CN1842342A - Compositions for treating pathologies that necessitate suppression of gastric acid secretion - Google Patents

Compositions for treating pathologies that necessitate suppression of gastric acid secretion Download PDF

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CN1842342A
CN1842342A CN 200480024634 CN200480024634A CN1842342A CN 1842342 A CN1842342 A CN 1842342A CN 200480024634 CN200480024634 CN 200480024634 CN 200480024634 A CN200480024634 A CN 200480024634A CN 1842342 A CN1842342 A CN 1842342A
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globule
ppi
orally administered
carbonate
administered composition
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阿叶列特·大卫
萨比娜·格洛兹曼
拉达·保罗
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VECTA Ltd
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Abstract

The present invention is related to novel oral compositions comprising an irreversible gastric H<+>/K<+>-ATPase proton pump inhibitor (PPI) as a gastric acid secretion inhibitor, pentagastrin (PG) or a PG analogue as an activator of parietal cells in the gastric lumen. In a preferred embodiment, the composition further comprises at least one agent that preserves the availability of PG in the gastric fluids, thus enabling PG to act locally in the stomach. Unexpectedly, the compositions of the present invention exhibit anti-acid activity locally in the stomach that is meal-independent, exhibit fast onset and prolonged inhibition of acid secretion.

Description

Treatment needs the compositions of the excretory condition of illness of gastric acid inhibitory
Invention field
The present invention relates to be used for the excretory new Orally administered composition of gastric acid inhibitory, described compositions has rapidly for gastric acid secretion and works, prolong the effect that suppresses and be independent of meals.
Background of invention
A large amount of pathological states are characterised in that needs the gastric acid inhibitory secretion.This symptom is including, but not limited to Zhuo-Emhorn syndrome (ZES), gastroesophageal reflux disease (GERD), peptic ulcer disease, duodenal ulcer, esophagitis or the like.May have severe complications and be some most popular diseases of industrialized country such as the symptom of peptic ulcer.
At present, the main therapy that is used for the treatment of GERD and peptic ulcer disease comprises for example by utilizing histamine H 2-receptor antagonist body or proton pump inhibitor (PPI ' s) reduce the medicine of gastric acidity '.PPI ' s is by suppress being responsible for the H by the parietal cell of these emiocytosis acid +/ K +-ATP enzyme proton pump works.PPI ' s for example is disclosed in EP05129 such as omeprazole and pharmaceutical salts thereof, in EP 124495 and the United States Patent (USP) 4,255,431.
The PPI agent is sour unsettled pro-drug, uses with the particulate form of enteric coating usually.After PPIs was by small intestinal absorption, weakly alkaline PPIs preference aggregation was in the sour environment of parietal cell.Sour environment in the acid environment of parietal cell changes into active sulfenamide with pro-drug, and it is combination and suppresses parietal cell H +/ K +The activating agent of ATP enzyme pump.
Although PPIs has the good efficacy that is confirmed, but still significant limitations is arranged.The time of dosed administration and the picked-up of meals can influence pharmacokinetics and the excretory ability of gastric acid inhibitory (Hatlebakk etc., the Aliment Pharmacol Ther.2000 of these medicaments; 14 (10): 1267-72).Particularly, PPI is must be before picked-up food edible so that realize optimal inhibition to gastric acid secretion.In addition, the pharmacological action of PPIs is relatively slow and may need several days ability to realize that maximum acidity suppresses and remission, limited its application (Sachs G, Eur J Gastroenterol Hepatol.2001 in the GERD treatment that needs immediately thus; 13 supplementary issue 1:S35-41).And, PPIs can not provide 24 hours gastric acid to suppress and cause GERD patient's heartburn pain and even the nocturnal acid that still takes place of twice daily dose administration PPIs inhibition (Tytgat GN, the Eur J Gastroenterol Hepatol.2001 that break through; 13 supplementary issue 1:S29-33).At last, these medicines demonstrate the significant variation of pharmacokinetics between the patient and may have significant interaction (people such as Hatlebakk, ClinPharmacokinet.1996 with other medicines; 31 (5): 386-406).Therefore, the active improvement of PPI mediation is the challenge that generally acknowledge in the gastroenterology field.
Pentagastrin (PG) (β-alanyl-L-tryptophanyl-L-methionyl-L-aspartyl-L-phenyl-alanyl amide; SEQ ID NO:2) is a pentapeptide that comprises the carboxyl terminal tetrapeptide of gastrin.This carboxyl terminal tetrapeptide is the active part of finding in all natural gastrins basically.In animal body, PG mainly works to induce gastric acid secretion by inducing the intestinal that exists in the stomach to have a liking for chromium sample (ECL) cell release histamine.The activation of the histamine receptor that exists on the release of histamine and the consequential parietal cell causes that thereby the activation of parietal cell is to gastral cavity active secretion proton ion.PG also can act directly on and induce its activation on the parietal cell.PG is generally used for this field as the diagnostic reagent of estimating the gastric acid secretion function.
Low solubility and the PG fact that be easy under one's belt by pepsin degraded of PG in sour environment makes its inducer as oral back gastric acid secretion unexpected fully, but but found should the fact for the applicant.Before the applicant found, those skilled in the art only thought that using PG by the parenteral path has effective activity inducing in the acid secretion.In fact, in 4 normal subjectses of oral PG, find, and in the unusual patient of other 3 gastrointestinals, find some influences (Morrell ﹠amp not influence of acid secretion; Keynes Lancet.1975; 2 (7937): 712).In fact, this research lacks the active evidence of PG (Martindale Thirty-second edition when being cited in pharmacology's textbook as Orally administered PG, p1616, theChapter: " Supplementary Drugs and Other Substances ").
People's such as Pisegna WO01/22985 (' 985 publication) discloses the application of associating proton pump inhibitor (PPI) systemic application PG.According to ' 985 publications, improved PPI with PPI co-administered PG and reduced/alleviating the effectiveness of gastric acid secretion aspect excessive.' 985 publications are open and instructed PG preferably to use through injection (for example, subcutaneous injection).Yet ' 985 publications disappearances discloses PG and PPI usually through intravenous, and parenteral or oral way are used.' 985 publications also disclose PPI and PG can be prepared into tablet usually.Yet arbitrary given dose or preparation that ' 985 publications openly should not used do not provide any work embodiment yet.In addition, ' 985 publications do not provide any relevant instruction or hint of how avoiding the instruction that the PG oral delivery is invalid in the prior art not provide PG may effectively advise the embodiment of oral dose yet.In addition, ' 985 publications do not disclose the unexpected PG that finds of the inventor yet Topically active under one's belt.' 985 publications do not instruct yet the PG retention agent in keeping stomach the activatory biologic activity of PG so that realize the application of the local effect in the gastral cavity.The level of prior art when of the present invention, ' 985 publications are can not inspire those skilled in the art to prepare because the Orally administered composition that comprises PG of local delivery.
People such as De Graef are at Gastroenterology, and 91, disclosing among the 333-337 (1986) (De Graef publication) can more effective gastric acid inhibitory secretion when omeprazole being applied to the pretreated Canis familiaris L. of PG intravenous.In the publication of De Graef, do not mention oral PG onset by the effect of the reinforcement of the local action in gastral cavity omeprazole.
License to the United States Patent (USP) 6,489,346 of Phillips; 6,645,988 and 6,699,885 (general designations " Phillips patent ") disclose pharmaceutical composition and have utilized by PPI, and the Orally administered composition that at least a buffer agent and specificity parietal cell activator are formed is discussed the method for the sour gastrointestinal disorder that causes.This parietal cell activator that is disclosed in the Phillips patent comprises for example chocolate, sodium bicarbonate, calcium, peppermint, oleum menthae viridis, coffee, tea and cola, caffeine, theophylline, theobromine and amino acid residue.As pointing out in the Phillips patent that the parietal cell activator of all these suggestions is all induced the release to the endogenous gastrin of acid secretion performance inhibition and stimulating effect.Yet the Phillips patent is not open or hint is used and only had stimulating activity, only is incorporated into the PG of CCK-B receptor, does not resemble the parietal cell activator of mentioning in the Phillips patent and will activate CCK-A and CCK-B receptor-comprise inhibition and stimulating effect.
Need the development of effective treatment of the excretory condition of illness of gastric acid inhibitory will realize for a long time demand.Use although PPI ' s has widely, still need to improve the effectiveness of PPI, for example more fast and effeciently work, prolong the time that effect comprises that nocturnal acid is broken through, more effective and be independent of using of meals when dosage reduces.
Summary of the invention
The purpose of this invention is to provide owing to the excretory Orally administered composition of gastric acid inhibitory, described compositions is independent of meals and gastric acid secretion is demonstrated the inhibition effect of fast-acting and prolongation property.
Another object of the present invention provides and is used for the excretory Orally administered composition of gastric acid inhibitory, comprises irreversible stomach H +/ K +-ATP enzyme proton pump inhibitor (PPI) and parietal cell activator, wherein the antiacid activity of PPI is independent of meals and acid secretion is demonstrated the inhibition effect of fast-acting and prolongation property.
In one embodiment of the invention, described Orally administered composition comprises the irreversible stomach H as gastric acid secretion inhibitor +/ K +-ATP enzyme proton pump inhibitor (PPI), as the pentagastrin (PG) of parietal cell activators and/or PG analog and one or multiple maintenance gastric juice in the medicament of effectiveness of PG make PG can play local action under one's belt thus so that keep the biologic activity of PG.Unexpectedly, compositions of the present invention has antiacid activity under one's belt, the inhibition that it is independent of meals and the acid secretion is demonstrated fast-acting and prolongation property.Compositions of the present invention can be used to treat the experimenter of the chronic or acute disorder of the sour excretory trouble that needs to suppress in the stomach.
Proton pump inhibitor of the present invention (PPIs) is to suppress H in the parietal cell +/ K +The active chemical compound of-adenosine triphosphatase (ATPase) proton pump.In its pro-drug form, PPI is non-ionized, therefore can be by the cell membrane of parietal cell.In case reach parietal cell, non-ionized PPI will be moved to the part of the secretion acid of activatory parietal cell, secretory tubyle.The PPI that catches in the tubule is by protonated, therefore become can with the active sulfenamide of cysteine residues form two sulfur covalent bonds in the α subunit of proton pump, irreversibly suppress proton pump thus.
As mentioned above, the present invention be based on the inventor surprised find when oral PG, play local action, preferably activate parietal cell by acting locally on gastral cavity.Active parietal cell has acid pH, and it is that PPI is changed into active proton sulfenamide form is necessary.
Therefore, directly acting on gastral cavity by PG makes parietal cell activation synchronously make the inhibition maximization of PPI to pump.
Orally administered composition of the present invention demonstrates the following advantage based on the compositions of PPI that is better than becoming known for reducing gastric acid secretion.Compositions of the present invention can allow PG activation parietal cell since the local effect in gastral cavity without any the side effect relevant with being administered systemically of PG.PG activates parietal cell in advance and promotes PPI to causing that PPI brings into play the transformation of the active sulfenamide form of effect fast.In addition, compositions of the present invention demonstrates the antiacid activity of fast-acting under one's belt in the mode that is independent of meals.Therefore, the combined activity agent in the Orally administered composition is given needs the sour excretory acute situation of minimizing fast that effective scheme is provided.At last, Orally administered composition of the present invention utilizes single medicine to provide the gastric acid secretion prolongation inhibition of 24h at least.
Orally administered composition of the present invention comprises as the PG of the local activation agent of parietal cell in the gastral cavity or PG analog.Except comprising aminoacid sequence β Ala-Trp-Met-Asp-PheNH 2The PG of (SEQID NO:2), the present invention also comprise the application as the parietal cell activator of gastrin or its derivant of PG analog.This variant is including, but not limited to the 34-of gastrin, and 17-and 14-aminoacid reach other and comprises gastrin Trp-Met-Asp-PheNH 2The truncate variant of the active C-terminal tetrapeptide of (SEQ ID NO:1) it is reported to have whole pharmacological activities (referring to (1964) Nature (London) of Tracey and Gregory, 204:935) in the literature.
The present invention also comprises the variant of gastrin and/or truncate gastrin, and wherein natural aminoacid was replaced by conservative the replacement.The different analog that also comprise these molecules are such as but not limited to PGBoc-β Ala-Trp-Met-Asp-PheNH 2The derivant of N-protected, wherein Boc is a tertbutyloxycarbonyl, perhaps F-Moc-β Ala-Trp-Met-Asp-PheNH 2, wherein Moc is a methoxycarbonyl group.
In nonrestrictive embodiment, Orally administered composition of the present invention further comprises one or the various medicaments that keeps the effectiveness of PG in the acidic gastric juice.The amount of these pharmacy optimizations is enough to by the dissolubility of keeping PG in the gastric juice and prevents that its degraded from keeping the effectiveness of PG in gastric juice, so that PG local biologic activity is under one's belt kept.Thereby this can make PG play local action activation parietal cell under one's belt.This pharmacy optimization is antiacid or basic agent, when being dissolved in gastric juice the pH of gastric juice is brought up to immediately and suppresses pepsic value, suppresses in the gastric juice pepsin thus to the degraded of PG.Because PG is only solvable under alkali condition, the raising of the moment of pH guarantees that the PG of major part keeps soluble state in gastric juice at least in the gastric juice.
It should be noted that any weak or highly basic (and composition thereof) can be as the basic agent in the Orally administered composition of the present invention.Be present in the basic agent in the compositions or the amount of antacid and be enough to keep substantially stability and the dissolubility of PG in acidic gastric juice.The pH of stomach can be brought up to when therefore, basic agent of the present invention is in being dissolved in gastric juice is enough to realize that PG plays the competent effectiveness of therapeutic effect.
According to embodiment preferred, the amount of the basic agent in the compositions is enough to pH with gastric juice and brings up to value more than 4, preferably is higher than 5, and the time is enough to make PG to reach the parietal cell in the stomach and makes its activation.In more preferred, basic agent can be brought up to the pH of gastric juice the value more than 5, and the time is from 5 to 60 minutes, and the preferred time is from 5 to 30 minutes.Therefore, basic agent of the present invention has kept the dissolubility of PG in gastric juice to be enough to make the time of PG activation parietal cell.In addition, the moment alkali condition in the gastric juice has only stoped when acid pH activatory pepsin to the degraded of PG.
According to multiple embodiments, Orally administered composition of the present invention further comprises other medicament of the effectiveness that keeps PG in the acidic gastric juice.This medicament for example for pepsin inhibitor (that is, Pepstatin and deutero-bacitracin-cycle dodecapeptide thereof) that reduces the degraded of peptide in the stomach or the molten stick that reduces the viscosity of gastric mucosa, improves PG thus and reaches the ability of being responsible for sour excretory cell.This molten stick is a Reducing agent for example, such as N-acetylcystein, and dithiothreitol, DTT, citric acid or mannitol.Compositions of the present invention may further include the antibiotic of resident antibacterial in effective anti-stomach.
Active component of the present invention can be mixed with single peroral dosage form, preferred solid dosage form.Also can use liquid dosage form such as suspension.Therefore, in one embodiment, PPI, the medicament of PG and the effectiveness of maintenance PG in gastric juice can be formulated as multilayer tablet, suspension tablet, effervescent tablet, powder, pill, granule contains the hard capsule of a plurality of globules, perhaps comprises the soft capsule based on the medium of lipid.
According to an embodiment, solid dosage forms of the present invention is the PPI particle that contains the polymer that dependence time of polymer that the dependence pH-that is surrounded by enteric coating discharges or non-enteric coating discharges, the particle of PG and one or the capsule or the multilayer tablet of the particle of multiple basic agent.In order to guarantee by the parietal cell in the PG activation gastral cavity with partly to adsorb PPI at contiguous small intestinal synchronous, single peroral dosage form can comprise the PG globule that is surrounded by the polymer that the dependence time discharges, and described polymer has prolonged PG release time under one's belt.Therefore, the prolongation that PG discharges in the stomach can make the activity of PG on the parietal cell and the active synchronization of PPI.
Active component of the present invention also can be mixed with dosage form separately.For example, keep the PG of PG effectiveness in gastric juice and medicament can be mixed with oral suspension or solid dosage forms such as capsule, tablet, suspension tablet or effervescent tablet and PPI can be mixed with solid dosage forms separately, the capsule or the tablet of the globule of the polymer that the dependence time of polymer that dependence pH-with enteric coating discharges or non-enteric coating of preferably including discharges.Dosage form separately may be provided in the medicament that comprises PG and the effectiveness of maintenance PG in gastric juice in a dosage form and has the test kit of PPI in the dosage form of separating.In this case, PG is united PPI uses together in case its physiologically active at least some arrange chronologically overlapping.Can while and/or order administration of ppi and PG.
Be used for the polymer that dependence pH-that PPI particle of the present invention can be surrounded by enteric coating discharges, the polymer that the dependence time of non-enteric coating discharges or may not have coatings.The stability of not having coating PPI when the stomach is by being present in one in the compositions or multiple basic agent is kept.The buffering suspension of previous verified non-enteric coating-coating PPI in the absorption of small intestinal neighbouring part than the particulate absorption of the PPI of enteric coating faster (Pilbrant and Cederberg, Scand.J.Gastroenterol 1985:20 (supplementary issue 108): 113-120).Therefore, be not used to just need not in the compositions to delay PG release under one's belt if there is coating PPI particle.Yet, when using coating PPI particle, just need for example make the release of PPI and the release synchronization of PG by delaying PG release under one's belt by the PG particle that uses polymeric coatings.
In another embodiment, the present invention relates to treat the experimenter's who suffers from the disorder that needs the excretory disorder of gastric acid inhibitory or pass through usually to treat method through the gastric acid inhibitory secretion.This method comprises to the experimenter uses the PPI that contains as gastric acid secretion inhibitor, as the PG or the PG analog of parietal cell activators in the gastral cavity, and the pharmaceutical composition of the retention agent of at least a amount that is enough to keep the effectiveness of PG in gastral cavity.
Compositions of the present invention can be used for preventing or treatment needs the excretory mammiferous condition of illness of gastric acid inhibitory.Mammal preferably is the people.Compositions of the present invention not only can effectively be treated condition of illness but also can before the symptom morbidity danger that this condition of illness worsens be minimized.
Pharmaceutical composition of the present invention can be used for secreting by gastric acid inhibitory in a large number the pathological condition of treatment.This symptom is including, but not limited to Zhuo-Emhorn syndrome (ZES), gastroesophageal reflux disease (GERD), esophagitis, peptic ulcer disease, duodenal ulcer, gastritis and gastric erosion, dyspepsia or the like.
The present invention also comprises oral pharmaceutical kit.This test kit generally includes the following composition as the medicine effective quantity of active component: the peptide that (i) comprises the aminoacid sequence of SEQ ID NO:1; (ii) irreversible stomach H +/ K --ATP enzyme proton pump inhibitor (PPI); And the medicament of the effectiveness of (iii) at least a maintenance peptide in gastric juice.In one embodiment, active component is formulated into unit dosage forms separately.This test kit can be used for the treatment of or prevent need be by using the excretory experimenter's of active component gastric acid inhibitory disorder to the experimenter.Peptide at administration of ppi simultaneously, is used usually before or afterwards.
These and other embodiment can be by following detailed description and embodiment and is more apparent.
Description of drawings
Fig. 1 shows NaHCO 3Keep the stability of PG in the artificial gastric juice;
Do not degrade when the having shown different pH value percentage ratio of PG of Fig. 2;
Fig. 3 comprises PG, the sketch map of the omeprazole of non-enteric coating and the bilayer tablet of buffer agent;
Fig. 4 is the particulate sketch map of PG that is used for the multiparticulates capsule preparations;
Fig. 5 is the capsular sketch map that comprises the sustained release coating globule;
Fig. 6 shows the gastric acid secretion of PG with dose-dependent mode stimulation in rats;
Fig. 7 shows that PG strengthens the influence to rat tolerance secretion of PPI-mediation;
Fig. 8 shows that lansoprazole suppresses the gastric acid secretion of conscious mind animal in dose-dependent mode;
Fig. 9 shows when lansoprazole PG when PG (A) uses before but not uses behind PG (B) has improved lansoprazole and is blocking effectiveness in the gastric acid secretion;
Figure 10 is presented at during 3 Consecutive Days with the co-administered lansoprazole of PG and compares the remarkable rising that causes gastric pH (A) and the reduction of gastric acid secretion (B) with independent lansoprazole.
Detailed Description Of The Invention
Term " basic agent " refer to when with (for example, during and/or afterwards) PG bring into play immediately when preparing together or sending with pH moment in the gastral cavity bring up to any medicinal suitable weak base that basically kept the function of the value of the validity of PG in the stomach or highly basic (and composition thereof).
Term " medicament that keeps PG validity in the stomach " refers to keep PG dissolubility under one's belt and any medicament of stability. Particularly, this medicament can maintain the PG of significant quantity at least soluble form and not degrade in gastric juice, in order to keep the BA of PG in the stomach.
Term " BA of PG in the stomach " refers to that its activation is arranged in the parietal cell of gastral cavity.
Term " associating " refers to when PPI and PG use together with the formulation of separating, and their physiologically active has overlapping that at least some arrange chronologically. Therefore can while and/or order administration of ppi and PG.
The present invention can keep active after being based on oral PG, thereby preferably by playing under one's belt the surprised discovery of local effect activation parietal cell. Importantly, the activation of parietal cell is that the PPI pro-drug is changed into as stomach H+/K +The activity form of-ATP enzyme proton pump irreversible inhibitor is necessary. Orally administered composition of the present invention provides and has improved PPI to the unique combination of the activating agent of the effectiveness of gastric acid secretion inhibiting.
Composition of the present invention can be used for preventing or treating the mammiferous symptom that needs gastric acid secretion inhibiting. Composition of the present invention not only can effectively be treated symptom but also can before the symptom morbidity danger that this symptom worsens be minimized. This symptom for example comprises: reflux esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer. In addition, it is in disorder that composition of the present invention can be used to other the stomach and intestine of hope hydrochloric acid in gastric juice inhibition of Prevention, for example non-steroidal antiinflammatory drugs (SAID) is treated the patient of (comprising low dosage aspirin), the patient who suffers from non-ulcer dyspepsia has the patient of Symptomatic gastroenteritis-esophageal reflux sick (GERD) and the patient who suffers from gastrinoma. They also can suffer from the patient of acute hemorrhage of upper gastrointestinal tract for the patient that need to provide special care to, and the patient under the perioperatively situation is with suction and prevention and the treatment stress ulcer of prevention hydrochloric acid in gastric juice. In addition, they can also be used for the treatment of infection and the relevant disease of pylori. Other situation that is suitable for treating is including, but not limited to Zhuo-Emhorn syndrome (ZES), Werner's syndrome and systemic mastocytosis.
Parietal cell activator of the present invention is preferably the PG with the amino acid sequence shown in the SEQ ID NO:2. Yet, comprise gastrin Trp-Met-Asp-PheNH2Any PG analog of the terminal tetrapeptide of C (being expressed as SEQ ID NO:1) all can be used as the parietal cell activator. This analog is including, but not limited to the 34-of gastrin, 17-, and 14-amino acid and other truncate variants. The gastrin that also comprises and/or the variant of truncate gastrin are that wherein natural amino acid is guarded and replaced displacement. Also comprise the multiple analog of these molecules, comprise, such as but not limited to the PG derivative of N-protected. The appropriate protection base of PG comprises standard hydroxyl protecting group known in the art; methoxy (MOM) for example; 'beta '-methoxy ethoxyl methyl (MEM); trialkylsilkl; trityl (trityl), and uncle-butoxy carbonyl (uncle-BOC), ethoxyethyl group (EE); f-MOC (methoxycarbonyl group), TROC etc. Thereby protecting group can produce desired PG derivative (T.W.Green, Protective Groups in Organic Synthesis, the 2nd chapter, 10-69 page or leaf (1981)) by using standard method well known in the art to remove.
Gastrin, pentagastrin or its analog can commercially availablely obtain. In addition, synthetic schemes also is known. Therefore, for example PG can use the chemical synthesis of well-known peptide synthetic method (referring to, the Solid-Phase Peptide Synthesis of Barany and Merrifield for example; The 3-284 page or leaf, The Peptides:Analysis, Synthesis, Biology.Vol.2:Special methods in peptide synthesis, a. part; The people such as Merrifield (1963) J.Am.Chem. Soc., 85:2149-2156; And people (1984) the Solid Phase Peptide Synthesis such as Stewart, second edition, Pierce Chem.Co.Rockford, ILL.). In addition, PG can for example pass through Boc-Ala residue and tetrapeptide Trp-Met-Asp-PheNH2In conjunction with chemical synthesis.
Composition of the present invention comprises to realize that the pharmacotoxicological effect to parietal cell does not have effective dose PG or its analog of excessive adverse side effect simultaneously. Exist the rough amount of standard of PG to be preferably 1-100mg in the composition, more preferably 2-60mg, the most preferably amount of 4-40mg PG (the perhaps a great deal of of PG analog).
Composition of the present invention also comprises as stomach H+/K +The PPI that the irreversible inhibitor of-ATP enzyme proton pump works. Being used for PPI of the present invention can be for having H+，K +The benzimidazole compound of any replacement of-ATP enzyme inhibition activity. For the purposes of the present invention, term " PPI " should refer to have as H+，K +The benzimidazole of any replacement that the pharmacology of-atpase inhibitor is lived, include but not limited to the Omeprazole of neutrality or salt form, Lansoprazole, Pantoprazole, Rabeprazole, dontoprazole, perprazole (perprazole), habeprazole, ransoprazole, pariprazole and Leminoprazole, the basic salt of single enantiomter or isomers or other derivative or its enantiomter.
Can be used for stomach H of the present invention+/K +The example of-ATP enzyme proton pump inhibitor for example is disclosed in that described can be effectively in the United States Patent (USP) 6,093,738 as the new thiadiazole compound of proton pump inhibitor. European patent 322133 and 404322 discloses quinazoline derivant, and European patent 259174 has been described quinoline, the pyrimidine derivatives that WO 91/13337 and United States Patent (USP) 5,750,531 disclose as proton pump inhibitor. The proton pump inhibitor that is fit to also is disclosed in for example EP-A1-174726, EP-A1-166287, and GB 2163747 and W090/06925, W091/19711, W091/19712 is among W094/27988 and the W095/01977.
PPI particle in the present composition can be dressing or dressing not. The prepared product that comprises the enteric coating powder of PPI such as Omeprazole for example is disclosed in US patent 4,786,505 and 4,853, in 230.
Composition of the present invention comprises to realize that pharmacotoxicological effect does not have the PPI of the effective dose of excessive adverse side effect simultaneously. Treatment improve including, but not limited to: improve stomach pH, reduce gastrointestinal bleeding or improvement or eliminate symptom. According to a preferred embodiment, the typical daily dose of PPI can change and will depend on such as patient's independent needs and the different factors of disease to be treated. Usually, the daily dose of PPI will be in the scope of 1-400mg. The rough amount of preferred standard that is present in the PPI in the composition is generally the Omeprazole of about 20-40mg, the Lansoprazole of about 30mg, the Pantoprazole of about 40mg, the following PPIs:habeprazole of the Rabeprazole of about 20mg and pharmacology dose,equivalent, pariprazole, dontoprazole ransoprazole, perprazole (perprazole) and leminoprazole.
In preferred embodiments, composition of the present invention further comprises one or more medicaments that keeps the validity of PG in acidic gastric juice. More particularly, anti-corrosion agent has been kept stability or the dissolubility of PG in gastric juice. Thereby it can make PG play under one's belt local effect activation parietal cell. This medicament be preferably when being dissolved in gastric juice, the pH of gastric juice can be brought up to the peptase of inhibition stomach-middle existence and also at least the PG of major part in gastric juice, keep basic agent or the antacids of soluble pH.
Being used for basic agent of the present invention for example comprises: sodium acid carbonate or saleratus, magnesia, magnesium hydroxide or magnesium carbonate, magnesium lactate, magnesium gluconate (magnesium glucomate), aluminium hydroxide, the carbonate of aluminium, calcium, sodium or potassium, phosphate or citrate, sodium carbonate, sodium hydrogen phosphate, the mixture of aluminum glycinate and buffer, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate and other calcium salts. Although it is water-soluble to it should be noted that sodium acid carbonate is easy to, calcium carbonate is water-insoluble and only slowly dissolving in sour environment. Therefore, when continuing dissolving under one's belt, the expectation basic agent can use calcium carbonate.
The example that is used for antacids of the present invention comprises one or more following materials: aluminium oxide, calcium carbonate and sodium acid carbonate; Aluminium oxide and magnesia; Aluminium oxide, magnesia, calcium carbonate and dimethione; Aluminium oxide, magnesia and magnesium carbonate; Aluminium oxide, magnesia, magnesium carbonate and dimethione; Aluminium oxide, magnesia, and dimethione; Aluminium oxide, alginic acid magnesium and magnesium carbonate; Aluminium oxide and magnesium carbonate; Aluminium oxide, magnesium carbonate and dimethione; Aluminium oxide, magnesium carbonate, and sodium acid carbonate; Aluminium oxide and magnesium trisilicate; Aluminium oxide, magnesium trisilicate, and sodium acid carbonate; Aluminium oxide and dimethione; Aluminium oxide and sodium acid carbonate; Aluminium carbonate, alkalescence; Aluminium carbonate, alkalescence, and dimethione; Aluminium hydroxide; Calcium carbonate; Calcium carbonate and magnesia; Calcium carbonate, magnesia and dimethione; Calcium carbonate and dimethione; Calcium carbonate and magnesium carbonate; Magaldrate; Magaldrate and dimethione; Magnesium carbonate and sodium acid carbonate; Magnesium hydroxide; Magnesia.
Preferably, composition of the present invention comprises one or basic agent or the antacids of multiple effective realization pharmacological effect amount. Particularly, the amount of the basic agent in the composition or antacids is enough to pH with gastric juice brings up to is enough to make parietal cell in the PG activation stomach more than the suitableeest pH of the protease found in the stomach time period. In preferred embodiments, the amount of basic agent or antacids is enough to pH with gastric juice and brings up to more than 5 from 5 to 60 minutes time, preferably from 5 to 30 minutes time. The amount of required basic agent is inevitable in the present composition change along with the change of following factor: the equivalent of the type of the basic agent of use and the alkali that provided by given basic agent. In fact, provide the required amount of the good validity of PG in the stomach to satisfy when the solution that is added to 200 milliliters artificial gastric juice and when (preparing according to American Pharmacopeia (USP) guide) pH of HCl solution is brought up at least pH5.0. Preferably, at least 100 milligrams, more preferably at least 300 and most preferably at least 500 milligrams basic agent be used in the pharmaceutical composition of the present invention.
In another embodiment, composition of the present invention further comprises the medicament of other the validity of maintenance PG in acidic gastric juice. For example, said composition can comprise such as the pentapeptide Gastric inhibitory polypeptide of the activation in natural or synthetic source and the pepsin inhibitor of derivative thereof. These inhibitor can reduce pepsin to the degraded of PG. In addition, said composition can comprise the molten stick that reduces gastric mucosa viscosity, accelerates thus the ability that PG reaches parietal cell. This molten stick for example be reducing agent such as, N-acetylcystein, dithiothreitol (DTT), citric acid or mannitol. Composition or can also comprise the polymer coating of PG, thus avoid the destruction of the sour environment of stomach such as the enteric coating protection PG of polymer.
Active component of the present invention preferably is mixed with the single peroral dosage form that comprises all active components. Composition of the present invention can be mixed with solid or liquid dosage form. It should be noted that in view of the improvement of comparing solid dosage forms stability with liquor, preferred solid dosage form.
In one embodiment, the PPI particle, one or various medicaments of PG and the validity of maintenance PG in gastric juice are formulated into single solid dosage forms such as multilayer tablet; suspension tablet, effervescent tablet, powder; pill, particle or comprise the capsule of a plurality of globules. In another embodiment, activating agent can be formulated into single liquid dosage form such as the suspension that comprises all active components or the dry suspension of rebuilding before use.
In single formulation, PPI particle and PG particle can be surrounded by polymer that the Time-Dependent of polymer that the dependence pH-of enteric coating discharges or non-enteric coating discharges so that PG local BA and the systemic effect synchronization of PPI on parietal cell under one's belt. For example, if the PPI particle of dressing causes delaying of blood absorption, preferably also PG particle dressing is delayed its release. In a specificity embodiment, the PPI particle is surrounded by thick non-enteric layer so that the release of PPI is preferably delayed 20-80 minute, more preferably 25-75 minute, most preferably 30-60 minute, and the PG particle is surrounded by thin non-enteric polymer layer as long as the release of PG is preferably delayed 5-60 minute, more preferably 8-45 minute, most preferably 10-30 minute. These conditions can make parietal cell just can be activated in advance by PG before reaching the pharmacology PC of PPI.
The limiting examples that is used for the enteric polymer of suitable dependence pH-of the present invention is: CAP, HPMCP, the phthalic acid polyvinylacetate, methacrylic acid copolymer, shellac, hydroxypropyl methyl cellulose succinate, acetic acid trimellitic acid cellulose and above-mentioned arbitrary mixture. The commercially available enteric coating material that is fit to is for example sold with trade mark Eudragit L 100-55. This dressing can be wrapped on the base material by spraying.
The polymer that dependence time of non-enteric discharges for example comprises, one or the multiple polymer that produces thick coating under one's belt by the size that improves particle from the gastric juice imbibition thus.The coating that the dependence time discharges has irrelevant corrosion and/or the diffusion property with the pH of outside aqueous medium usually.Therefore, this active component is by diffusion or then slowly corrode particle in the stomach from the particle slow release.
The etching characteristic that comes from polymer in the stomach of surface interaction of fluid and dosage form is mainly by polymer molecular weight and the decision of drug/polymer ratio.In order to ensure the delayed discharge of PG and PPI about 10 minutes to about 60 minutes, the molecular weight of polymer was preferably about 10 5To about 10 7Gram/mole.In addition, PG or PPI/ polymer ratio are preferably in about 2: 3 in about 9: 1 scope, and preferred about 3: 2 to 9: 1, most preferably from about 4: 1 to 9: 1.
The coating that the non-enteric dependence time that is fit to discharges for example is: film forming compound is such as cellulose derivative, such as methylcellulose, hydroxypropyl emthylcellulose (HPMC), hydroxyethyl-cellulose, and/or acrylic polymer comprises that the trade mark of non-enteric form is the polymer of Eudragit.Other filmogen can use separately or combine with one another or be used in combination with above-mentioned substance.These other filmogens generally include poly-(vinyl pyrrolidone), zein, poly-(ethylene glycol), poly-(oxirane), poly-(vinyl alcohol), poly-(vinylacetate) and ethyl cellulose and other medicinal hydrophilic and hydrophobic film-forming material.These filmogens can make water or a solvent system be used to the base material core as medium.The medium that also can adopt the water-ethanol system to form as thin film.
Other material that is suitable for making the coating that the dependence time of the present invention discharges for example comprises and is not limited to water miscible polysaccharide gum, such as carrageenin, and fucoidan, ghatti gum, Tragacanth, arabinogalactan, pectin and xanthan gum; The water-soluble salt of polysaccharide gum is such as sodium alginate, tragacanthin sodium and ghatti gum sodium; Water miscible hydroxy alkyl cellulose, wherein alkyl be the straight chain of 1 to 7 carbon or side chain such as, hydroxy methocel, hydroxyethyl-cellulose and hydroxypropyl cellulose; Based on synthetic thin slice template such as the methylcellulose of water-cellulose of solubleness and hydroxyalkyl methylcellulose cellulose derivative thereof such as being selected from: hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose and hydroxy butyl methyl cellulose; Other cellulosic polymer is such as sodium carboxymethyl cellulose; And other materials well known by persons skilled in the art.Other can be used for the object of the invention sheet form material and comprises poly-(vinyl pyrrolidone), polyvinyl alcohol, poly(ethylene oxide), the mixture of gelatin and polyethylene-ketopyrrolidine, gelatin, glucose, sugar, polyvinylpyrrolidone, copolymerization of ethylene ketopyrrolidine, poly-(vinyl pyrrolidone)-poly-(vinylacetate) copolymer.
Another method that delays that PG discharges under one's belt is to utilize density to be lower than the floating granules of gastric juice, delays the release of PG from particle thus.In a preferred embodiment, floating granules obtains by the carbon dioxide in the sodium bicarbonate globule that contacts release ethyl cellulose-coating in back with gastric juice.Can guarantee that from the sodium bicarbonate core release of carbon dioxide of ethyl cellulose-coating the floatability of particle delays the release of PG from particle thus.
That can use other delays the gastric emptying method to delay PG release under one's belt.These methods comprise that use is converted into the heavy polymer or the soap of feed state with the motor pattern of stomach, reduces gastric emptying rate and the release of prolong drug greatly (for example being disclosed in J.of Controlled Release 63 (2000) 235-259 of Singh and Kim) thus.
Under certain conditions, people wish the dosage form that is deployed into anti-gastric emptying size rapidly at gastric by using to prolong PG retention time under one's belt.This system keeps time that its integrity prolongs and can be from gastric emptying up to resolving into fritter.Caldwell (Caldwell, L.J., Gardener, C.R., Cargill, R.C. (1988), United States Patent (USP) 4,767,627) has described and has a kind ofly been made by corrosion-prone polymer, and is loaded with folding and inserts cross device in the hard capsule.After oral, gelatin shell is decomposed and folding device launches.1.6cm minimum dimension and the full-size of 5cm will be not can to erode to this system by pylorus up to polymer from stomach little of the degree that can pass from stomach.
Another prolong PG under one's belt the method for retention time be to use the corrosion-prone polymer system of hydrophilic, such as poly-(oxirane) of the suitable size that is suitable for being administered to the people (Polyox) and hydroxypropyl-methylcellulose (HPMC).After sucking fluid, system's short-term expand into impels the size that prolongs gastric retention, thereby makes contained medicine continue to be delivered to adsorption site in the upper gastrointestinal zone.Because these systems are made by corrosion-prone hydrophilic polymer or polymeric blends, so thereby be easy to pass stomach in the reasonable time internal corrosion.The expansible time can make it can not be present in the esophagus, and if this system enter intestinal with the state of demi-inflation, the corrosivity of hydrated polymer and elastic characteristic will be got rid of by this device and cause ileac probability.
In a concrete example, compositions of the present invention is formulated into the single dosage form that contains a plurality of globules in hard or soft capsule.This capsule comprises the blended following bead populations that is selected from: the globule or comprise that comprises the PPI of enteric coating is surrounded by the globule of the polymer P PI that the dependence time discharges, comprise the globule of calcium carbonate and comprise and be surrounded by PG, the globule of the ethyl cellulose sodium bicarbonate globule of calcium carbonate and hydroxypropyl emthylcellulose.Can make the PG globule floating so delay the release of PG based on cellulosic polymer in the compositions from globule.The rate of release of PG is by the thickness and the corrosion rate decision of hydroxypropyl emthylcellulose.
In another concrete example, capsule is blended to be selected from following bead populations: the globule or comprise that comprises the PPI of enteric coating is surrounded by the globule of the PPI that the dependence time discharges, comprise the globule of calcium carbonate and comprise and be surrounded by PG, the globule of the alginate of calcium carbonate and hydroxypropyl emthylcellulose.
In another concrete example, capsule contains and is selected from following mixing bead populations: the globule that contains the PPI of enteric coating, contain the globule of the PPI of the polymer that is surrounded by the release of dependence time, contain the globule of calcium carbonate and the particle that the micro-tablet form contains PG calcium carbonate and hydroxypropyl emthylcellulose.
In another example, compositions of the present invention is configured to compress coating or contains the PPI that one deck is an enteric coating, and another layer is PG, the bilayer tablet of calcium carbonate and hydroxypropyl emthylcellulose.
In another example, compositions of the present invention can be configured to be filled into the double-deck anhydrous semi-solid in the hard capsule, wherein PPI be dissolved in room temperature above for liquid but form after cooling that (anhydrous, as to discharge rapidly) is filled in the capsule thus in the semisolid lipid matrix.In for example the lipid solubility of the fine suspension of amine or sodium bicarbonate alkalescence medicament is also contained in.
One-pack type compositions of the present invention preferably comprises PPI rather than the PPI particle of enteric coating or the particle of dependence time release of nothing-coating.Nothing-coating PPI is faster than the absorption of coating PPI in the absorption of upper part of small intestine.Therefore, utilize nothings-coating PPI can make the biological activity of PG in the stomach and activatory time cycle of PPI more accurate synchronous and need not to delay the release of PG in the compositions.Thus, according to multiple embodiment preferred, compositions of the present invention is formulated into and contains PG, the bilayer tablet of nothing-coating PPI and one or more basic agent, tablet, effervescent tablet or the suspension tablet of compression coating.
Active component of the present invention can be mixed with a plurality of peroral dosage forms, and wherein PG and one or more medicaments of keeping PG effectiveness in the gastric juice are with dosage form separately but not use with the bonded mode of PPI.For example, PG and one or more keep the medicament of PG effectiveness in gastric juice can be mixed with oral or solid dosage forms capsule for example, tablet, suspension tablet, or effervescent tablet and PPI can be formulated in the solid dosage forms separately the globule that the globule of the enteric coating that contains in preferred capsule or the tablet or dependence time discharge.
When using a plurality of peroral dosage form, PG and keep one or more medicament of the effectiveness of PG in the gastric juice can be before PPI, simultaneously or use afterwards.Use in order, between PG and PPI use, have some and delay (for example, a few minutes and even several hours) significantly, as long as PG has brought into play some physiological effecies when administration of ppi or its activate.In preferred embodiments, the PPI that uses is dosage form enteric coating or that the dependence time discharges.According to this embodiment, the using to use so that guarantee the PPI of the part absorption of contiguous small intestinal prior to PG of preferred PPI can be used for suppressing H +/ K +-ATP enzyme pump and PG still has activity under one's belt.
Active component of the present invention can insert on the inert pharmaceutical carrier.In this case, medicine can mix with other component before coating is to the globule.Component includes but not limited to separately or binding agent, surfactant, filler, disintegrating agent, alkalinity additive or other medicinal component of form of mixtures.Binding agent comprises for example cellulose, such as hydroxypropyl emthylcellulose, and hydroxy propyl cellulose and sodium carboxymethyl cellulose, polyvinyl pyrrolidone, sugar, starch and other have the medical substance of adhesion characteristic.Suitable surfactant comprises medicinal nonionic or ionic surfactant.The example of suitable surfactant is a sodium lauryl sulphate.
Particle can be shaped as the filling agglomerate that is used to swallow by traditional method.For example, particle can utilize known encapsulation methods encapsulate to become " hard-filled capsules ".The encapsulate material should highly dissolve in gastric juice, so particle can disperse under one's belt rapidly after swallowing capsule.
In another embodiment, active component of the present invention is packaged in the tablet agent.Term " tablet agent " typically refers to level and smooth, is used for the tablet of the oral no coating of swallowing, and finally compresses then by simple compression or by the precompressed effluent to prepare to come.This solid dosage forms can technology production well known in the art.Tablet for example can comprise, one or more of following composition: lactose, mannitol, corn starch, potato starch, microcrystalline Cellulose, Radix Acaciae senegalis, gelatin, silica sol, cross-linked carboxymethyl cellulose sodium, Talcum, magnesium stearate, stearic acid and other excipient, pigment, diluent, buffer agent, wetting agent, retention agent, flavoring agent and pharmaceutical carrier.This production method can be utilized following a kind of or four kinds of combinations of method for building up: (1) is done and is mixed; (2) directly compression; (3) mill and (4) anhydrous particleization.Lachman etc., The Theory and Practice of Industrial Pharmacy (1986).This tablet also may comprise film coating, and it preferably contacts the back dissolving after oral swallowing or with diluent.
Non--restriction the example that can be used for the basic agent of this tablet comprises sodium bicarbonate, and alkali salt is such as calcium carbonate, calcium hydroxide, calcium lactate, calcium glycerophosphate, calcium acetate, magnesium carbonate, magnesium hydroxide, magnesium silicate, magnesium aluminate, aluminium hydroxide or aluminum magnesium hydroxide.The specific alkali salt that can be used for preparing antiacid tablet is a calcium carbonate.
Perhaps, compositions of the present invention can be mixed with compressed dosage forms, and such as suspension tablet and effervescent tablet, therefore after reacting with water or other diluent, the compositions that produces moisture form is used for oral.These forms especially can be used for curing child and old people and in some sense than swallowing or more acceptant other crowd of chewable tablet.Medicinal tablet of the present invention or other solid dosage forms only need minimum vibration or stir and just can decompose basic agent.
Here the term of Shi Yonging " suspension tablet " is meant and they is being placed the water back decompose and disperse easily to form the PPI that contains exact dose, the tablet agent of PG and basic agent rapidly.In a non--restriction example, suspension tablet can comprise the omeprazole of 20-40mg, and the sodium bicarbonate of the PG of 4mg and about 1-4 gram or calcium are as basic agent.For the purpose that realizes that tablet decomposes fast, can in said preparation, add disintegrating agent such as cross-linked carboxymethyl cellulose sodium.Disintegrating agent can be separately or is combined with microcrystalline Cellulose and to be blended in the tablet agent, and described microcrystalline Cellulose is known to have the constrictive ability that is difficult to be compressed into the tablet material of improving.Separately or with other component altogether-microcrystalline Cellulose of processing also is the universal additive of tablet agent and knownly has a constrictive ability that is difficult to be compressed into the tablet material of improving.It is commercially available with the Avicel trade mark.
The suspension tablet compositions comprises flavoring agent except that containing the component that other usually is used for medicinal tablet the component as mentioned above, sweeting agent, and fluidizer, lubricant or other this area be the conspicuous general agent aid of personnel almost.Can utilize other disintegrating agent, such as crospovidone (crospividone) and sodium starch glycolate, though preferred cross-linked carboxymethyl cellulose sodium.
Except that said components, aforesaid peroral dosage form also can contain conventional other material that uses of technical field of pharmaceuticals of appropriate amount, for example diluent, lubricant, binding agent, granulating assistant, pigment, spice and fluidizer.These other amount of substances are enough to provide Expected Results to target formulation.Can be used to the pharmaceutical carrier of formulate oral dosage forms and the instantiation of excipient and be described in Handbook of Pharmaceutical Excipients, among the American PharmaceuticalAssociation (1986), be incorporated herein by reference herein.
The embodiment of following existence is in order to illustrate certain embodiments of the present invention more fully.They never should be construed as limiting the scope of the invention.Those skilled in the art can be at an easy rate design many variations and improvement to disclosed principle here, only otherwise deviate from scope of the present invention.
Embodiment
Embodiment 1:NaHCO 3Keep the stability of PG in the artificial gastric juice
The external artificial gastric juice of utilization measures NaHCO 3The stability of PG in the acid pH under existing.The 235th page of preparation artificial gastric juice according to American Pharmacopeia (USP) 2000 versions.In order to prepare the gastric juice of 200ml, the NaCl of 0.4g and the pepsin of 0.64g are dissolved in the water of 16ml 1M HCl and 184ml.The pH of gastric juice is 1.2.With 10 or 8.4% (1M) NaHCO of 20ml 3The 250ppmPG solution (0.25mg/ml) of (final concentration is respectively 3.72mg/ml or 7.12mg/ml) and 16ml adds in the solution.The concentration of PG is 16ppm in the final solution.When indication, also add omeprazole granules (solution B and C).In order to measure the stability of PG in the final solution in time, carry out HPLC on the sample of the following time point collection after preparation and analyze: 0 ' (after the preparation immediately), 5 ', 10 ', 20 ', 40 ', 60 '.For cessation reaction, utilize NH 4OH arrives 7.5-8.5 with pH regulator.
As shown in fig. 1, at the NaHCO of 3.72mg/ml 3Exist (pH1.2) down to comprise the quick degraded of observing PG among the solution A of PG and the B.Yet, containing 7.12mg/mlNaHCO 3(pH5.7) PG keeps stablizing 1 hour in the solution C.These results show add be enough to pH bring up to 5.0 above concentration such as NaHCO 3Basic agent stoped PG to be degraded by pepsin.Fig. 2 confirms that further at least 80% PG keeps not being degraded at least 15 minutes when pH4.8.
A. preparation describe-contain non--enteric coating-the tablet of omeprazole:
Embodiment 2: contain PG, non--enteric coating-omeprazole, the compression coating or the bilayer tablet of sodium bicarbonate and calcium carbonate
Compression-coating or bilayer tablet are formulated into single dosage form, and wherein each tablet contains following component:
Omeprazole (powder) 40mg
PG 4mg
NaHCO 3 500mg
CaCO 3 500mg
Cross-linked carboxymethyl cellulose sodium
Hydroxypropyl emthylcellulose (HPMC)
Microcrystalline Cellulose (Avicel)
Magnesium stearate
Starch
Preparation compression coating or bilayer tablet in two-step process.For single tablet, with 4mg PG, 250mg calcium carbonate and microcrystalline Cellulose mix the ground floor that also precommpression becomes tablet.The layer that contains PG further is surrounded by and allows PG to delay to discharge the thin layer of 10-15 minute HPMC from tablet.For the second layer, with non--enteric coating of 40mg-Omeprazole powder associating 500mg NaHCO 3, 250mg CaCO 3And suitable bonding is compressed to the second layer of form tablet on the PG layer.Thereby the decomposition immediately after degraded of the second layer of tablet discharges omeprazole rapidly.Contain PG, the omeprazole of non--enteric coating, the sketch map of the bilayer tablet of sodium bicarbonate and calcium carbonate is presented among Fig. 3.
Embodiment 3: contain PG, non--enteric coating-omeprazole, the quick decomposition tablet of the tablet of sodium bicarbonate and calcium carbonate
Decompose tablet fast and be formulated into the single dosage that contains following component:
Omeprazole (powder) 40mg
PG 4mg
NaHCO 3 500mg
CaCO 3 500mg
Cross-linked carboxymethyl cellulose sodium
Microcrystalline Cellulose
Magnesium stearate
Starch
The omeprazole (40mg) that mixes non--enteric coating, PG (4mg), NaHCO 3, CaCO 3, cross-linked carboxymethyl cellulose sodium, microcrystalline Cellulose and magnesium stearate and utilize the tablet machine of standard to be compressed into tablet in the mixture that generates to produce the tablet (intravescent) that decomposes fast.
Embodiment 4: contain PG, the effervescent sacs of the omeprazole of enteric coating and sodium bicarbonate
Effervescent tablet is formulated into the single dosage that contains following component:
Omeprazole 40mg
PG 4mg
NaHCO 3 958mg
Citric acid 832mg
Potassium carbonate 312mg
Magnesium stearate
Starch
The omeprazole (40mg) of enteric coating and PG (4mg) dropped in the mortar and with pestle grind to form fine powder.Add sodium bicarbonate to mixture, citric acid, other excipient such as potassium carbonate forms the homogeneous mixture of effervescent powder.The powder that produces mixes with the omeprazole of 40mg enteric coating and is packaged into the unit dose bag.
B. the multiparticle capsule of coating omeprazole is described-contained to preparation:
Embodiment 5: contain ethyl cellulose-PG globule, the omeprazole globule of enteric coating and the capsule of calcium carbonate.
Present embodiment has been set forth the step that participates in production multiparticle hard capsule.Hard capsule is formulated into the single dosage form that contains the mangcorn subgroup.Each capsule contains following component:
The 40mg omeprazole is as the globule of enteric coating
4mgPG loads on the sodium bicarbonate globule of ethyl cellulose-coating
600mg calcium carbonate (CaCO 3)
Hydroxypropyl emthylcellulose (HPMC)
PG solution is by being prepared in the ammonium carbonate buffer that PG is dissolved in pH8.In fluid unit, PG solution is injected on the sodium bicarbonate globule of ethyl cellulose coating.After the drying, PG-sodium bicarbonate globule further is surrounded by CaCO 3And hydroxypropyl emthylcellulose (HPMC) thus form final PG particle.The final PG particle and the omeprazole globule of enteric coating and calcium carbonate powder are packaged into the hard capsule of 0 size together, and each capsule amount is equivalent to the 40mg omeprazole, 4mg PG and 600mg calcium carbonate.
After capsule decomposes, contain the HPMC layer expansion of globule of PG and gastric acid and reaction of sodium bicarbonate at globule core inner form CO in the gastric juice of stomach 2Can make by the sodium bicarbonate core release of carbon dioxide of ethyl cellulose coating that particle is floating to delay PG and calcium carbonate discharges from particle thus.The speed that PG discharges is by the thickness and the erosion rate decision of the HPMC layer of PG globule.CaCO 3Thereby the lasting time of pH increase of stomach is protected PG after release.The omeprazole globule of enteric coating is through stomach and without any the top that delays just omeprazole to be adsorbed on small intestinal.
Embodiment 6: contain alginate-PG globule, the omeprazole globule of enteric coating and the capsule of calcium carbonate
Hard capsule is formulated into the single dosage form that contains the mangcorn subgroup.Each capsule contains following component:
The 40mg omeprazole is as the globule of enteric coating
4mgPG loads on the alginate particle
600mg calcium carbonate (CaCO 3)
Hydroxypropyl emthylcellulose (HPMC)
Produce alginate particle preparation alginate particle by alginate soln being dripped in the calcium chloride solution lyophilization then.The PG solution of embodiment 5 preparations is ejected in fluid unit on the alginate particle.After the drying, PG-alginate globule further is surrounded by CaCO 3And hydroxypropyl emthylcellulose (HPMC) thus form final PG particle.The final PG particle and the omeprazole globule of enteric coating and calcium carbonate powder are packaged into the hard capsule of 0 specification together, and each capsule amount is equivalent to the 40mg omeprazole, 4mg PG and 600mg calcium carbonate.
After capsule decomposes under one's belt.Because contacting the PG globule with gastric juice, the HPMC layer expands.Cryodesiccated alginate particle is because its low-density can make the floating release that delays PG from particle thus of particle.The speed that PG discharges is by the thickness and the erosion rate decision of the HPMC layer of PG globule.The omeprazole globule of enteric coating is through stomach and without any the top that delays just omeprazole to be adsorbed on small intestinal.
Embodiment 7: contain sucrose-PG globule, the omeprazole globule of enteric coating and the capsule of calcium carbonate
Hard capsule is formulated into the single dosage form that contains the mangcorn subgroup.Each capsule contains following component:
The 40mg omeprazole is as the globule of enteric coating
4mg PG loads on the inert sugared globule
600mg calcium carbonate (CaCO 3)
Hydroxypropyl emthylcellulose (HPMC)
In fluid unit, PG solution is ejected into inertia sugar pill (Nu-Pareils, 25/30 on).After the drying, PG-sugar globule further is surrounded by CaCO 3And hydroxypropyl emthylcellulose (HPMC) thus form final PG particle.The particulate sketch map of PG is presented among Fig. 4.The final PG particle and the omeprazole globule of enteric coating and calcium carbonate powder are packaged into the hard capsule of 0 specification together, and each capsule amount is equivalent to the 40mg omeprazole, 4mgPG and 600mg calcium carbonate.
After capsule decomposes under one's belt and since the HPMC layer that contains the PG globule and gastric juice contact expansion PG globule, delay the release of PG thus from particle.The speed that PG discharges is by the thickness and the erosion rate decision of the HPMC layer of PG globule.The omeprazole globule of enteric coating is through stomach and without any the top that delays just omeprazole to be adsorbed on small intestinal.
Embodiment 8: contain the HPMC-PG micro-tablet, the omeprazole globule of enteric coating and the capsule of calcium carbonate
Hard capsule is formulated into the single dosage form that contains the mangcorn subgroup.Each capsule contains following component:
The 40mg omeprazole is as the globule of enteric coating omeprazole
4mgPG loads on the inertia sugar globule
600mg calcium carbonate (CaCO 3)
Hydroxypropyl emthylcellulose (HPMC)
PG and HPMC and CaCO 3The combination granulation also is compressed into micro-tablet.Micro-tablet have with stomach gastric juice contact back rapid expanding ability and thus be retained in the stomach.The release of PG in stomach is by the erosion rate control of the polymeric matrix of expansion micro-tablet.The omeprazole globule of PG micro-tablet and enteric coating and calcium carbonate powder are packaged into the hard capsule of 0 specification together, and each capsule amount is equivalent to the 40mg omeprazole, 4mgPG and 600mg calcium carbonate.
Embodiment 9: the multiparticle capsule that contains the omeprazole and the PG globule of the coating that is surrounded by non--enteric coating dependence time release
Present embodiment has been illustrated the step that participates in making the multiparticle hard capsule.Capsule is formulated into the single dosage form that contains following mangcorn subgroup and calcium carbonate: be surrounded by the PG globule of the coating of dependence time release, be surrounded by the omeprazole globule of the coating of dependence time release.Capsular sketch map is presented among Fig. 5.Each capsule contains following component:
40mg is surrounded by the omeprazole globule of thick HPMC layer
4mg loads on the sugared ball and is surrounded by the PG of thin HPMC layer
600mg calcium carbonate (CaCO 3)
The compositions of this coating is designed to and can core decomposes in the aqueous environment rapidly when medium contact core the time.For this purpose.The sugar ball will be surrounded by antacid (NaHCO 3Or CaCO 3) layer.PG solution is by being prepared in the ammonium carbonate buffer that PG is dissolved in pH8.In fluid unit, the injection of PG solution is on the globule of above-mentioned antacid coating.After the drying, has the PG particle that delayed to discharge in about 10 minutes with the further coating globule generation of thin layer HPMC.On the sugared ball of antacid coating with the omeprazole stratification and covering thicker slow release HPMC coating.The core that also disintegrating agent is added into particle promotes the release of HPMC dissolving back omeprazole.The target of coating omeprazole globule is the process stomach and is attracted to the top of small intestinal and discharges omeprazole immediately after the HPMC dissolving.Final PG particle and omeprazole globule and calcium carbonate powder are packaged into the hard capsule of 0 specification together, and each capsule amount is equivalent to the 40mg omeprazole, 4mgPG and 600mg calcium carbonate.The speed of the release of PG and OMP is by the thickness and the erosion rate decision of the HPMC layer of globule.CaCO 3Thereby the pH of stomach is improved the time that prolongs after release, keep PG.
The tablet of the omeprazole of enteric coating is described-contained to the C preparation:
Embodiment 10: contain PG, the omeprazole globule of enteric coating and the compression-coated tablet of calcium carbonate
To compress--coated tablet is mixed with the single dosage form that contains following component:
The 40mg omeprazole is as the omeprazole globule of enteric coating
The 4mgPG granule
Calcium carbonate
Hydroxypropyl emthylcellulose (HPMC)
Preparation compression-coated tablet in two-step process.For single tablet, with 4mgPG, the 900mg calcium carbonate mixes the prostheses that also precommpression becomes tablet with HPMC.The omeprazole globule compression coating of the enteric coating of 40mg is formed the skin of tablet on the PG core.Final tablet is formed by the release immediately of controlled release PG core layer and omeprazole enteric-coated coating globule is outer.In another embodiment, active component is compressed into bilayer tablet, wherein ground floor contains 4mgPG, and 900mg calcium carbonate and HPMC, the second layer contain the omeprazole globule of the enteric coating of 40mg.
This tablet agent can comprise one or more following excipient: lactose, mannitol, corn starch, potato starch, microcrystalline Cellulose, Radix Acaciae senegalis, gelatin, silica sol, cross-linked carboxymethyl cellulose sodium sodium, Talcum, magnesium stearate, stearic acid and other excipient, pigment, diluent, buffer agent, wetting agent, retention agent, flavoring agent and pharmaceutical carrier.
Embodiment 11: contain PG, the quick decomposition of the omeprazole globule of enteric coating and the tablet of calcium carbonate
Be mixed with the single dosage form that contains following component with decomposing suspension tablet fast:
The 40mg omeprazole is as the omeprazole globule of enteric coating
The 4mgPG granule
The 900mg calcium carbonate
Cross-linked carboxymethyl cellulose sodium
Microcrystalline Cellulose
Magnesium stearate
Hydroxypropyl emthylcellulose (HPMC).
The PG granule is surrounded by CaCO 3And hydroxypropyl emthylcellulose (HPMC) thus form final PG particle.The final PG particle and the omeprazole globule of enteric coating and above-mentioned mixed with excipients also utilize the tablet machine of standard to be compressed into tablet the mixture that generates.Thereby the tablet that produces can decompose fast and can swallow under one's belt decomposition fast with water.
After suspension tablet is decomposed and since the HPMC layer that contains the PG globule and aqueous environment contact expansion PG particle, delay the release of PG thus from particle.The speed that PG discharges is by the thickness and the erosion rate decision of the HPMC layer of PG globule.The omeprazole globule of enteric coating is through stomach and without any the top that delays just omeprazole to be adsorbed on small intestinal.
Experiment in the D body
Embodiment 12: gastric acid secretion behind the oral PG of rat
Combination gastric acid inhibitory secretion by PG and PPI is based on the merocrine ability of oral PG triggering gastric.In order to address this problem, the PG that uses (oral) recruitment for the rat of anaesthetizing also monitors the gastric acid secretion in the stomach that connects pylorus.The PG of recruitment (10,30, with 90 μ g/kg) is administered to the rat that is connected pylorus by oral gavage.
After handling 30 minutes, collect gastric juice, by determining acid concentration with the NaOH titration and calculating the total acid content of expressing with μ Eq HCl by sample volume being multiply by acid concentration from gastral cavity.The result represents with meansigma methods ± SEM of each experimental group 7-8 animal.As shown in Figure 6, Orally administered PG has significantly improved gastric acid secretion in dose-dependent mode, hints that Orally administered PG has successfully induced gastric acid secretion with local mode.
Embodiment 13: the PG that uses with omeprazole is to the effect of gastric pH
In order to measure PG-PPI combination effect to the inhibition of gastric acid secretion, with the rat of anesthesia accept gastric inject separately omeprazole (10mg/kg) or with PG (350 μ g/kg) combined administration.Accepted PG with the rat of this combined treatment in 15 minutes before the omeprazole.By after processing 30,45 and 60 minutes through draw collecting gastric juice and by of the effect of monitoring pH detection of drugs to gastric acid secretion.Data show is at all time points of the rat of using PG and omeprazole combined treatment, and the pH value of gastric all is significantly higher than the pH value of handling with omeprazole separately (Fig. 7).These results show that PG has improved anti--secreted activity of the PPI of rat.
Embodiment 14: lansoprazole suppresses the gastric acid secretion of conscious animal in dose-dependent mode.
In this experiment, that uses different models allows to carry out the rat of medicine to the pylorus-connection of the function analysis of the gastric acid secretion of conscious animal.This model has been got rid of the influence of anesthesia to gastric acid secretion.Orally administered independent research medicine or its combination.One or utilize the short time (5 minutes) of anesthetic gases machine anesthetized animal after two hours, just be enough to carry out the time that pylorus connects and sew up abdominal part.Then animal being put back to cage waits for clear-headed.Put to death animal behind the several hrs, ligature is twined around the esophagus, take out stomach and also collect gastric content.Centrifugal back is titrated to terminal point pH 7 with 0.01N NaOH automatically with the gastric juice sample and calculates the amount of titratable acid.
Lansoprazole is used as simplifying suspension (SLS) oral administration gavage.According to following preparation SLS: the content of 1 30mg capsule (Zoton) is suspended in 8.4% the sodium bicarbonate.2 hours lansoprazoles with 3 dosage before pylorus connects (20,5 and 1.25mg/kg) are handled rat.NaHCO with 8.4% 3Be administered to matched group as placebo.Fig. 8 shows that lansoprazole has suppressed gastric acid secretion in dose-dependent mode.
Embodiment 15: with the influence that be connected pylorus rat tolerance secretion of the co-administered lansoprazole of PG to conscious mind.
In this experiment, with the dosage of 5mg/kg PG (300 μ g/kg) before (A) or afterwards (B) handled rat with SLS in 15 minutes.Control rats injection 8.4%NaHCO 3With the combination of PG-medium as placebo.2 hours oral administration gavages are used all medicines before connecting pylorus.During 3 hours, collect gastric juice.Data are expressed as meansigma methods ± SEM.The animal number of each experimental group is 8-9.
Fig. 9 A used SLS as can be seen before the PG in 15 minutes and compares with independent lansoprazole and cause that acid suppresses greatly, and with the PG pretreatment then with SLS handle the acid amount of rat be not different from the rat (Fig. 9 B) of independent lansoprazole processing.These results show that PG has improved the effectiveness of lansoprazole in the blocking-up gastric acid secretion.And the timing between two chemical compounds is very important for the raising that obtains PG/ lansoprazole combined therapy effect.
In another experiment, during 3 Consecutive Days, use SLS and medium or the SLS and PG (300, μ g/kg) the processing rat of 2.5mg/kg dosage once a day.Before PG or medium, used SLS in 15 minutes.Control rats injection 8.4%NaHCO 3With the combination of PG-medium as placebo.All medicines are used through oral gavage.Carrying out pylorus in back 2 hours treatment in the 3rd day connects.During 3 hours, collect gastric juice.Data are expressed as meansigma methods ± SEM.The animal number is 8-9 in each experimental group.Shown in Figure 10 A and 10B, compare the remarkable rising that causes gastric pH with the co-administered SLS of PG with independent SLS during 3 Consecutive Days.Similarly, using independent SLS reduction with the continuous gastric acid secretion ratio of handling 3 days rat of SLS/PG combination.
Embodiment 16:CCK-B antagonist is to the influence of the gastric acid secretion of P of Rats G-mediation
Because PG is gastrin homologue, its local effect is considered to through gastrin approach mediation, i.e. the activation of gastrin-receptor (CCKB).In order to test this hypothesis, check of the sour excretory influence of concrete CCKB antagonist (Itriglumide) to P of Rats G-mediation.
In this research, with ketamine and Domitor mixture anesthetized rat, and provide the Itriglumide of 20mg/kg to rat, promptly use in the duodenum (i.d.).After 15 minutes, connect the stomach pylorus and the PG of 300 μ g/kg is administered to (i.g.) in the stomach.After 30 minutes, obtain gastric juice, centrifugal and measure the volume and the pH of supernatant.By calculating total acid yield that μ Eq HCl represents with NaOH titration gastric juice sample analysis acid concentration (titrable acidity) and by multiply by acid concentration with sample volume.The result of following table 1 shows that the antagonist (ant.) of injection suppresses the local effect of PG to rat tolerance secretion in the duodenum of CCKB.
Table 1:
Group Acid yield
Meansigma methods ±SEM
Prostaglandin (i.g.), 300 μ g/kg 60.056 10.43
CCKB ant.(i.d.)20mg/kg 15.24 2.82
PG(i.g.)-NH 4HCO 3Placebo 19.25 3.03
The placebo of CCKB ant.-saline (i.d.) 12.93 1.55
PG (i.g.), 300 μ g/kg and CCKB ant. (i.d.) 20mg/ml 22.884 2.70
PG (i.g.), the placebo of 300 μ g/kg and CCKB ant.-saline (i.d.) 51.74 9.35
Student t-check
PG vs.ant.+PG P＝0.0023
P＝0.0042
P＝0.0016
Injection is to the excretory influence of connection pylorus rat acid of anesthesia in the duodenum of embodiment 17:PG
Injection PG is to the sour excretory influence of the connection pylorus rat of anesthesia in the check duodenum.In this research, use the PG of 300 μ g/kg in the rat preduodenal of connection pylorus to anesthesia and after 30 minutes, measure the level of gastric acid secretion.Obtain gastric juice, centrifugal and measure the volume and the pH of supernatant.By calculating total acid yield that μ Eq HCl represents with NaOH titration gastric juice sample analysis acid concentration (titrable acidity) and by multiply by acid concentration with sample volume.The PG of gastric injection equivalent also determines the influence of PG to gastric secretion in contrast.As shown in table 2, the gastric acid secretion that is connected the pylorus rat of gastric and the equal induced anesthesia of duodenum interior injection PG.
Table 2:
Group Acid yield
Meansigma methods ±SEM
PG(i.g.)，300μg/kg 45.89 6.37
Placebo (i.g.) 12.46 2.65
PG(i.d.)，300μg/kg 42.26 6.95
Placebo (i.d.) 11.65 1.44
Student t-check
G (i.g.) vs. placebo P＝0.000125
P＝0.000243
P＝1.981×10 5
Those skilled in the art will recognize that the present invention is not limited to the content in specific demonstration of context and description.Certainly, scope of the present invention is limited in claims.
Sequence table
＜110〉Vecta Ltd. (Vecta, Ltd.)
＜120〉treatment needs compositions (the Compositions for Treating Pathologies of the excretory condition of illness of gastric acid inhibitory
That Necessitate Suppression of Gastric Acid Secretion)
<130>SCT060447-47
<140>PCT/IB04/002745
<141>2004-08-25
<150>US 60/497,930
<151>2003-08-27
<150>US 60/544,318
<151>2003-02-17
<160>2
<170>PatentIn version 3.3
<210>1
<211>4
<212>PRT
<213>Artificial sequence
<220>
<223>Synthetic peptide
<400>1
Trp Met Asp Phe
1
<210>2
<211>5
<212>PRT
<213>Artificial Sequence
<220>
<223>Synthetic peptide
<400>2
Ala Trp Met Asp Phe
1 5

Claims (28)

1. combination of oral medication that contains the following ingredients of medicine effective quantity as active component: (i) contain the peptide of the aminoacid sequence of SEQ ID NO:1, it activates parietal cell; (ii) irreversible stomach H +/ K +-ATP enzyme proton pump inhibitor (PPI); The medicament of the effectiveness of the described peptide of (iii) at least a maintenance in gastric juice.
2. the Orally administered composition of claim 1, peptide wherein is pentagastrin (PG) or its synthetic analogues with aminoacid sequence of SEQ ID NO:2.
3. the Orally administered composition of claim 2, retention agent wherein are one or multiple basic agent, and wherein the amount of basic agent is enough to keep the effectiveness of PG in the stomach so that keep the biologic activity of PG.
4. the Orally administered composition of claim 3, basic agent wherein is selected from: calcium carbonate, sodium bicarbonate or potassium bicarbonate, magnesium oxide, magnesium hydroxide or magnesium carbonate, magnesium lactate, magnesium gluconate, aluminium hydroxide, aluminium carbonate, calcium carbonate, sodium carbonate or potassium carbonate, aluminum phosphate, calcium phosphate, sodium phosphate or potassium phosphate or aluminium citrate, calcium citrate, sodium citrate or potassium citrate, sodium carbonate, sodium hydrogen phosphate, the mixture of aluminum glycinate and buffer agent, calcium hydroxide, calcium lactate, calcium carbonate and calcium bicarbonate.
5. the Orally administered composition of claim 3, wherein Orally administered composition is formulated into single unit dosage forms and basic agent and is the content of 300mg at least.
6. the Orally administered composition of claim 2, wherein the amount of peptide is enough to the parietal cell that local activation is arranged in gastral cavity.
7. the Orally administered composition of claim 2, wherein active component is formulated into single unit dosage forms.
8. the Orally administered composition of claim 7, wherein the amount of PG is between 2 to 60mg.
9. the Orally administered composition of claim 7, wherein single unit dosage forms is for containing the PPI globule, the bilayer tablet of PG globule and at least a basic agent, compression coated tablets agent, multiparticle capsule, effervescent tablet, suspension tablet, solution or suspension.
10. the Orally administered composition of claim 9, wherein the amount of basic agent is enough to keep the effectiveness of PG in the stomach so that keep the biologic activity of PG.
11. the Orally administered composition of claim 10, wherein PPI globule and PG globule are surrounded by the polymer that enteric coating and dependence time discharge, wherein PPI from the release of PPI globule with respect to the delayed discharge of PG from the PG globule.
12. the Orally administered composition of claim 11, wherein the polymer that discharges of dependence time comprise at least a can be in aqueous environment expansible polymer.
13. the Orally administered composition of claim 12, wherein at least a polymer is selected from: synthetic polymer and based on the derivant of cellulosic polymer or its replacement.
14. the Orally administered composition of claim 11, wherein the PG globule further comprises at least a carbonate, and this carbonate can form the carbon dioxide that is captured in the PG globule with the gastric acid reaction, induces described PG globule to swim on the gastric juice thus.
15. the Orally administered composition of claim 14, wherein carbonate is sodium bicarbonate or calcium carbonate.
16. the Orally administered composition of claim 10 comprises the PPI globule of no coating, PG globule and at least a basic agent, wherein PG from the release of PG globule with respect to the delayed discharge of PPI from the PPI globule.
17. the Orally administered composition of claim 16, wherein one or multiple basic agent are selected from: calcium carbonate, sodium bicarbonate or potassium bicarbonate, magnesium oxide, magnesium hydroxide or magnesium carbonate, magnesium lactate, magnesium gluconate, aluminium hydroxide, aluminium carbonate, calcium carbonate, sodium carbonate or potassium carbonate, aluminum phosphate, calcium phosphate, sodium phosphate or potassium phosphate or aluminium citrate, calcium citrate, sodium citrate or potassium citrate, sodium carbonate, sodium hydrogen phosphate, the mixture of aluminum glycinate and buffer agent, calcium hydroxide, calcium lactate, calcium carbonate and calcium bicarbonate.
18. the Orally administered composition of claim 16, compositions wherein comprise the tablet that is mixed with the compression coating, bilayer tablet, the multiparticle capsule, effervescent tablet, suspension tablet, the PPI globule of the no coating of solution or form of suspension, PG globule and one or multiple basic agent.
19. the Orally administered composition of claim 1, PPI wherein is selected from: rabeprazole, omeprazole, different omeprazole, lansoprazole, pantoprazole, leminoprazole, its single enantiomer, its basic salt and composition thereof.
20. the Orally administered composition of claim 1, wherein said composition further comprises pepsin inhibitor, the antibiotic of resident antibacterial in molten stick or the effective anti-stomach.
21. the Orally administered composition of claim 2; wherein peptide is the PG derivant that is selected from following N-protected: methoxy (MOM); 'beta '-methoxy ethoxyl methyl (MEM); trialkylsilkl; trityl, TIPSO, uncle-butoxy carbonyl (uncle-BOC); ethoxyethyl group (EE), F-MOC and TROC.
22. oral drugs test kit that contains the following ingredients of medicine effective quantity as active component: (i) contain the peptide of the aminoacid sequence of SEQ ID NO:1; (ii) irreversible stomach H +/ K +-ATP enzyme proton pump inhibitor (PPI); The medicament of the effectiveness of (iii) at least a maintenance peptide in gastric juice.
23. the test kit of claim 22, active component wherein are formulated into unit dosage forms separately.
24. treatment or prevention need the method for the excretory experimenter's disorder of gastric acid inhibitory, comprise the compositions to the claim 1 of experimenter's administering therapeutic effective dose of this treatment of needs.
25. the method for claim 24, disorder wherein is selected from: reflux esophagitis, gastritis, duodenitis, gastric ulcer, duodenal ulcer, with the relevant condition of illness of non-steroidal antiinflammatory drugs (NSAID), non-ucler dyspepsia, gastroenteritis esophageal reflux disease, gastrinoma, acute hemorrhage of upper gastrointestinal tract, stress ulcer, Helicobacter pylori infection, Zhuo-Emhorn syndrome (ZES), Werner's syndrome and systemic mastocytosis.
26. the method for claim 24, experimenter wherein is the human experimenter.
27. treatment or prevention need the method for the excretory experimenter's disorder of gastric acid inhibitory, comprise the compositions to the claim 22 of experimenter's administering therapeutic effective dose of this treatment of needs.
28. the method for claim 27 wherein in administration of ppi, is used described peptide before or afterwards.
CN 200480024634 2003-08-27 2004-08-25 Compositions for treating pathologies that necessitate suppression of gastric acid secretion Pending CN1842342A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102565391A (en) * 2011-12-23 2012-07-11 王滔 Immunoassay method for helicobacter pylori in gastric mucosa sample
CN113425717A (en) * 2021-04-22 2021-09-24 成都欧林生物科技股份有限公司 Medicament for improving efficacy of oral helicobacter pylori vaccine and application thereof

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102565391A (en) * 2011-12-23 2012-07-11 王滔 Immunoassay method for helicobacter pylori in gastric mucosa sample
CN113425717A (en) * 2021-04-22 2021-09-24 成都欧林生物科技股份有限公司 Medicament for improving efficacy of oral helicobacter pylori vaccine and application thereof

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