CN101961334B - Combined drug of pantoprazole and domperidone - Google Patents
Combined drug of pantoprazole and domperidone Download PDFInfo
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- CN101961334B CN101961334B CN200910060079A CN200910060079A CN101961334B CN 101961334 B CN101961334 B CN 101961334B CN 200910060079 A CN200910060079 A CN 200910060079A CN 200910060079 A CN200910060079 A CN 200910060079A CN 101961334 B CN101961334 B CN 101961334B
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Abstract
The invention provides a combined drug of pantoprazole and domperidone and in particular provides application of pantoprazole and domperidone to preparing combined injections for treating gastric ulcer, duodenal ulcer, gastro-esophageal reflux diseases or functional dyspepsia. The invention also provides the combined injections for treating gastric ulcer, duodenal ulcer, gastro-esophageal reflux diseases or functional dyspepsia, including different specifications of unit preparations, pantoprazole and domperidone for simultaneous, respective or successive administration and preparations prepared by pharmaceutically acceptable vectors. The weight ratio of pantoprazole and domperidone is 1:1-5:1, and the pantoprazole and domperidone contain excipients, stabilizing agents, etc. Through combined injection administration, the invention improves the bioavailability of pantoprazole and domperidone and ensures the treatment effects to be obviously better.
Description
Technical field
The present invention relates to the combination medicine of pantoprazole and domperidone, particularly, is in uniting with the purposes in the injectable drug at preparation treatment gastric ulcer, duodenal ulcer, GERD or functional dyspepsia.
Background technology
Pantoprazole is a kind of proton pump inhibitor (PPI), and is relatively stable under neutral and solutions of weak acidity, rapid activation under strong acidic condition, and the activation characteristic that its pH relies on makes its effect to H+, K+-ATP enzyme have better choice property.Can suppress secreted microtubule that parietal cell top film constitutes and the H+ on the intracytoplasmic tubular foam, K+-ATP enzyme specifically, cause the inhibition of this enzyme irreversibility, thus the secretion of gastric acid inhibitory effectively.Because being parietal cell, H+, K+-ATP enzyme secrete last process of acid, so that pantoprazole presses down sour ability is powerful.It can not only noncompetitive suppresses the gastric acid secretion that gastrin, histamine, choline cause, and can suppress not receive choline or H
2The part basal gastric acid secretion of-receptor blocking agent influence, the gastric acid secretion that can stop a variety of causes to cause.PPI gets into that after effect time can reach more than 24 hours in the human body, thus PPI to press down acid strength big, the time is long, can effectively alleviate the acid regurgitation of GERD, symptom such as heartburn clinically.A large amount of technology about aspects such as freeze-dried pantoprazole injectable powder and method for preparinies is disclosed in the prior art.For example, one Chinese patent application 99112872.9 discloses freeze-dried powder injection of pantoprazole sodium and method for preparing; One Chinese patent application 200810001189.0 discloses a kind of Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method; One Chinese patent application 200510023469.8 discloses Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method; One Chinese patent application 200610156621.4 discloses Pantoprazole Sodium Freezing Injectable Powder And Its Preparation Method.Above patent all is that pantoprazole is prepared into lyophilized injectable powder, is used for diseases such as treatment treatment gastric ulcer, duodenal ulcer.One Chinese patent application 200810088954.7 discloses pantoprazole sodium liposomes freeze-dry preparations and preparation method thereof, and Pantoprazole Sodium is prepared into liposome, reaches the targeting purpose and improves curative effect.A large amount of technology that is prepared into aspects such as oral formulations and method for preparing about pantoprazole is disclosed in the prior art.For example, one Chinese patent application 200310112607.0 discloses enteric coated mini-pill of pantoprazole sodium; One Chinese patent application 200410097130.8 discloses the oral enteric micro-pills and the preparation technology thereof of pantoprazole or its salt; One Chinese patent application 200610085227.6 discloses a kind of enteric coated mini-pill of pantoprazole sodium.These three patents all are that pantoprazole is improved enteric coated technology, are prepared into enteric coated micropill and reach the purpose that discharges at enteral.One Chinese patent application 200810111783.5 discloses natrium pantoprazole sustained-release dropping pill and preparation method thereof, and this technology is that natrium pantoprazole is prepared into slow releasing preparation, improves curative effect through slow release medicine.
Domperidone is a kind of dopamine-receptor antagonist, and specific effect can be removed upper gastrointestinal dyskinesis symptom effectively in upper digestive tract, and is more obvious to symptom treatment effects such as acid regurgitation, anti-food, abdominal distention, belch especially.One Chinese patent application 031190421.1 provides a kind of dopan oral disintegrating tablet formulation, and its composition comprises active constituents of medicine, filler, correctives, disintegrating agent, lubricant and fluidizer etc.The active constituents of medicine of this application is a kind of medicine for stomach dynamic; Disintegrating agent is chosen self-crosslinking polyvinylpyrrolidone, carboxymethyl starch sodium, microcrystalline Cellulose or their mixture; Correctives is selected from aspartame.One Chinese patent application 200310100909.6 then discloses a kind of domperidone drip pill that micronizing and drop pill production Technology are processed of using; It can improve disintegrate and dissolve loose speed, dissolution rate and dissolution; Onset is rapid; Carry on a shoulder pole high medicine stability, reduce supplementary product consumption, easy to carry and use.Also have in the prior art and utilize domperidone and other active constituents of medicine to process composite drug, reach some therapeutic use.For example, 98802318.0 of Chinese patents disclose through using to the patient and have contained the Pharmaceutical composition treatment migraine that domperidone or its salt of effective dose are gone up in ibuprofen or its salt that treatment goes up effective dose and treatment.200410014337.4 of one Chinese patent application disclose a kind of Chinese medicine composition of treating bowel dysfunction, can comprise the extract of Radix Bupleuri, white peony root, Radix Pseudostellariae and Radix Glycyrrhizae etc. in the said composition; Can also increase medicine or its extracts such as the Rhizoma Atractylodis Macrocephalae, Rhizoma Chuanxiong, Poria, Radix Puerariae, Ramulus Uncariae Cum Uncis, Fructus Aurantii Immaturus; Or chemical compounds such as increase dioctahedral smectite, domperidone.A kind of treatment digestive system and ulcer pharmaceutical composition is disclosed in the one Chinese patent application 200410023583.6; Said composition contains at least a histamine receptor antagonists and at least a proton pump inhibitor; Wherein histamine receptor antagonists is that cimetidine, ranitidine, lafutidine, famotidine and roxatidine etc. replace class D chemical compound or medicine, and proton pump inhibitor is Omprazole compound or medicines such as Tenatoprazole, omeprazole, lansoprazole, rabeprazole, pantoprazole and S-omeprazole.Said composition can be made into graininess, lamellar, capsule, glue etc., and is used for the prevention and the treatment of stomach and duodenal ulcer through effective gastric acid inhibitory secretion.In addition; A kind of slow releasing preparation that contains domperidone pantoprazole sodium and preparation method thereof is disclosed in the one Chinese patent application 200410023583.6; Said composition is that half processes slow releasing preparation with domperidone, and half processes quick releasing formulation, and Pantoprazole Sodium is processed normal release formulation; Oral administration is combined in three kinds of releases, intestines and stomach diseases such as treatment GERD, functional dyspepsia.
Aspect route of administration, although oral domperidone can reach peak value after 10 to 30 minutes, yet experimental study shows that because " first pass effect " and the metabolism of intestinal wall of liver, the bioavailability of administration has only 13-17% on an empty stomach.If when changing administration in 90 minutes after meal into by the empty stomach administration, then its bioavailability can be increased to 23% by 13%; And injection gives domperidone, and its bioavailability improves greatly, is about 90%.And behind the pantoprazole oral administration, its bioavailability differs bigger because of individual variation, is generally 35-50%, and its reason is that oral being prone to of Pantoprazole Sodium destroyed by acid degradation.And drug administration by injection can not destroyed by acid degradation without the intestines and stomach, and its bioavailability will improve greatly.
So far, there is bibliographical information that pantoprazole and domperidone oral combination are treated gastroenteropathys such as gastric ulcer, duodenal ulcer, GERD, functional dyspepsia.As: Hu Yimin, wait pantoprazole and domperidone coupling treatment GERD effect observation, North China national defence medicine; 2007 19 3 phases of volume, wherein: GERD 66 examples, adopt at random, double-blind method is divided into two groups; 34 examples are organized in treatment, give pantoprazole 20mg, 2/d; Domperidone 10mg, 3/d, oral.Matched group 32 examples give famotidine 20mg, 2/d, domperidone 10mg, 3/d, oral, observe heartburies, acid regurgitation, breastbone in 2,4,6 weeks of treatment back after the alleviation situation of symptom such as pain, and in 6 week the back check gastroscopic observation esophagitis cure rates.This evidence, pantoprazole and domperidone coupling are the effective schemes of treatment GERD.The king appoints it, the clinical research of times agent pantoprazole associating domperidone treatment GERD, modern digestion and intervention diagnosis and therapy; 2006 11 1 phases of volume, disclose and adopted oral pantoprazole 40mg, every day 2 times; Domperidone 10mg, every day, 3 times mode was used a times agent pantoprazole associating domperidone treatment GERD; Patient's symptom is improved rapidly, and the pathological changes cure rate is high, and centering, severe GERD are evident in efficacy.
The relevant report of present no-trump pantoprazole still and the medication of domperidone joint injection.
Summary of the invention
Technical scheme of the present invention has provided the combination medicine of pantoprazole and domperidone, particularly, is uniting with the purposes in the injectable drug at preparation treatment gastric ulcer, duodenal ulcer, GERD or functional dyspepsia.The present invention also provides the joint injection medication of a kind of treatment gastric ulcer, duodenal ulcer, GERD or functional dyspepsia.
The invention provides pantoprazole and domperidone uniting at preparation treatment gastric ulcer, duodenal ulcer, GERD or functional dyspepsia with the purposes in the injectable drug.
Wherein, the weight ratio of described pantoprazole and described domperidone is 1: 1-5: 1.
Further preferably, the weight ratio of described pantoprazole and described domperidone is 4: 1.
The present invention also provides a kind of the treatment uniting of gastric ulcer, duodenal ulcer, GERD or functional dyspepsia to use injectable drug; It comprises the unit formulation of different size; The pantoprazole and the domperidone that are used for while, difference or administration successively, and the preparation of pharmaceutically acceptable preparing carriers one-tenth.Wherein, the weight ratio of described pantoprazole and described domperidone is 1: 1-5: 1.Further preferably, the weight ratio of described pantoprazole and described domperidone is 4: 1.
Described preparation is an injectable powder.
Wherein, the adjuvant that contains following weight percent in the described injectable powder: stabilizing agent 0.1-3.0%; Excipient 25-75%; Isoosmotic adjusting agent 1-10%; Cosolvent 0.5-20%.Wherein, described stabilizing agent is selected from sodium salt, the ethylenediamine tetrapropionic acid of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, sodium salt, malonic acid, the sodium salt of malonic acid and/or the sodium salt of succinic acid or succinic acid of ethylenediamine tetrapropionic acid; Described excipient is to be selected from like one or more the material of next group in the material: mannitol, pregelatinized Starch, sucrose, lactose, microcrystalline Cellulose, glucose or fructose; Isoosmotic adjusting agent is selected from sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, calcium chloride, sodium lactate, calcium lactate, glucose and/or xylitol.Described cosolvent choosing is taken from Polyethylene Glycol-6000 and polyvinylpyrrolidone-K30.
Further preferably, the adjuvant that contains following weight percent in the described injectable powder: stabilizing agent 0.2-2.0%; Excipient 30-70%: isoosmotic adjusting agent 1-5%; Cosolvent 0.5-15%; Described stabilizing agent choosing is taken from the sodium salt of sodium salt, malonic acid and/or the malonic acid of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid.Described cosolvent choosing is taken from Polyethylene Glycol-6000.
Further preferably, the weight percentage of the adjuvant in the described injection is: stabilizing agent 0.5%; Excipient 53%: isoosmotic adjusting agent 12%; Cosolvent 5%.Wherein particularly, the optimum amount of each preparation unit is: sodium ethylene diamine tetracetate 1mg; Mannitol 100mg; Sodium chloride 22.5mg; Polyethylene Glycol-6000 10mg.
Wherein, also contain alkaline pH value regulator in the described freeze-dried powder, pH value is 10-12; Described alkaline pH value regulator is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and/or potassium bicarbonate.
In composite injection of the present invention, in order to overcome the solubility problem of pantoprazole, preferred pantoprazole is Pantoprazole Sodium, pantoprazole potassium or pantoprazole salt hydrate.
Pantoprazole Sodium, pantoprazole potassium or pantoprazole salt hydrate (abbreviation pantoprazole) have the acid of pressing down effect; Be the parietal cell proton pump inhibitor; Relatively stable under neutral and solutions of weak acidity; Rapid activation under strong acidic condition, the activation characteristic that its pH relies on makes its effect to H+, K+-ATP enzyme have better choice property.These article can suppress secreted microtubule that parietal cell top film constitutes and the H+ on the intracytoplasmic tubular foam, K+-ATP enzyme specifically, cause the inhibition of this enzyme irreversibility, thus the secretion of gastric acid inhibitory effectively.Because being parietal cells, H+, K+-ATP enzyme secrete last sour process, so it is powerful to press down sour ability.It can not only noncompetitive suppresses the gastric acid secretion that gastrin, histamine, choline cause, and can suppress not receive choline or H
2The part basal gastric acid secretion of-receptor blocking agent influence.The pantoprazole injection has high bioavailability, and the bioavailability ratio of intravenous injection and oral administration is 1.2.Tmax during oral 40mg is 2～4 hours, and Cmax is about 2～3 μ g/ml, removes the half-life to be about 1.1 hours.The metabolite of oral or quiet these article of notes of about 80% is drained in urine, and renal insufficiency does not influence pharmacokinetics, can delay during hepatic insufficiency to remove.t
1/2, clearance rate and apparent volume of distribution and dosage be irrelevant.
In composite injection of the present invention, domperidone is a kind of stomach dynamics-promoting medicine of resisting emesis effect of brute force, and main site of action is the chemoreceptor trigger zone that is positioned at the bottom, ventriculus quartus outside the blood brain barrier, and rare have domperidone can pass blood brain barrier.Domperidone also can with D
2Receptor, particularly gastrointestinal dopamine receptor have stronger affinity.Domperidone is different from other stomach dynamics-promoting medicine, no cholinergic activity, and do not receive that atropine is inhibiting to be influenced, the motivator effect is similar with metoclopramide.But 15～30 minutes peaking blood drug level in oral back.Distribution is the highest with the gastrointestinal local drug concentration, and blood plasma takes second place, and does not almost have in the brain.Domperidone is almost all at intrahepatic metabolism, and the half-life (t1/2) is 7 hours, is 31.23% through the urine excretion total amount, and the original shape medicine accounts for 0.4%; Defecate total amount 65.7%, the original shape medicine accounts for 10%.
When the composite injection that adopts pantoprazole of the present invention and domperidone comes therapeutic alliance gastric ulcer, duodenal ulcer, GERD (or stomach esophagus reflux disease); Pantoprazole is the gastric acid pump inhibitor, and it suppresses the proton pump H in the parietal cell film through selectivity
+-K
-ATP and block the excretory last passage of acid produces the strong and persistent acid effect that presses down, and reaches the effect that gastric ulcer and duodenal ulcer are treated in treatment.But discovering in recent years, the acid anti-stream in pantoprazole treatment back reduces, anti-after the meal rheology is for mainly being non-acid, and nonacid anti-stream also can produce heartburn symptom with (or) damage the esophagus mucosa.Therefore only use single acid inhibitor treatment reflux esophagitis, some cases can not be obtained satisfactory effect.Domperidone is periphery dopamine receptor antagonist optionally, and it can directly act on gastrointestinal wall, prevents gastroesophageal reflux; Strengthen gastric peristalsis simultaneously; Prevent bile reflux, regulate and recover upper gastrointestinal motion, and can suppress nausea and vomiting through chemoreceptor being listened the lasing region effect.If Combined application proton pump inhibitor and domperidone treatment reflux esophagitis; Then when pressing down acid, can increase the tension force of LES; Promote gastric emptying; Reduce gastroesophageal reflux, dispeled the main paathogenic factor of gastroesophageal reflux disease, make patient's the clinical symptom remission rate and the improvement rate of esophagus mucosa inflammation obviously be superior to singly using pantoprazole.
When the composite injection that adopts pantoprazole of the present invention and domperidone comes the therapeutic alliance functional dyspepsia; Pantoprazole is as proton pump inhibitor (PPI); Can stop the secretion of the gastric acid that a variety of causes causes, after it got into human body, it is big that it presses down acid strength; Time is long, thereby can alleviate symptoms such as doing pain, acid regurgitation rapidly; Simultaneously, pantoprazole also has direct anti-Hp effect, can suppress urease, suppresses or kills Hp, can suppress attack factor, the enhance protection factor.Domperidone then is a dopamine D
2Receptor antagonist, alternative blocking-up dopamine D
2Receptor, specific effect increase gastric emptying in upper digestive tract, also can increase esophageal peristalsis and expand about muscular tension with following esophagus, effectively remove upper digestive tract dyskinesis property disease.Because the functional dyspepsia clinical symptoms is complicated, Combined application pantoprazole and domperidone can significantly improve the indigestion symptom of FD.
During clinical use, must two medicines be transformed into solution could use, and domperidone is water-fast.Lyophilized injectable powder of the present invention can be processed solution or emulsion directly with the water for injection dissolving; If do not contain isoosmotic adjusting agent in the freeze-dried powder, then can use the water for injection that contains 0.9%NaCl.Composite injection of the present invention also can be processed the liquid drugs injection form.
The advantage of composite injection of the present invention is to use conveniently, and a shot is administration pantoprazole and domperidone simultaneously, and drug administration by injection is without the intestines and stomach; Can do not destroyed by acid degradation; Metabolism has been avoided first pass effect without liver, and its bioavailability will improve greatly.Simultaneously, the effect of this administering drug combinations is superior to individually dosed, and effects such as therapeutic alliance gastric ulcer, duodenal ulcer, bone esophageal reflux sick (or stomach esophagus road reflux disease), functional dyspepsia are obvious.
Below, come at length to explain the present invention in conjunction with specific embodiments.But these specific embodiment are not to be to qualification of the present invention.On basis of the present invention, those of ordinary skill in the art can make when changing accordingly without creative work or change fully, but these improvement or change are still in protection scope of the present invention.
Specific embodiments:
Embodiment 1
Lyophilized injectable powder by following formulation Pantoprazole Sodium and domperidone:
Pantoprazole Sodium (being equivalent to pantoprazole 40g) 45.1g
Domperidone 10g
Mannitol 100g
Sodium chloride 22.5g
Polyethylene Glycol-6000 10g
Sodium ethylene diamine tetracetate 1.0g
Sodium hydroxide is an amount of
Its preparation method is: the Pantoprazole Sodium, domperidone, mannitol, Polyethylene Glycol-6000 and the sodium ethylene diamine tetracetate that take by weighing recipe quantity are dissolved in it in proper amount of water for injection, and the control temperature stirs for about 70 ℃ and makes its dissolving; The sodium hydroxide solution that adds 0.1mol/L is regulated pH value and is about 10, adds the active carbon of 0.1% (W/V) again, is incubated 20 minutes; Coarse filtration is taken off charcoal, adds to the full amount of water for injection, and mixing is measured content and pH value; After qualified, with 0.22 μ m filtering with microporous membrane, fill false add plug is put lyophilization in the freeze drying box under 100 grades of environment; The tamponade outlet rolls lid, after the assay was approved the lamp inspection decals.
Embodiment 2
Lyophilized injectable powder by following formulation Pantoprazole Sodium and domperidone:
Pantoprazole Sodium (being equivalent to pantoprazole 40g) 45.1g
Domperidone 20g
Mannitol 150g
Sodium chloride 30g
Polyethylene Glycol-6000 20g
Ethylenediaminetetraacetic acid 1.0g
Sodium hydroxide is an amount of
Its preparation method is: the Pantoprazole Sodium, domperidone, glucose, Polyethylene Glycol-6000 and the ethylenediaminetetraacetic acid that take by weighing recipe quantity are dissolved in it in proper amount of water for injection, and the control temperature stirs for about 70 ℃ and makes its dissolving; The sodium hydroxide solution that adds 0.1mol/L is regulated pH value and is about 10, adds the active carbon of 0.1% (W/V) again, is incubated 20 minutes; Coarse filtration is taken off charcoal, adds to the full amount of water for injection, and mixing is measured content and pH value; After qualified, with 0.22 μ m filtering with microporous membrane, fill false add plug is put lyophilization in the freeze drying box under 100 grades of environment; The tamponade outlet rolls lid, after the assay was approved the lamp inspection decals.
Embodiment 3
Lyophilized injectable powder by following formulation Pantoprazole Sodium and domperidone:
Pantoprazole Sodium (being equivalent to pantoprazole 20g) 22.6g
Domperidone 10g
Glucose 60g
Sodium chloride 15g
Polyethylene Glycol-6000 15g
Sodium ethylene diamine tetracetate 1.0g
Sodium hydroxide is an amount of
Its preparation method is: the Pantoprazole Sodium, domperidone, glucose, Polyethylene Glycol-6000 and the ethylenediaminetetraacetic acid that take by weighing recipe quantity are dissolved in it in proper amount of water for injection, and the control temperature stirs for about 70 ℃ and makes its dissolving; The sodium hydroxide solution that adds 0.1mol/L is regulated pH value and is about 10, adds the active carbon of 0.1% (W/V) again, is incubated 20 minutes; Coarse filtration is taken off charcoal, adds to the full amount of water for injection, and mixing is measured content and pH value; After qualified, with 0.22 μ m filtering with microporous membrane, fill false add plug is put lyophilization in the freeze drying box under 100 grades of environment; The tamponade outlet rolls lid, after the assay was approved the lamp inspection decals.
Embodiment 4
Injectable powder by following formulation Pantoprazole Sodium and domperidone:
Pantoprazole Sodium (being equivalent to pantoprazole 40g) 45.1g
Domperidone 10g
Mannitol 100g
Sodium chloride 22.5g
Polyethylene Glycol-6000 12g
Sodium ethylene diamine tetracetate 0.8g
Its preparation method is: take by weighing Pantoprazole Sodium, domperidone, mannitol, Polyethylene Glycol-6000 and the sodium ethylene diamine tetracetate mix homogeneously of recipe quantity, and packing under 100 grades of environment, the tamponade outlet rolls lid, after the assay was approved the lamp inspection decals.
Embodiment 5
Injection by following formulation Pantoprazole Sodium and domperidone:
Pantoprazole Sodium (being equivalent to pantoprazole 40g) 45.1g
Domperidone 10g
Mannitol 40g
Sodium chloride 22.5g
Polyethylene Glycol-6000 18g
Sodium ethylene diamine tetracetate 0.8g
Sodium hydroxide is an amount of
Water for injection is an amount of
Its preparation method is: the Pantoprazole Sodium, domperidone, mannitol, Polyethylene Glycol-6000 and the sodium ethylene diamine tetracetate that take by weighing recipe quantity are dissolved in it in proper amount of water for injection, and the control temperature stirs for about 70 ℃ and makes its dissolving; The sodium hydroxide solution that adds 0.1mol/L is regulated pH value and is about 10, adds the active carbon of 0.1% (W/V) again, is incubated 20 minutes; Coarse filtration is taken off charcoal, adds to the full amount of water for injection mixing; Measure content and pH value, qualified after, with 0.22 μ m filtering with microporous membrane; Lid is rolled in fill under 100 grades of environment, after the assay was approved the lamp inspection decals.
Below further prove beneficial effect of the present invention through the clinical test of pesticide effectiveness.
The best proportioning screening test of pantoprazole and domperidone in Test Example 1 combination medicine of the present invention
In comparative study, with medicine different size of the present invention once-a-day single PPI of injection for curing or H
2-receptor antagonist is failed the gastric ulcer and the duodenal ulcer of effectively treatment, and the therapeutic effect data are following:
| Specification | The gastric ulcer total cure rate | The duodenal ulcer total cure rate |
| Pantoprazole 50mg/ domperidone 10mg | 87.5％ | 91.4％ |
| Pantoprazole 40mg/ domperidone 10mg | 93.6％ | 95.6％ |
| Pantoprazole 30mg/ domperidone 10mg | 82.5％ | 79.6％ |
From above data show, uniting of pantoprazole and domperidone uses the best compatibility consumption of ejection preparation to be: pantoprazole 40mg, domperidone 10mg.
The injection of Test Example 2 pantoprazole domperidone combination preparations is estimated with oral medication GERD clinical effectiveness
In comparative study, treat single PPI or H with intravenous injection with these article (pantoprazole 40mg and domperidone 10mg) 2 times on the one are oral respectively
2-receptor antagonist is failed the effectively GERD of treatment, and the therapeutic effect data are following:
| Route of administration | The GERD total effective rate | Mucous membrane of esophagus decreases healing rate | The functional dyspepsia total effective rate |
| Injection | 94.2％ | 92.5％ | 93.8％ |
| Oral | 83.4％ | 78.7％ | 85.6％ |
From above data show, pantoprazole and domperidone combination preparation injection for curing effect obviously are better than the oral formulations of said composition.
The injection of Test Example 3 pantoprazole domperidone combination preparations is estimated with folk prescription pantoprazole treatment GERD clinical effectiveness
In comparative study, these article (pantoprazole 40mg and domperidone 10mg) 2 intravenous injections on the one treatment old people GERD 26 examples, 1 all backs, 2 all backs total effective rates are respectively 57.2%, 83.4%; And concurrent control (pantoprazole 40mg, 2 times on the one) group symptom improvement total effective rate is 21.8%, 56.7%.All there were significant differences (P＜0.05) for two groups of symptom improvement condition effective percentage after 2 weeks, after 4 weeks.Treatment back check scope, the mucous membrane of esophagus pathological changes healing rate of treatment group and matched group is respectively 87.5%, 55.2%, difference significance (P＜0.05).From above data show, pantoprazole and domperidone combination preparation therapeutic effect are better than the folk prescription pantoprazole.
Test Example 4 pantoprazole domperidone combination lyophilized formulations stability test
With the product of embodiment 1, put in the exsiccator of RH 75% ± 5% (saturated NaCl solution), put into 40 ℃ ± 2 ℃ calorstats, carry out accelerated test, sampling after 1,3,6 month, detection level is with relevant, and the result sees table:
Above data show, the lyophilized formulations of pantoprazole and domperidone combination is highly stable.
Above-mentioned pharmacodynamics test proves that combination medicine of the present invention is easy to use, and a shot is administration pantoprazole and domperidone simultaneously; And drug administration by injection can not destroy by acid degradation without the intestines and stomach, and metabolism is without liver; Avoided first pass effect, its bioavailability will improve greatly.Simultaneously; The effect of this administering drug combinations is superior to individually dosed; And with the weight ratio of pantoprazole and described domperidone be 4: 1 be the best, effects such as therapeutic alliance gastric ulcer, duodenal ulcer, bone esophageal reflux sick (or stomach esophagus road reflux disease), functional dyspepsia are obvious.
Claims (2)
1. pantoprazole and domperidone are treated uniting with the purposes in the injectable drug of gastric ulcer or duodenal ulcer in preparation;
The weight ratio of described pantoprazole and described domperidone is 4:1.
2. treat uniting of gastric ulcer, duodenal ulcer and use injectable drug for one kind; It is characterized in that: it comprises the unit formulation of different size; The pantoprazole and the domperidone that are used for while, difference or administration successively, and the preparation of pharmaceutically acceptable preparing carriers one-tenth; Wherein, the weight ratio of described pantoprazole and described domperidone is 4:1.
3, the according to claim 2 associating used injectable drug, it is characterized in that: described preparation is injectable powder and injection.
4, the according to claim 3 associating used injectable drug, it is characterized in that: said preparation is a lyophilized injectable powder.
5, the according to claim 3 associating used injectable drug, it is characterized in that: the adjuvant that contains following weight percent in the described injection: stabilizing agent 0.1-3.0%; Excipient 25-75%; Isoosmotic adjusting agent 5-20%; Cosolvent 1-30%; Wherein, described stabilizing agent is selected from sodium salt, the ethylenediamine tetrapropionic acid of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid, sodium salt, malonic acid, the sodium salt of malonic acid and/or the sodium salt of succinic acid or succinic acid of ethylenediamine tetrapropionic acid; Described excipient is to be selected from like one or more the material of next group in the material: mannitol, pregelatinized Starch, sucrose, lactose, microcrystalline Cellulose, glucose or fructose; Isoosmotic adjusting agent is selected from sodium chloride, sodium bicarbonate, sodium dihydrogen phosphate, calcium chloride, sodium lactate, calcium lactate, glucose and/or xylitol; Described cosolvent is chosen Polyethylene Glycol-6000 and polyvinylpyrrolidone-K30.
6, the according to claim 5 associating used injectable drug, and it is characterized in that: the weight percentage of the adjuvant in the described injection is: stabilizing agent 0.2-2.0%; Excipient 30-70%: isoosmotic adjusting agent 7-15%; Cosolvent 2-20%; Described stabilizing agent choosing is taken from the sodium salt of sodium salt, malonic acid and/or the malonic acid of ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid; Described excipient choosing is taken from mannitol; Described isoosmotic adjusting agent choosing is taken from sodium chloride; The cosolvent choosing is taken from Polyethylene Glycol-6000.
7,The according to claim 5 associating used injectable drug, it is characterized in that: the weight percentage of the adjuvant in the described injection is: stabilizing agent 0.5%; Excipient 53%: isoosmotic adjusting agent 12%; Cosolvent 5%.
8, joint injection medicine according to claim 7 is characterized in that: described stabilizing agent is a sodium ethylene diamine tetracetate; Excipient is a mannitol; Isoosmotic adjusting agent is a sodium chloride; Hydrotropy is Polyethylene Glycol-6,000 10 mg.
9, the according to claim 5 associating used injectable drug, it is characterized in that: also contain alkaline pH value regulator in the described injection, pH value is 9-12; Described alkaline pH value regulator is sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and/or potassium bicarbonate.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910060079A CN101961334B (en) | 2009-07-22 | 2009-07-22 | Combined drug of pantoprazole and domperidone |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200910060079A CN101961334B (en) | 2009-07-22 | 2009-07-22 | Combined drug of pantoprazole and domperidone |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN101961334A CN101961334A (en) | 2011-02-02 |
| CN101961334B true CN101961334B (en) | 2012-09-05 |
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| CN200910060079A Expired - Fee Related CN101961334B (en) | 2009-07-22 | 2009-07-22 | Combined drug of pantoprazole and domperidone |
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| CN103054797B (en) * | 2013-01-23 | 2014-02-26 | 海南锦瑞制药股份有限公司 | Pharmaceutical composition of pantoprazole sodium and preparation method thereof |
| CN104288150A (en) * | 2014-09-02 | 2015-01-21 | 广州市伟曦医药科技有限公司 | Drug composition containing domperidone |
| CN106214634A (en) * | 2016-08-31 | 2016-12-14 | 安徽省润生医药股份有限公司 | A kind of good fortune department fluconazole injection and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1736378A (en) * | 2005-07-20 | 2006-02-22 | 张志生 | Injection with omeprazole and domperidone |
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| CN1736378A (en) * | 2005-07-20 | 2006-02-22 | 张志生 | Injection with omeprazole and domperidone |
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