CN101259108A - Double-unit tablet containing acid-labile medicaments - Google Patents
Double-unit tablet containing acid-labile medicaments Download PDFInfo
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- CN101259108A CN101259108A CNA2007100379658A CN200710037965A CN101259108A CN 101259108 A CN101259108 A CN 101259108A CN A2007100379658 A CNA2007100379658 A CN A2007100379658A CN 200710037965 A CN200710037965 A CN 200710037965A CN 101259108 A CN101259108 A CN 101259108A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
The invention describes an oral solid preparation of labile active ingredient of acid which comprises two laminas that are disintegrated according to priority, wherein the lamina A comprises a highly effective disintegrant and a basifier, so the disintegrating speed is quicker, the lamina A can quickly release the basifier in gastric juice, and in virtue of which the pH value of the gastric juice is raised; the labile active ingredient of acid of the lamina B is dispersed in the material of a carrier with retarding action to ensure the release of the active ingredient a certain time of lag. A double-unit tablet provided by the invention has simple preparation technique and good stability in storage, which is especially applicable to drugs of labile acid such as proton pump inhibitor.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, is a kind of solid pharmaceutical preparation of the acid labile drug that comprises, particularly proton pump inhibitor specifically, and the preparation method and the purposes of said preparation.
Background technology
H
+/ K
+-adenosinetriphosphataes (H
+K
+--ATP enzyme) inhibitor is also referred to as proton pump inhibitor (PPIs), comprises following chemical compound: omeprazole (omeprazole), lansoprazole (lansoprazole), pantoprazole (pantoprazole), rabeprazole (rabeprazole), Tenatoprazole (tenatoprazole), Pa Lila azoles (pariprazole), Lan Minuola azoles (leminoprazole) and other.These reactive compounds can use with neutral form or with the form of alkali salt, and the form of magnesium salt, calcium salt, sodium salt or potassium salt for example can also be used a kind of single enantiomer or its alkali salt of this chemical compound, also can solvate forms use.
This type of medicine suppresses to be positioned at the H on the secretion surface of parietal cell by specificity irreversibly
+K
+-The secretion of-ATP enzyme enzyme system and gastric acid inhibitory.These active substances are useful for inhibition mammal especially people's gastric acid secretion, therefore can be used for treating the disease relevant with gastroxia, as other symptoms that gastrinoma, gastric ulcer, duodenal ulcer, serious aggressivity esophagitis and pathologic gastroxia cause, also can be used for the related indication alleviation of other reasons as the gastric mucosa infringement of taking NSAIDs and causing.On therapeutic effect, PPIs class medicine does not have effect to excretory gastric acid, and as now known, in the treatment disease relevant with gastroxia, apace in and gastric acid, the pH value in the lifting stomach is useful to rapid relief of symptoms.
PPIs to degraded/conversion sensitivity, is used for should avoiding the influence of gastric acid to its stability when oral in acid and neutral medium.Therefore, the peroral dosage form of this class medicine adopts the enteric technology usually, promptly with the enteric material coating, is prepared as enteric coated micropill or tablet.In documents such as Chinese patent ZL96193594.4, ZL96190090.3, U.S. Pat 4786505, European patent EP 0519365, the technical scheme of this class enteric coating preparation has been described.In this technical scheme, preparation includes ball core or label, buffering clothing layer and outer field enteric coating layer.In ball core or label, need make medicine and basifier (or claiming buffer agent) coexistence usually, to keep the high pH value of subenvironment, increase the stability of PPIs.And be to avoid dissociating in the enteric material influence of carboxyl to such stability of drug, in enteric coating layer, also need to have certain thickness buffering clothing layer, this causes multiple coatings, has increased the operation of preparation, has also increased the weight of preparation and is unfavorable for that the patient takes.And the certain operations in the preparation process as high-temperature operation for a long time, influences the stability of PPIs, and the distortion that coated particle produces in pressing process, or coating thickness is inhomogeneous, also easily causes the instability outside the medicine expection.
Therefore imagine a kind of ideal superacid pharmaceutical preparation that is used for the treatment of, on technology, avoid the complicated procedures of forming of multiple coatings, also avoid because of of uncontrollable influence of clothing layer thickness to stability; This preparation can pass through oral administration, and the control symptom that hyper acid causes provides the lasting acid effect that presses down with PPIs simultaneously rapidly.
Existing similar medicine as the omeprazole dry suspension in U.S.'s listing, is made up of omeprazole, sodium bicarbonate and magnesium hydroxide and excipient.But still there is deficiency in it: it is dry suspension for (1), need require to have preferable mouthfeel with mixing in water for oral taking; (2) it is a dry powder formulations, and volume is big, and this class preparation is very high to the humidity resistance requirement of packing, easily causes the instability of preparation, and promotes packing cost; (3) omeprazole and basifier mix, and take the back and directly contact with gastric juice, may produce degraded.
Also also have many parts of open source literatures to disclose the scheme that does not contain enteric material and adopt paraffin and/or aliphatic alcohol, triglyceride and fatty acid ester material in addition, disclosed as CN02817249.3, WO2004066924, WO2004004682, CN01820221.7, CN01820259.4, CN01820220.9.
At the deficiency that such scheme exists, the invention provides a kind of oral solid formulation of acid-labile active ingredient, it can avoid the complicated procedures of forming of multiple coatings, avoids using enteric material, paraffin and/or aliphatic alcohol, triglyceride and fatty acid ester material.This solid preparation is specially adapted to PPIs class medicine, by in can be rapidly behind the oral administration and gastric acid, provides the lasting acid effect that presses down simultaneously.
Summary of the invention
An object of the present invention is to provide a kind of can be rapidly in and the solid orally ingestible of gastric acid.
A special purpose of the present invention provide a kind of can be rapidly in and gastric acid, and can continue the excretory solid orally ingestible of gastric acid inhibitory.
Another object of the present invention provides a kind of enteric material coating that need not, do not need paraffin and/or aliphatic alcohol, triglyceride and fatty acid ester material yet, contain basifier and acid-labile active ingredient, PPIs class medicine particularly, and the release to described acid-labile active ingredient can well be controlled, the oral formulations that keeps it not degraded by gastric acid before absorbing.
Another object of the present invention provides a kind of preparation method of preparation of acid-labile active ingredient, need not the coating operation.
More known basifiers, as sodium bicarbonate, aluminium hydroxide, magnesium hydroxide, magnesium oxide, sodium carbonate, sulphuric acid magnalium etc., these basifiers can be used alone or in combination, its effect mainly be in and gastric acid and alleviate ulcer pain.When these basifiers were used to promote ulcer healing, needing heavy dose repeatedly to take just can prove effective.The inconvenience of repeatedly taking medicine and take the untoward reaction that heavy dose of basifier may bring for a long time and limited its application.PPIs acts on the key enzyme in the whole last step of gastric acid secretion, makes its irreversible inactivation, treats that new enzyme generates, and parietal cell could recover to secrete acid function.Therefore PPIs can provide persistent gastric acid inhibitory excretory effect.The medicine that this two classes mechanism of action is different is applied to the patient of the relevant disease that ulcer patient or other gastroxias cause simultaneously, can reach following beneficial effect: (1) on curative effect, can be promptly in and gastric acid, relief of symptoms; Simultaneously play inhibitory action, can keep the acid effect that presses down of long period proton pump by PPI; (2) alkaline environment of basifier manufacturing, can avoid making PPIs to be exposed in the low PH environment, make PPIs can avoid degraded under the situation that does not have enteric coating, safe transport is to absorption site, thereby avoid the influence of enteric material, and avoid the operation of multiple coatings preparation.
Known PPIs is unsettled under the low pH of gastric juice, therefore should avoid PPIs directly to contact gastric juice.Existing as taking basifier earlier, after a few minutes, take PPIs more excessively.Make troubles to the patient but take medicine twice, ideal situation is to take back basifier or part basifier simultaneously to discharge prior to PPIs, promotes in the stomach behind the pH value, and PPIs discharges again.Therefore when alkali compound and PPIs being present in a unit preparation and taking simultaneously, its release needs temporal order, but not release simultaneously.
For reaching this purpose, the present invention adopts two parts tablet, is respectively lamella A and lamella B.Lamella A comprises the basifier and the high performance disintegrating agent of capacity, make it enter in the stomach after disintegrate rapidly, discharge basifier; And the excipient that lamella B includes PPIs and has retardation, thereby PPIs is discharged again in lamella A in the basifier and in the gastric acid lifting stomach after the pH value.Through research, we are surprised to find that, by selecting appropriate excipients, adopt conventional preparation means, can make these two kinds of compositions in the short period of time strictly order discharge, basifier at first discharges, in and gastric acid, and offer the stable alkaline environment of PPI, simultaneously not because of adopting delay, slow release or enteric technology to cause the delay of PPIs absorption.Concrete summary of the invention is as follows:
Lamella A
Lamella A comprises basifier and disintegrating agent, and necessary additional excipient.Through repeatedly screening combination, we obtain the desirable combination of basifier, disintegrating agent and other excipient among the lamella A, make it can disintegrate in 3 minutes, discharge basifier.
Any weak base, highly basic or its compositions all may be suitable alkali compounds, basifier can be selected from but is not limited to comprise cation sodium among the present invention, potassium, calcium, magnesium, the electrolyte of aluminum or bismuth, as sodium bicarbonate, potassium bicarbonate, magnesium lactate, magnesium carbonate, magnesium silicate, gluconic acid magnesium and other magnesium salts, aluminium hydroxide/sodium bicarbonate coprecipitate, basic amino acid, and also comprise magnesium oxide, magnesium hydroxide, sodium citrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphposphate, tetrasodium pyrophosphate, potassium pyrophosphate, sodium hydrogen phosphate, dipotassium hydrogen phosphate, tertiary sodium phosphate, tripotassium phosphate, potassium metaphosphate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate and other calcium salt etc.Above-mentioned these alkali compounds can be used alone or in combination.But it should be noted that the alkali compound that causes gastrointestinal mucosa to stimulate for producing too high pH value is not to be suitable for independent use.
The gastric juice that exists in the consumption of alkali compound and the stomach and the speed of gastric secretion are relevant, and is simultaneously relevant with the buffering ability with the neutralising capacity of himself.The gastric acid that the basifier of rapid release should be able to neutralize rapidly and exist among the lamella A, but simultaneously, as is well known, take too much basifier and may cause user's cylinder electrolyte unbalance.In the unit formulation of the present invention, the initial release amount of basifier should be 350～800mg, in and the hydrochloric acid of about 4～10mEq.
The technical scheme of lamella A of the present invention is: select for use sodium bicarbonate, magnesium hydroxide, magnesian combination as basifier.In sodium bicarbonate and the equivalent hydrochloric acid and after, the pH value of generation is the pKa value of its conjugate acid (carbonic acid), about 6.14 or bigger.The speed of magnesium hydroxide and magnesium oxide and hydrion reaction is slower, but antacid ability is strong, and possesses strong buffer capacity.
Disintegrating agent is selected from cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose among the lamella A, its consumption is 4%～10% of a lamella A gross weight, its role is to make the disintegration time of lamella A in the 150ml simulated gastric fluid to be no more than 3 minutes.
Known, for reaching the preparation purpose,, also can add suitable excipient such as filler, binding agent etc. among the lamella A as the needs of tabletting.The use of these excipient should not exert an influence to the disintegration time of lamella A.
A preparation scheme of lamella A material is: the basifier of above-mentioned consumption, comprise sodium bicarbonate, magnesium hydroxide and magnesium oxide, and with disintegrating agent and other excipient pulverize separately, mix; Or another one prepares scheme: magnesium hydroxide, magnesium oxide are granulated with the alcoholic solution of PVP K29/30, and drying is mixed mutually with all the other excipient, obtains the material of lamella A.
Lamella B
Lamella B comprises sour unsettled active component, basifier, disintegrating agent, and the excipient with retardation; Wherein sour unsettled active component is scattered in the carrier with retardation, suitably delays the purpose that discharges to reach.But it should be explicitly made clear at this point that this temporary transient slack time can't cause the delay of active component release and absorption within 10 minutes.
The sour unsettled active component that comprises among the lamella B can be selected from racemic modification, the alkaline salt forms that is fit on omeprazole, pantoprazole, lansoprazole, rabeprazole, Tenatoprazole, Pa Lila azoles, Lan Minuola azoles and the pharmacology thereof, or their single enantiomer a kind of or its alkaline salt forms, or solvate forms, preferably have Pantoprazole Sodium sesquialter hydrate, pantoprazole-magnesium dihydrate, Aura azoles magnesium, omeprazole and esomeprazole magnesium especially and draw azoles.In the preparation unit of once taking, these absorption of active ingredient are consistent with the dosage of present clinical use, are 10mg as omeprazole dosage, 20mg, 40mg, pantoprazole dosage are 20mg, 40mg, lansoprazole dosage is 15mg, and 30mg, rabeprazole dosage are 20mg.
These active component and basifier exist jointly, the kind of the basifier of mentioning among alternative basifier such as the lamella A.In the preparation unit of once taking, the summation of the basifier consumption among the lamella B among the consumption of basifier and the lamella A, should be able in and the hydrion of 4～45mEq.Kind/the combination of basifier and consumption thereof are adjusted the difference of the stability of pH to some extent because of active component, and purpose is to keep that Gastric pH is at least active component pKa value+1 in the process that medicine stops under one's belt, to prevent degraded.
In the present invention, the carrier with retardation be selected from the pH sensitive polymer and have water-swellable can carrier material.Described have water-swellable can carrier material for example: polymer, contact water or the aqueous medium that the polymer of high level expansion, contact water or aqueous medium form gel when contact water or aqueous medium has and expands and polymer, hydrogel, glycosyl material, protein material or its mixture of gelling characteristics, specifically has:
The polymer of high level expansion is selected from sodium carboxymethyl cellulose, crosslinked hydroxypropyl cellulose, high molecular hypromellose, carboxymethyl amide, methacrylic acid potassium divinyl benzene copolymer, polymethyl methacrylate, cross-linked pvp, high molecular weight polyvinyl alcohol etc. when contact water or aqueous medium such as gastric content.
Form the polymer of gel when contact water or aqueous medium such as gastric content, be selected from MC, CMC, low molecular weight HPMC, low molecular weight polyethylene alcohol, polyoxyethylene alcohol, non-crosslinked PVP, xanthan gum etc.
Can expand and form the polymer of gel when contact water or aqueous medium such as gastric content simultaneously, in being selected from viscosity HPMC such as low with in viscosity polyvinyl alcohol such as low.
Also can use other known polymer with blocking medicine release, comprise hydrocolloid such as natural or paragutta, above cellulose derivative, glycosyl material such as tragacanth, guar gum, agar, pectin, angle dish glue, solubility and insoluble alginate, carboxypolymethylene, casein, zein beyond listed etc., and protein substance such as gelatin.
Above-mentioned these materials can use alone or in combination together.Preferred as in low isoviscous HPMC, MC, CMC, in viscosity polyvinyl alcohol, non-crosslinked polyvinylpyrrolidone, xanthan gum etc. such as low.
In lamella B, select above-mentioned carrier material with retardation and/or disintegrating agent to reach accurate control, neither instantaneous rapid release can not produce retardation or the slow release of not expecting yet to active component release time and speed.The carrier material that preferably has the water-swellable energy.Purpose as an example illustrates this have carrier material of water-swellable energy and/or the selection and the amount ranges of disintegrating agent with the following example that is combined as.
One is combined as: viscosity is the hydroxypropyl emthylcellulose of 3～50cP, as commercially available METHOCEL E3PREMIUM, METHOCEL E5 PREMIUM, METHOCEL E6 PREMIUM, PHARMACOAT 603, PHARMACOAT 606, PHARMACOAT 615 etc., consumption is 8%～30% of a lamella B gross weight; And as the PVPP XL of disintegrating agent, consumption is 6%～8% of a lamella B gross weight.
Another is combined as: viscosity is the sodium alginate of 20～400cP, is the sodium alginate of 20～400cP as viscosity, and consumption is 8%～30% of a lamella B weight, and PVPP XL is as disintegrating agent, and consumption is 6%～10% of a lamella B gross weight.
Another is combined as: viscosity is 5～130cP sodium carboxymethyl cellulose, and consumption is 8%～30% of a lamella B weight.Select the low-substituted hydroxypropyl methylcellulose as disintegrating agent, its consumption is 8%～10% of a lamella B weight.
Another is combined as: viscosity is the methylcellulose of 5～15cP, and consumption is 8%～30% of a lamella B weight.Cross-linking sodium carboxymethyl cellulose is as disintegrating agent, and its consumption is 5%～10% of a lamella B weight.
Another is combined as: the xanthan gum that granularity 200 orders are above, consumption is 5%～20% of a lamella B weight.Cross-linking sodium carboxymethyl cellulose is as disintegrating agent, and its consumption is 6%～10% of a lamella B weight.
In combinations thereof, can add other excipient, as filler binding agent, lubricant, surfactant etc.Described filler can be selected from one or more in microcrystalline Cellulose, mannitol, starch, pregelatinized Starch, dextrin, sucrose, lactose, calcium sulfate, the calcium phosphate, optional in polyvidone, hypromellose, Carboxymethyl cellulose sodium, methylcellulose, ethyl cellulose one or more of described binding agent, described lubricant can be selected from one or more in stearic acid, calcium stearate, magnesium stearate, Pulvis Talci, dodecyl sodium sulfonate magnesium, the Polyethylene Glycol, and described surfactant is optional from Tweens Surfactant and dodecyl sodium sulfate etc.
The method that active component is scattered in the carrier material with retardation is, with acid-labile active ingredient and described carrier material pulverize separately, sieves, and mixes, and adds or do not add other compositions, granulates drying; Or employing fluidized bed granulation.
A preparation scheme of lamella B material is: with composition pulverize separately among the lamella B, sieve; With active component, basifier and if necessary and excipient that adds such as filler, binding agent, with have water-swellable can macromolecular material mixes, granulation, drying, granulate with all the other mixed with excipients, obtains the material of lamella A.
In above-mentioned preparation scheme, basifier can all be granulated with active component, or only a part is used for granulating.
Grasp as those skilled in that art, other have the material that can produce retardation, are applicable to purpose of the present invention too, and its consumption reaches the compatibility with disintegrating agent, can obtain by simple experiment screening, thereby be also contained in the technical scheme of the present invention.
Double-unit tablet
Above-mentioned lamella A material and lamella B material are compressed to double-layer tablet with the double-layer tablet drawing method of routine, or can earlier the lamella B material tabletting that contains active component be got label B, wrap into label B is complete with lamella A material, tabletting gets clad sheet.
With PPIs is that the double-unit tablet that active component makes can be used for preparing the too much disease medicament of therapic acid.With the purpose of giving an example, to being that the technical scheme and the implementation result of the double-unit tablet of active component describes with PPIs.
Lamella A: sodium bicarbonate 350～800mg, magnesium hydroxide 250～350mg, heavy-burned magnesia 20～50mg, filler 150～200mg, disintegrating agent 50～100mg, PVP K29/305～20mg adds an amount of magnesium stearate, and mix homogeneously gets lamella A material.Maybe can be with partial material such as magnesium hydroxide and heavy-burned magnesia granulation earlier.
Lamella B: 10～20mg PVP k29/32 and about 5mg sodium bicarbonate are dissolved in the suitable quantity of water, with PPIs, sodium bicarbonate 95～345mg, heavy-burned magnesia 20～70mg, the filler 30～40mg of unit effective dose, with fluid bed system granule.With the granule that makes and the disintegrating agent of 20～40mg, mix with the macromolecular material and the moderate lubrication agent of the water-swellable of 60～140mg, lamella B material.
Prepare: with lamella A and lamella B two parts material difference mix homogeneously, use the double-layer tablet tablet machine, suppress the B part earlier, repress system A part gets the pantoprazole bilayer tablet, the thick about 9.0mm of sheet, and sheet focuses on 1000mg～2000mg.
The tablet that makes is carried out dissolution and acid-resistant strength mensuration, and assay method is as follows:
Dissolution method (2005 editions pharmacopeia appendix X C three therapeutic methods of traditional Chinese medicine) device is adopted in the stripping experiment, (gets sodium chloride 2.0g, adds hydrochloric acid 7.0ml with acid solution, be dissolved in water and be diluted to 1000ml, pH value is 1.2) 150ml is solvent, rotating speed is that per minute 100 changes, operation in accordance with the law.Pick up counting at the input bilayer tablet, in the time of 45 minutes, it is an amount of to get solution, filter, precision is measured the 0.5ml pH10 aqueous solution (sodium hydroxide that adds 0.4ml 1mol/l in the 1000ml water, the sodium hydroxide of reuse 1mol/l or spirit of vinegar liquid are regulated pH to 10.00 ± 0.10) be diluted to 10ml, measure component content with high performance liquid chromatograph, calculate drug dissolution.
Acid-resistant strength is measured and to be got this product, adopts dissolution method (2005 editions pharmacopeia appendix X C three therapeutic methods of traditional Chinese medicine) device, is dissolution medium with 150ml acid solution (get sodium chloride 2.0g, add hydrochloric acid 7.0ml, be dissolved in water and be diluted to 1000ml, pH value is 1.2).Rotating speed is that per minute 100 changes, pick up counting at the input bilayer tablet, in the time of 120 minutes, suspension in the stripping rotor is all transferred in the brown measuring bottle of 250ml, (1g NaOH is dissolved in the 10ml water with the ethanol aqueous slkali of about 90ml, be diluted with ethanol to 1000ml) the flushing stripping rotor, flushing liquor is transferred in the brown measuring bottle of 250ml in the lump, and ultrasonic 10min makes dissolving fully.Add entry: the solution of ethanol aqueous slkali (5: 3) is settled to scale, shakes up, and is centrifugal, filter, precision is measured subsequent filtrate 4ml and is put in the brown measuring bottle of 10ml, adds the pH10 aqueous solution and is diluted to scale, shake up, measure component content, estimate the acid-resistant strength of preparation with high performance liquid chromatograph.
Dissolution and acid-resistant strength to double-unit tablet of the present invention are measured, and dissolution is 90%～104% as a result; Under the condition of acid resistance test, the degraded of active component is no more than 10%.
Such scheme purpose as an example provides, and does not constitute the restriction of selection, preparation prescription composition, preparation method, dosage form and preparation performance parameter to active component of the present invention.For other sour unsettled medicine, those skilled in that art can similar approach calculate the consumption of alkali compound, and according to active component with have the character of the carrier of retardation, through simple experiment, screening is reasonably made up, thereby also is suitable for double-unit tablet of the present invention.
Below term used herein is specifically noted:
Term used herein " PPIs " claims again " proton pump inhibitor ", refers to that irreversibly specificity inhibition is positioned at the H on the secretion surface of parietal cell
+, K
+-ATP enzyme system (proton pump) and the excretory benzimidazoles compound of gastric acid inhibitory.PPIs of the present invention comprises the benzimidazole PPIs of all replacements, their salt, ester, amide, enantiomer, racemic modification, prodrug, derivant etc., and be not limited to be used for illustrational those chemical compounds.
Term used herein " alkali compound ", " basifier " have same implication, refer to can with the alkaline matter of hydrochloric acid generation neutralization reaction.
Term used herein " double-unit tablet " refers to two parts tablet of disintegrate in proper order, and two unit is regardless of with particular form and is existed, bilayer tablet about can being, also can be the double-deck clad sheet agent that skin contains the capacity basifier, perhaps left and right sides two parts tablet, and be not limited to this.
Term used herein " unit formulation ", refer to comprise the preparation of once taking effective dose, usually exist with independent dosage form, as comprise 10mg, 20mg, the omeprazole of 40mg, or 20mg, the pantoprazole of 40mg, or 15mg, the lansoprazole of 30mg, or the independent preparation of the rabeprazole of 20mg.
The present invention is further detailed explanation below in conjunction with embodiment.Embodiment provides by way of example, is not construed as limiting the invention.
Comparing embodiment: non-pair of unit preparation
Prescription: sodium bicarbonate 600g
Magnesium hydroxide 300g
Heavy-burned magnesia 100g
Pantoprazole Sodium 44.7g
By the said components amount, get sodium bicarbonate and pulverized 60 mesh sieves, progressively increase method with active component and above-mentioned other component mix homogeneously with equivalent, pressure is 1000.
Inventive embodiments 1 Pantoprazole Sodium double-layer tablet
Write out a prescription as following table:
The preparation: PVP k29/32 among the lamella B and 3g sodium bicarbonate are dissolved in the 200ml water, with Pantoprazole Sodium 44.7g, sodium bicarbonate 117g, heavy-burned magnesia 20g and mannitol 35g with fluid bed system granule.The granule that makes is mixed mutually with 20g PVPP XL, 120g pharmcoat 603 and an amount of magnesium stearate, get lamella B material.Composition among the lamella A is pulverized mixing.Use the double-layer tablet tablet machine, suppress the B part earlier, repress system A part gets 1000 Pantoprazole Sodium bilayer tablets, the thick about 9.0mm of sheet.
Effect: the double-layer tablet that makes is carried out dissolution and acid-resistant strength mensuration, and assay method as previously mentioned.Recording dissolution is 96.6%.
Inventive embodiments 2 omeprazole double-layer tablet
Write out a prescription as following table:
Preparation: composition pulverize separately among lamella A and the lamella B is mixed.Use the double-layer tablet tablet machine, suppress the B part earlier, repress system A part gets 1000 omeprazole bilayer tablets, the thick about 9.0mm of sheet.
Effect: the double-layer tablet that makes is carried out dissolution and acid-resistant strength mensuration, and assay method as previously mentioned.Recording dissolution is 101.2%.
Inventive embodiments 3 lansoprazole clad sheets
Write out a prescription as following table:
Preparation: PVP k29/32 among the lamella B and 5g sodium bicarbonate are dissolved in the 200ml water, carry out granule with lansoprazole 30g, sodium bicarbonate 345g, heavy-burned magnesia 50g and starch 30g with wet granulation process, 50～60 ℃ of dryings, granulate.The granule that makes is mixed mutually with 35g carboxymethyl starch sodium, 60g sodium carboxymethyl cellulose and an amount of magnesium stearate, get lamella B material.Composition among the lamella A is pulverized mixing, use the double-layer tablet tablet machine, compacting B partly obtains label B earlier, with lamella A material label B is coated again, gets the double-deck clad sheet agent of 1000 lansoprazoles, the thick about 10.0mm of sheet.
Effect: the double-deck clad sheet that will make carries out dissolution and acid-resistant strength is measured, and assay method as previously mentioned.Recording dissolution is 94.4%.
Inventive embodiments 4 pantoprazole double-layer tablet
Write out a prescription as following table:
Preparation: PVP k29/32 among the lamella B and 5g sodium bicarbonate are dissolved in the 200ml water, with pantoprazole, sodium bicarbonate 95g, heavy-burned magnesia and lactose with fluid bed system granule, the granule that makes is mixed mutually with 30g cross-linked carboxymethyl fiber sodium, 90g methylcellulose and an amount of magnesium stearate, get lamella B material.Composition pulverizing among the lamella A is mixed, use the double-layer tablet tablet machine, suppress the B part earlier, repress system A part gets 1000 pantoprazole bilayer tablets, the thick about 9.0mm of sheet.
Effect: the double-layer tablet that makes is carried out dissolution and acid-resistant strength mensuration, and assay method as previously mentioned.Recording dissolution is 96.7%.
Inventive embodiments 5 rabeprazole double-layer tablet
Write out a prescription as following table:
Preparation: composition pulverize separately among lamella A and the lamella B is mixed.Use the double-layer tablet tablet machine, suppress the B part earlier, repress system A part gets 1000 rabeprazole bilayer tablets, the thick about 9.0mm of sheet.
Effect: the double-layer tablet that makes is carried out dissolution and acid-resistant strength mensuration, and assay method as previously mentioned.Recording dissolution is 101.2%.
The acid resisting test result
Test method as previously mentioned.In comparing embodiment and the inventive embodiments 1 to 5 the acid-resistant strength measurement result of prepared tablet following (drug degradation percentage ratio, unit: %):
Claims (19)
1. double-unit tablet of forming by two lamellas, it is characterized in that, lamella A includes basifier, disintegrating agent, lamella B comprises sour unsettled active component, basifier, disintegrating agent, and the carrier with water-swellable energy, wherein sour unsettled active component is scattered in the carrier with water-swellable energy.
2. double-unit tablet as claimed in claim 1 is characterized in that, described basifier is selected from one or more of magnesium hydroxide, sodium bicarbonate, magnesium oxide, potassium bicarbonate, in unit formulation, its total amount can in and the hydrochloric acid of 4～45mEq.
3. double-unit tablet as claimed in claim 2 is characterized in that, in unit formulation, basifier is selected from sodium bicarbonate among the lamella A, its consumption be can in and the hydrochloric acid of 4～10mEq.
4. double-unit tablet as claimed in claim 2 is characterized in that, in unit formulation, basifier is selected from sodium bicarbonate among the lamella A, and its consumption is 350～800mg.
5. as claim 3 or 4 arbitrary described double-unit tablets, it is characterized in that, the disintegrating agent that comprises among the lamella A is selected from cross-linking sodium carboxymethyl cellulose, crospolyvinylpyrrolidone, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, and its consumption is 4%～10% of a lamella A gross weight.
6. double-unit tablet as claimed in claim 5, it is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from hydroxypropyl emthylcellulose, sodium alginate, sodium carboxymethyl cellulose, methylcellulose, xanthan gum, and its consumption accounts for 5%～30% of lamella B weight.
7. double-unit tablet as claimed in claim 6 is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from the hydroxypropyl emthylcellulose that viscosity is 3～50cP, and its consumption is 10%～30% of a lamella B weight.
8. double-unit tablet as claimed in claim 6 is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from the sodium alginate that viscosity is 20～400cP, and its consumption is 8%～30% of a lamella B weight.
9. double-unit tablet as claimed in claim 6 is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from the sodium carboxymethyl cellulose that viscosity is 5～130cP, and its consumption is 8%～30% of a lamella B weight.
10. double-unit tablet as claimed in claim 6 is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from the methylcellulose that viscosity is 5～15cP, and its consumption is 8%～30% of a lamella B weight.
11. double-unit tablet as claimed in claim 6 is characterized in that, the carrier with water-swellable energy that comprises among the described lamella B is selected from 100～400 purpose xanthan gum, and its consumption is 5%～20% of a lamella B weight.
12. as the arbitrary described double-unit tablet of claim 7 to 11, it is characterized in that, described lamella B comprise disintegrating agent be selected from polyvinylpolypyrrolidone, carboxymethyl starch sodium, cross-linking sodium carboxymethyl cellulose, low-substituted hydroxypropyl methylcellulose, its consumption 5%～10%.
13. double-unit tablet as claimed in claim 12, it is characterized in that, the sour unsettled active component that comprises among the described lamella B is selected from omeprazole, pantoprazole, lansoprazole, rabeprazole, it exists with a kind of of racemic modification, alkaline salt forms or its single enantiomer suitable on the pharmacology or its alkaline salt forms, is scattered in the carrier with water-swellable energy.
14., it is characterized in that described lamella A and lamella B further comprise other excipient respectively as the arbitrary described double-unit tablet of claim 1 to 13, contain in filler, binding agent, lubricant, the surfactant one or more.
15. double-unit tablet as claimed in claim 14, it is characterized in that, described filler is selected from microcrystalline Cellulose, mannitol, starch, pregelatinized Starch, dextrin, sucrose, lactose, calcium sulfate, in the calcium phosphate one or more, described binding agent is selected from polyvidone, hypromellose, Carboxymethyl cellulose sodium, methylcellulose, in the ethyl cellulose one or more, described lubricant is selected from stearic acid, calcium stearate, magnesium stearate, Pulvis Talci, dodecyl sodium sulfonate magnesium, in the Polyethylene Glycol one or more, described surfactant is selected from Tweens Surfactant or dodecyl sodium sulfate.
16. as the arbitrary described double-unit tablet of claim 1 to 15, described lamella A and lamella B are two-layer up and down.
17. as the arbitrary described double-unit tablet of claim 1 to 15, described lamella A is with the complete coating of lamella B.
18. as the arbitrary described double-unit tablet of claim 1 to 15, the gross weight of described double-unit tablet is at 1000～2000mg.
19. be used to prepare the purposes of the too much disease of therapic acid as the arbitrary described double-unit tablet of claim 1 to 18.
Priority Applications (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100379658A CN101259108A (en) | 2007-03-09 | 2007-03-09 | Double-unit tablet containing acid-labile medicaments |
| PCT/CN2008/000475 WO2008110070A1 (en) | 2007-03-09 | 2008-03-10 | Double-unit tablet comprising acid labile drug |
| CN2008800032753A CN101626755B (en) | 2007-03-09 | 2008-03-10 | Double-unit tablet comprising acid labile drug |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100379658A CN101259108A (en) | 2007-03-09 | 2007-03-09 | Double-unit tablet containing acid-labile medicaments |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101259108A true CN101259108A (en) | 2008-09-10 |
Family
ID=39759000
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100379658A Pending CN101259108A (en) | 2007-03-09 | 2007-03-09 | Double-unit tablet containing acid-labile medicaments |
| CN2008800032753A Active CN101626755B (en) | 2007-03-09 | 2008-03-10 | Double-unit tablet comprising acid labile drug |
Family Applications After (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2008800032753A Active CN101626755B (en) | 2007-03-09 | 2008-03-10 | Double-unit tablet comprising acid labile drug |
Country Status (2)
| Country | Link |
|---|---|
| CN (2) | CN101259108A (en) |
| WO (1) | WO2008110070A1 (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843600A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Quick-release capsules of proton pump inhibitor |
| CN114980867A (en) * | 2020-01-23 | 2022-08-30 | 韩美药品株式会社 | Pharmaceutical combination preparation comprising proton pump inhibitor and antacid |
| CN115279348A (en) * | 2020-02-21 | 2022-11-01 | 株式会社钟根堂 | Esomeprazole and sodium bicarbonate pharmaceutical composition with excellent release characteristics |
Families Citing this family (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR102006777B1 (en) | 2018-01-29 | 2019-10-08 | 주식회사 종근당 | Pharmaceutical formulation comprising esomeprazole and sodium bicarbonate |
| KR102080023B1 (en) | 2018-01-29 | 2020-02-21 | 주식회사 종근당 | Stable pharmaceutical composition comprising esomeprazole and sodium bicarbonate |
| JP2021533177A (en) * | 2018-08-23 | 2021-12-02 | チョン クン ダン ファーマシューティカル コーポレイション | A pharmaceutical formulation with excellent dissolving properties, including esomeprazole and sodium bicarbonate. |
| CN112022827B (en) * | 2020-09-30 | 2023-03-31 | 上海信谊天平药业有限公司 | Cyproheptadine hydrochloride quick-release pharmaceutical preparation and preparation method thereof |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004066924A2 (en) * | 2003-01-24 | 2004-08-12 | Andrx Labs Llc | Novel pharmaceutical formulation containing a proton pump inhibitor and an antacid |
| AU2005291302A1 (en) * | 2004-10-05 | 2006-04-13 | Altana Pharma Ag | Oral pharmaceutical preparation comprising a proton pump antagonist and a basic excipient |
| WO2006116583A2 (en) * | 2005-04-26 | 2006-11-02 | The Curators Of The University Of Missouri | Compositions comprising a polymerized benzimidazole and a buffering agent and methods of using same |
-
2007
- 2007-03-09 CN CNA2007100379658A patent/CN101259108A/en active Pending
-
2008
- 2008-03-10 WO PCT/CN2008/000475 patent/WO2008110070A1/en active Application Filing
- 2008-03-10 CN CN2008800032753A patent/CN101626755B/en active Active
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101843600A (en) * | 2009-03-23 | 2010-09-29 | 杭州锐思医药科技有限公司 | Quick-release capsules of proton pump inhibitor |
| CN114980867A (en) * | 2020-01-23 | 2022-08-30 | 韩美药品株式会社 | Pharmaceutical combination preparation comprising proton pump inhibitor and antacid |
| CN114980867B (en) * | 2020-01-23 | 2024-03-15 | 韩美药品株式会社 | Pharmaceutical combination formulation comprising proton pump inhibitor and antacid |
| CN115279348A (en) * | 2020-02-21 | 2022-11-01 | 株式会社钟根堂 | Esomeprazole and sodium bicarbonate pharmaceutical composition with excellent release characteristics |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008110070A1 (en) | 2008-09-18 |
| CN101626755B (en) | 2011-11-30 |
| CN101626755A (en) | 2010-01-13 |
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