypropyl cellulose and polyvinylpyrrolidone.Other material comprises, for example methylcellulose, carboxymethyl cellulose, arabic gum and gelatin.The consumption that adheres to excipient is the about 4%～12% of product weight, and this consumption depends on the amount of waiting to adhere to the Tenatoprazole on the nuclear core to a great extent;

Or the serosity that contains Tenatoprazole by spraying accumulates in Tenatoprazole on the inert core may, the described serosity that contains Tenatoprazole is the aaerosol solution of a kind of Tenatoprazole and excipient, and described excipient is dissolved or suspended in the water of capacity so that described serosity can be sprayed.The machine of this serosity with grinding suspension can be ground to reduce the pollution problems of Tenatoprazole.The method for optimizing of this suspension coating is to use electrostatic medicine fluid bed coating device, and this device is made up of a vertical cylinder, and cylinder has a gas-pervious bottom and near the nozzle that makes progress of bottom top, or places the downward nozzle of product top.Add in cylinder and treat coated granules, the air by the enough volumes of cylinder bottom suction makes particle suspending, with liquid spray to be coated on granule.The temperature and the spray rate of fluidization air balance each other, so that micropill or tablet keep required humidity and levels of viscosity when coating;

Described excipient is known for pharmacy man and is often used many such materials, a kind of or its mixture in preferred hypromellose, hyprolose or the polyvinylpyrrolidone;

Or Tenatoprazole sneaked in the inert core material, the known granulating technique of granular materials that adopt pharmaceutical field then, prepares tabletting when special is prepared the nuclear core that contains Tenatoprazole.The particle diameter of nuclear core is too little, so can not be prepared by compress technique, but Tenatoprazole can be sneaked in the inert core material, then water or solvent with its moistening, drying, be crushed to the size range granule identical and prepare the nuclear core with above-mentioned inert core may, can finish said process by the method for extruding.

(2) parcel sealing coat:

With polymeric material, as the aqueous solution of the fine-powder solid pharmaceutical excipients of filler by conventional method, prepare the method for examining core as the aforementioned, be wrapped on the nuclear core of step (1); In case of necessity, can in aqueous solution, add non-reducing sugar or/and optical screen barrier material;

In the aqueous solution, polymeric material, as the weight content of the fine-powder solid pharmaceutical excipients of filler with 5～20% for suitable;

(3) parcel enteric coating layer:

To contain the method that enteric polymer, aqueous solution of plasticizer or organic solution adopt this area routine, prepare the method for examining core as the aforementioned, be wrapped on the nuclear core that has sealing coat of step (2);

By conventional method discussed above, the device of usefulness fluid bed type with warm air drying, is coated to enteric layer on the nuclear core in spraying enteric polymer solution or suspension.The temperature of dry air and mobile nuclear core material temperature should remain in the temperature range of being advised when producing enteric polymer.

At present, coat with organic solvent and not exclusively to be suitable for pharmaceuticals industry, because the solvent cost height, solvent vapo(u)r is difficult to handle or be difficult to reclaim the solvent of evaporation.Therefore, the present invention does not go through and with an organic solvent coats enteric layer, and the situation needs but pharmacy man is appreciated that, this method for coating are fully feasible.

When the form with aqueous suspension coated enteric polymer, common problem was the film that is difficult to obtain uniformity.Therefore, preferably buy the polymer of fine grained level or before coating, polymer beads is ground to superfine.Can polymer be ground with the form of serosity with dry polymer in the air blast grinding machine for grinding or be prepared into suspension.Usually preferred serosity grinds, and especially can use this method to grind the filler part of enteric layer in same step.The particle mean size of enteric polymer should be reduced in the scope of about 1 μ m～5 μ m, preferably be not more than 3 μ m.

When the form with suspension coats enteric polymer, it is highly important that and to guarantee that suspension keeps evenly, and avoid polymer to be easy to accumulative condition.These preventive measures comprise: suspension is leniently stirred, and stirring can not be too violent, to prevent to form foam; Guarantee that suspension can be not slack in the eddy current in for example nozzle or the excessive transfer tube.If the temperature of suspension is too high, the polymer of form of suspension can be assembled usually, and therefore, the critical temperature under the various situations can be hanged down and be reached 30 ℃.Because in the device of the fluid bed type of routine, nozzle and pipe are exposed in the hot-air, therefore must be noted that and guarantee that suspension can promptly flow through device with cooling pipe and nozzle.Particularly when using L30D-55, should be before coating suspension be cooled to and be lower than 20 ℃, before pumping into suspension, in pipe and nozzle, pump into a small amount of cold water earlier and make its cooling, and guaranteeing to use diameter feeder sleeve as small as possible under the spray rate ground condition, so that suspension can flow rapidly in pipe.

In the present invention, adopt under the situation of L30D-55, can by in and polymer make its dissolving, preferably neutralize with magnesium hydroxide, preferably the form with magnesium hydroxide aqueous solution adds in the water slurry of polymer, neutralizes fully at about pH5.7-5.9, causes the dissolving fully of polymer.When add that magnesium hydroxide in shortage makes in the polymer moieties and the time, also can obtain good result.In this case, unneutralized polymer still keeps the form that suspends, is suspended in the solution of the polymer that has neutralized.As mentioned above, when this method of use, the particle diameter of controlling polymers is very important.With the polymer phase ratio that use to suspend, use that the polymer that has neutralized is easier to obtain smooth, consistent enteric layer, can obtain moderate smoothness and concordance when using the neutral polymer of part.When particularly enteric layer being coated on the very slick separate layer, can obtain extraordinary result with the neutral enteric polymer of part.

When needing, can in containing enteric polymer, aqueous solution of plasticizer or organic solution, add one or more pharmaceutically acceptable carriers;

(4) parcel outermost layer:

When needs parcel outermost layer, antistatic composition or the simple powder of wax are coated in the surface of examining core;

With polymeric material or contain opacifier or/and solubilizing agent or/and the aqueous solution of the polymeric material of coloring agent be sprayed at nuclear core the surface, drying gets final product.Baking temperature should remain in the temperature range of being advised when producing polymeric material.

Preparation of the present invention, enteric coated and sealing coat outside the nuclear core more can improve its stability under acid and responsive condition.The present invention has measured the acid-resistant strength of Tenatoprazole enteric coated-pellet, the result shows, Tenatoprazole is made enteric coated-pellet good acid-resistant strength, and stable under acid condition, the Tenatoprazole of as seen making enteric coated-pellet has successfully solved the stability problem of medicine itself.After Tenatoprazole is prepared as pellet, because can be extensively after pellet is taken, be evenly distributed in the intestines and stomach, dosage inclines and decentralizedly, and medicine increases at the intestines and stomach surface distributed area, so drug bioavailability improves and reduces or eliminates the zest medicine to the gastrointestinal zest.Find also that in other experiments the preparation enteric coated-pellet can reduce the toxic and side effects of medicine.The invention solves the problem of Tenatoprazole slightly solubility and bioavailability difference.

Micropill among the present invention non-biodegradable material coating can obtain favorable reproducibility, not rely on the zero-order release speed of pH.

The specific embodiment

Following examples provide the preparation of the multiple different enteric coated micropills in the scope of the invention, and the purpose of these embodiment is further to the reader enteric coated-pellet of the present invention and preparation method thereof to be described.It is conspicuous that in the scope of the invention other change for the medicine scholar, and its preparation also is that the medicine scholar is known.

For each embodiment, what at first provide is stock chart, its expression be the particulate of preparation one unit dose the time used each component amount.Behind stock chart, will describe preparation method, be given in used loading amount and batch size of each production phase.

Embodiment 1

7.5mg Tenatoprazole/capsule, stock chart

The nuclear core

Sucrose-starch pillet, the 30-35 order	50mg
		Tenatoprazole	7.5mg
Sucrose	1.92mg
		Hydroxypropyl methylcellulose	2.5mg
Sodium hydrogen phosphate	1.5mg
		Pulvis Talci, 500 orders	1.5mg

Separate layer

Magnesium oxide	0.76mg
		PEG-6000	0.38mg
Hydroxypropyl methylcellulose	3.8mg
		Sucrose	8.472mg
Pulvis Talci, 500 orders	0.76mg

Enteric layer

L30D-5 5	42mg
		Triethyl citrate	1.26mg
Pulvis Talci, 500 orders	2.52mg

Outermost layer

Coloring mixture white (HPMC+ titanium dioxide)	3.225mg
		Hydroxypropyl methylcellulose	0.809mg
Pulvis Talci	0.4mg

By Tenatoprazole being suspended in the binder solution of forming by sucrose and hydroxypropyl methylcellulose, and regulate pH value with sodium hydrogen phosphate, again the suspension that obtains is passed through MS-12 type particle granular device (Coball Mill) to reduce the particle diameter of medicine, making particle diameter is 5 μ m, in the fluidized bed dryer that West (Wurster) post is housed, the suspension that ground is coated on the sucrose starch pillet.After having coated the Tenatoprazole suspension of aequum, Tenatoprazole is examined core micropill 60 ℃ of following finish-dryings in fluidized bed dryer.

Form with aqueous suspension is coated to separate layer on the Tenatoprazole nuclear core micropill then, described separate layer is made up of Pulvis Talci, PEG-6000, sucrose and hydroxypropyl methylcellulose, its weight content in aqueous solution is 35%, behind the suspension that has coated aequum, with micropill 50 ℃ of following finish-dryings in fluidized bed dryer.In the process of micropill bag separate layer, the whitewashing flow velocity be should control and 45 ℃, concentration of slurry are controlled at 10g/min, boiling temperature, if flow velocity is too fast, temperature is too high, the excessive adhesion phenomenon that is prone to of concentration of slurry, in case adhesion phenomenon occurs, stop whitewashing, with the micropill processing of sieving, screen cloth is controlled at 10 orders-40 order, then spray again.In addition, we are by regulating air quantity size (generally being controlled at 35%) and strengthen the sealing coat consumption, and weightening finish is 17%, avoid the preparation metachromatism that does not have Bao Yan to cause medicine and enteric coating to react to cause owing to sealing coat.

By adding magnesium hydroxide the enteric coating aqueous suspension is regulated pH value to 5.4, described suspension is made up of L30D-55, Pulvis Talci, triethyl citrate.The enteric coating suspension is coated on the micropill of Tenatoprazole separate layer coating.After having coated the enteric coating suspension of aequum, with micropill 50 ℃ of following finish-dryings and add a small amount of Pulvis Talci in fluidized bed dryer to reduce electrostatic charge.

Coat outermost layer then, described outermost layer (is made up of titanium dioxide and hydroxypropyl methylcellulose in vain coloring mixture.After having coated the color coating suspension of aequum, with micropill finish-drying and add a small amount of Pulvis Talci in fluidized bed dryer to reduce electrostatic charge.Tenatoprazole content in the micropill of analysis gained also fills it in the capsule to obtain containing the capsule of 7.5mg Tenatoprazole.

Embodiment 2

7.5mg Tenatoprazole/capsule

Stock chart

The nuclear core

Sucrose-starch pillet, the 30-35 order	50mg
		Tenatoprazole	7.5mg
Hydroxypropyl methylcellulose	2.5mg
		Sodium hydrogen phosphate	1.5mg
Pulvis Talci, 500 orders	1.5mg

Separate layer

Magnesium oxide	0.76mg
		PEG-6000	0.38mg
Hydroxypropyl methylcellulose	3.8mg
		Pulvis Talci, 500 orders	0.76mg

Enteric layer

L30D-55	42mg
		Triethyl citrate	1.26mg
Pulvis Talci, 500 orders	2.52mg

Outermost layer

Coloring mixture white (HPMC+ titanium dioxide)	3.225mg
		Hydroxypropyl methylcellulose	0.809mg
Pulvis Talci	0.4mg

Preparation method is with embodiment 1.

Embodiment 3～4

7.5mg Tenatoprazole/capsule, stock chart

The nuclear core

Raw material	Embodiment 3	Embodiment 4
			Sucrose-starch pillet, the 30-35 order	45mg	55mg
Tenatoprazole	7.2mg	7.8mg
			Sucrose	15mg	25mg
Hydroxypropyl methylcellulose	2.0mg	3.0mg
			Sodium hydrogen phosphate	1.0mg	2.0mg
Pulvis Talci, 500 orders	1.0mg	2.0mg

Separate layer

	Embodiment 3	Embodiment 4
			Magnesium oxide	0.7mg	0.85mg
PEG-6000	0.3mg	0.5mg
			Hydroxypropyl methylcellulose	3.0mg	4.5mg
Sucrose	8.0mg	9.0mg
			Pulvis Talci, 500 orders	0.7mg	0.85mg

Enteric layer

	Embodiment 3	Embodiment 4
			L30D-55	40	43mg
Triethyl citrate	1.1	1.4mg
			Pulvis Talci, 500 orders	2.3	2.8mg

Outermost layer

	Embodiment 3	Embodiment 4
			Coloring mixture white (HPMC+ titanium dioxide)	3.0mg	5.5mg
HPMC	0.5mg	1.5mg
			Pulvis Talci	0.3mg	0.5mg

Preparation method is with embodiment 1.

Said medicine Tenatoprazole consumption is generally 5%-30%.

Prepare micropill according to the foregoing description, and fully detect the capsule of filling with the micropill of each batch with pharmaceutical field method commonly used.The result of stability experiment shows that micropill and capsule have enough storage-stables, thereby can equally sell and use to conventional medicine.

Experiment shows that also described micropill and capsule have passed through the conventional enteric protection experiment under the generic condition of stomach, and experiment also shows, when described micropill touches the generic condition of small intestinal, can discharge contained Tenatoprazole in proper order.Therefore, the present invention has also solved the stability problem that Tenatoprazole discharges.

Preparation of the present invention can be used for treating gastric ulcer, duodenal ulcer, reflux esophagitis and Zollinger-Eillison syndrome etc. and gastric acid secretion imbalance diseases associated.

The concrete dosage of Tenatoprazole should be determined according to all correlated conditions such as disease to be treated, patient's sex, body weight, age and other physique characteristics by the doctor, however, use the Tenatoprazole of 7.5mg-20mg dosage for the many preferred dosage regimen that above-mentioned disease proposed.

Embodiment 5～8

7.5mg Tenatoprazole/capsule, stock chart

The nuclear core

Raw material	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
					Sucrose-starch pillet, the 30-35 order	50mg	50mg	50mg	50mg
Tenatoprazole	7.5mg	7.5mg	7.5mg	7.5mg
					Sucrose	1.92mg	0	0	1.92mg
Polyvinylpyrrolidone	0	7.5mg	7.5mg	2.5mg
					Sodium hydrogen phosphate	1.5mg	0	1.5mg	1.5mg
Pulvis Talci, 500 orders	1.5mg	0	0	1.5mg

Separate layer

	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
					Magnesium oxide	0.76mg	0.76mg	0.76mg	0.76mg
PEG-6000	0.38mg	0.38mg	0.38mg	0.38mg
					Hydroxypropyl methylcellulose	3.8mg	3.8mg	3.8mg	3.8mg
Sucrose	0	8.472mg	0	8.472mg
					Pulvis Talci, 500 orders	0.76mg	0.76mg	0.76mg	0.76mg

Enteric layer

	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
					L30D-55	42mg	42mg	42mg	42mg
Triethyl citrate	1.26mg	1.26mg	1.26mg	1.26mg
					Pulvis Talci, 500 orders	2.52mg	2.52mg	2.52mg	2.52mg

Outermost layer

	Embodiment 5	Embodiment 6	Embodiment 7	Embodiment 8
					Coloring mixture white (HPMC+ titanium dioxide)	3.225mg	3.225mg	3.225mg	3.225mg
Hydroxypropyl methylcellulose	0.809mg	0.809mg	0.809mg	0.809mg
					Pulvis Talci	0.4mg	0.4mg	0.4mg	0.4mg

Embodiment 9

Adopt high-efficient liquid phase technique that the preparation of embodiment 1～8 is detected, it is part table 1 as a result.

Table 1: the content of Tenatoprazole enteric coated micropill and acid-resistant strength

Embodiment	Content/%	Acid-resistant strength
			1	99.0±0.3	95.5±2.3
2	98.2±0.7	95.7±3.4
			3	102.4±0.2	96.3±1.2
4	104.5±0.4	98.9±2.2
			5	98.3±0.8	96.5±1.2
6	98.8±0.5	95.8±0.3
			7	97.6±0.2	95.4±0.8
8	98.7±0.6	96.4±0.4

Claims (27)

1. pharmaceutical preparation that contains Tenatoprazole, it is characterized in that, comprise nuclear core, sealing coat and enteric layer, said nuclear core comprises the inert core may that Tenatoprazole and one or more pharmaceutical excipients are formed, it is outer or/and mix in the inert core may that Tenatoprazole is coated on one or more pharmaceutical excipients, sealing coat is wrapped in outside the nuclear core, and enteric layer is wrapped in outside the sealing coat.

2. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, in the weight of product:

Nuclear core 10%～70%

Medicine 3%～35%.

Sealing coat 1%～40%

Enteric layer 5%～45%.

3. the pharmaceutical preparation that contains Tenatoprazole according to claim 2 is characterized in that, counts with the weight of product:

Nuclear core 20%～45%

Medicine 3%～20%.

Sealing coat 2%～20%

Enteric layer 20%～40%.

4. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 and 2 is characterized in that, also is provided with outermost layer outside enteric layer, and outermost weight is 0～10% of product weight.

5. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, described inert core may is to be prepared by starch that is used for confection or drug manufacture or sucrose, or adopts any other pharmaceutical excipient.

6. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, the size of nuclear core is about 0.3～0.8mm.

7. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, the particle diameter of Tenatoprazole is 0.1～10 μ m.

8. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, said sealing coat is to comprise by polymeric material and as the fine-powder solid pharmaceutical excipients of filler forming.

9. the pharmaceutical preparation that contains Tenatoprazole according to claim 8, it is characterized in that, polymeric material is selected from hydroxypropyl methylcellulose, polyvinylpyrrolidone or hydroxypropyl cellulose, the fine-powder solid pharmaceutical excipients is selected from thin powder Talcum, silicon dioxide, the content of polymeric material is the about 0.1～5% of product weight, and fine-powder solid pharmaceutical excipients content is about 5%～15% of product weight.

10. the pharmaceutical preparation that contains Tenatoprazole according to claim 8 is characterized in that, contains pharmaceutically useful non-reducing sugar and optical screen barrier material in sealing coat.

11. the pharmaceutical preparation that contains Tenatoprazole according to claim 10 is characterized in that, the content of sugar is about 0～10% of product weight in the sealing coat.

12. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that, said enteric layer is to comprise preparing with the enteric polymer and the plasticizer of Tenatoprazole compatibility.

13. the pharmaceutical preparation that contains Tenatoprazole according to claim 12 is characterized in that enteric polymer is an acrylic resin, plasticizer is a triethyl citrate, and its consumption is about 15%-30% of enteric polymer weight.

14. the pharmaceutical preparation that contains Tenatoprazole according to claim 13 is characterized in that, the particle mean size of enteric polymer is about 1 μ m～5 μ m.

15. the pharmaceutical preparation that contains Tenatoprazole according to claim 12 is characterized in that, also contains one or more pharmaceutically acceptable carriers in enteric polymer and plasticizer.

16. the pharmaceutical preparation that contains Tenatoprazole according to claim 1 is characterized in that outermost material is selected from antistatic composition, wax or polymeric material.

17. the pharmaceutical preparation that contains Tenatoprazole according to claim 16 is characterized in that polymeric material is selected from hydroxypropyl methylcellulose or polyvinylpyrrolidone.

18. the pharmaceutical preparation that contains Tenatoprazole according to claim 16 is characterized in that, also has opacifier, solubilizing agent or coloring agent in the polymeric material.

19. the preparation method of each described preparation of claim 1～18 is characterized in that, comprises the steps:

(1) preparation of nuclear core:

Inert core may is moistening with binding agent, add the Tenatoprazole powder, then with the mixture drying, or Tenatoprazole directly is dissolved in the binding agent, be sprayed on the inert core may, then with the mixture drying;

Or drug excipient is sprayed on the inert core may, then Tenatoprazole is sticked on the inert core may;

Or the serosity that contains Tenatoprazole by spraying accumulates in Tenatoprazole on the inert core may, and the described serosity that contains Tenatoprazole is the aaerosol solution of a kind of Tenatoprazole and excipient;

Or Tenatoprazole sneaked in the inert core material pelletize then;

(2) parcel sealing coat:

With polymeric material, as the aqueous solution of the fine-powder solid pharmaceutical excipients of filler by conventional method, be wrapped on the nuclear core of step (1);

(3) parcel enteric coating layer:

To contain the method that enteric polymer, aqueous solution of plasticizer or organic solution adopt this area routine, be wrapped on the nuclear core that has sealing coat of step (2).

20. the method according to claim 19 is characterized in that, the polymer grinding is reduced to about 1 μ m～5 μ m for particle mean size.

21. the method according to claim 19 is characterized in that, adopts in the magnesium hydroxide with polymer it to be dissolved fully.

22. the method according to claim 19 is characterized in that, adopts in the magnesium hydroxide part with polymer it to be partly dissolved.

23. the method according to claim 19 is characterized in that, said binding agent is selected from a kind of or its mixture in hypromellose, hyprolose or the polyvinylpyrrolidone.

24. the method according to claim 19 is characterized in that, when examining the preparation of core, adds inert powder in Tenatoprazole.

25. method according to claim 24, it is characterized in that, inert substance is selected from Pulvis Talci, PEG6000, Kaolin or titanium dioxide, magnesium stearate, fine silicon dioxide, crosslinked ketopyrrolidine and non-reducing sugar such as sucrose, pH regulator agent, and the weight of described material is product 1 ‰ to about 30%.

26. method according to claim 19, it is characterized in that, the excipient that drug excipient is sprayed on the inert core may is selected from hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, methylcellulose, carboxymethyl cellulose, arabic gum or gelatin, and the consumption that adheres to excipient is 4%～12% of a product weight.

27. the method according to claim 19 is characterized in that, polymeric material, the fine-powder solid pharmaceutical excipients as filler, non-reducing sugar are passed through conventional method or/and optical screen hinders the aqueous solution of material, is wrapped on the nuclear core of step (1).