CN107174662A - Compound of proton pump inhibitor and gastric mucosa protectant composition and application thereof - Google Patents
Compound of proton pump inhibitor and gastric mucosa protectant composition and application thereof Download PDFInfo
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- CN107174662A CN107174662A CN201710369804.2A CN201710369804A CN107174662A CN 107174662 A CN107174662 A CN 107174662A CN 201710369804 A CN201710369804 A CN 201710369804A CN 107174662 A CN107174662 A CN 107174662A
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Abstract
The present invention provides compound of a kind of proton pump inhibitor and gastric mucosa protectant composition and application thereof; the compound is made up of proton pump inhibitor and gastric mucosa protectant; it can directly be mixed; or be indirectly connected with by hydrogen bond; the cocrystallization sodium hydrate property to be formed is connected by hydrogen bond more stable, and pharmacokinetic property is significantly provided；Although proton pump inhibitor and gastric mucosa protectant mechanism of action are different, the compound that both form has unexpected synergy, has positive application prospect in the therapy field of peptic ulcer and hemorrhage of digestive tract.
Description
Technical field
The invention belongs to treat the drug field of disease of digestive system, more particularly to a kind of proton pump inhibitor and gastric mucosa
Compound of protective agent composition and application thereof.
Background technology
Disease of digestive system is a kind of more typical disease, the characteristics of having chronic and recurrent exerbation the course of disease more, and total incidence is accounted for
Population 10%~20%, principal disease includes acute gastritis, chronic gastritis, digestive tract ulcer, functional dyspepsia FD etc..
It is wherein again most commonly seen with functional dyspepsia FD and digestive tract ulcer.
Digestive tract ulcer refers mainly to occur in stomach and duodenal chronic ulcer, i.e. gastric ulcer and duodenal ulcer,
Gained the name because the generation of ulcer and formation are relevant with the digestion of hydrochloric acid in gastric juice-pepsin.The symptom and feature of early stage
It is dyspeptic similar, such as chronic or periodically occur pain in gastric area, gasteremphraxis, heating, acid reflux etc., severe patient then goes out afterwards
Now suffer from abdominal pain, melena, spitting blood etc..The specific pathogenesis of present medical field is also in research is discussed, it is now recognized that it bursts with causing
The attack factor of ulcer is relevant with the defense factor disequilibrium of mucous membrane.Attack factor includes hydrochloric acid in gastric juice, pepsin, the bile of reflux
Deng；Defense factor includes mucus barrier, cell migration function etc..Causing the factor of digestive tract ulcer mainly has work strain fatigue
Diet does not have rule, takes the medicine in excessive stimulating intestine and stomach road, habits and customs and psychological condition etc..
The medicine for the treatment of digestive tract ulcer is mainly divided to two classes at present, that is, reduces hydrochloric acid in gastric juice medicine (weakening attack factor), protection and stick
Film medicine (enhancing defense factor).Wherein reduction hydrochloric acid in gastric juice medicine is now clinical main based on proton pump inhibitor.Protect mucous membrane medicine this
The mechanism of action of class medicine is different, but all has the effect of protection Gastric Mucosal Cells.
Proton pump inhibitor (Proton Pump Inhibitor, PPIs), is the medicine of a class gastric acid secretion inhibiting,
Claim H+-K+ATP enzyme inhibitors, link --- the parietal cell last eventually of gastric acid secretion can be acted on specific and noncompetitively
On H+-K+ATP enzymes.Diseases related mainly the having of current clinical practice proton pump inhibitor therapy：Peptic ulcer, pylorus
Pylori (Hp) infection, GERD, UGB, Zollinger-Ellison syndromes, NSAIDs
(NSAIDS) disease such as correlation ulcer, indigestion, stress ulcer, Barrett oesophaguses.The proton pump of country's approval listing
Inhibitor class product includes：Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, esomeprazole etc..
The deficiency that proton pump inhibitor is present：
1. work slow.It is general to can be only achieved maximum acid suppression effect after the 3~5d that takes medicine.
2. acid suppression is unstable.Thus whole day 24h hydrochloric acid in gastric juice suppression, and can be in a balanced way can not still be obtained by receiving PPIs long-term treatments
Trigger a series of symptoms.
3. the individual difference of PPIs treatments is larger.PPIs is mainly metabolized through liver cell pigment P450 (CYP) 2C19 enzymes, for
There is the poor metabolizer of CYP2C19 gene mutations, in fact it could happen that PPIs clearance rates are reduced, and thus trigger drug effect unstable.
4. security has drawn attention.In recent years, the U.S., the relevant proton of drug regulatory department of European Union successively issue
The safety information of pump inhibitor similar drug, warn the fracture of this similar drug, hypomagnesemia equivalent risk and with clopidogrel
Drug interaction, and revised package insert.
5. acid suppression is not thorough, shows as investigation into nocturnal acid breakthrough；Other long-term suppression of the PPIs classes medicine to gastric acid secretion
Hypergastrinemia may be triggered, so as to further result in stomach lining or preventing precancerous lesion of stomach cancer.
In recent years it has been recognized that strengthening the importance of gastric mucosal defense function, it is believed that strengthen adjusting gastric mucosal protection,
The healing of ulcer can be played a positive role.The mechanism of action of this class medicine is all not quite similar.The main representative of this class medicine
Have：Prostanoid medicine, Teprenone, ulcerlmin, CBS etc..
1) prostanoid medicine
Gastric epithelial cell constantly synthesis and release endogenous prostaglandin (PG), has stronger protection to make its own
With.In recent years find that PG classes medicine can also be combined with the specific receptor on cell membrane, block the secretion of hydrochloric acid in gastric juice.Representing medicine has sieve
Husky prostatitis alcohol, Misoprostol, enprostil, ornoprostil etc..PG class preparations are particularly suitable for use in non-steroid anti-inflammatory drug institute
Cause ulcer or stress ulcer.
2) Teprenone
This product is direct increase mucous secretion and the new gastric mucosa protectant for promoting cytothesis, promotes point of gastric mucus
Secrete, maintain the normal configuration and function of mucus and flowing water layer, promote the replication capacity of mucomembranous epithelial cell, so as to mitigate gastric mucosa
It is impaired, and gastric mucosa in damaged condition even ulcer can be enable to recover.Direct protective action is risen to stomach film.It can be used in clinic
Treat gastric mucosa damage that peptic ulcer, chronic gastritis, NSAID induce etc..
3) ulcerlmin
Ulcerlmin can decomposite eight sulfuric acid sucrose anion compounds in acidic gastric juice, can with it is positively charged on ulcer surface
Protein combine, form protective barrier, absorption cholate and bile acid prevents hydrochloric acid in gastric juice, the erosion of pepsin.While thiosugar
Aluminium can increase the secretion of gastrointestinal mucosa and bicarbonate, suppress in the disperse of acid, reduction gastric juice pepsin concn and suppress
Its activity.In addition in Helicobacter pylori eradication for treatment, ulcerlmin can postpone intestines and stomach to the removing of antibiotic and suppress antibiosis
The absorption and degraded of element so that antibiotic concentration increase, and directly it is gathered in helicobacter pylori table with antibiotic formation compound
Face, so as to increase the eradication rate of helicobacter pylori.
4) bismuth agent
Bismuth agent is valued gastric mucosa protectant again in recent years, and main mechanism includes:(1) in hydrochloric acid in gastric juice pH environment
Under, denol forms a kind of firm bismuth oxide colloidal precipitation in skin surface or ulcer substrate granulation tissue, forms protectiveness
Film, completely cuts off invasion and attack of the pungents such as hydrochloric acid in gastric juice, pepsin, cholate and food to gastric mucosa and acts on；(2) stomach can be promoted to glue
Film PGE2 is synthesized and Bicarbonate secretion, improves gastric mucosa blood circulation, strengthens the defense function of gastric mucosa；(3) epidermis is delayed
The degraded of growth factor, promotes superficial epithelium hyperplasia.Accelerate the reparation and healing of chronic ulcer tissue；(4) bismuth agent is to helicobacter pylori
There is stronger inhibitory action, be conducive to improving the healing rate of peptic ulcer and reduce recurrence rate.Common drug has:Citric acid bismuth
Potassium, colloidal bismmth pectin, citric acid ranitidine bismuth etc..Bismuth agent toxicity is low, and liver, kidney and nervous system, but medication are not influenceed
It is in dark brown that period, which is likely to occur stool,.
In order to improve the therapeutic effect to message systemic disease, CN104225596 discloses that one kind treats gastritis and stomach is burst
The pharmaceutical composition of ulcer, said composition is made up of proton pump inhibitor and gastric mucosa protectant, and wherein gastric mucosa protectant is preferred
Allantoin.Said composition is still less desirable to peptic ulcer and the therapeutic effect of hemorrhage of digestive tract, and drug effect is slow,
In the presence of serious peak valley phenomenon.
The content of the invention
In order to solve the above-mentioned technical problem, what a kind of proton pump inhibitor of present invention offer and gastric mucosa protectant were constituted answers
Compound, the compound has good therapeutic effect to peptic ulcer and hemorrhage of digestive tract, and medicine frequency is low, administration time
Short, onset time is long.
The present invention provides the compound of a kind of proton pump inhibitor and gastric mucosa protectant composition, and the compound includes proton
Pump inhibitor and gastric mucosa protectant, the mol ratio of the proton pump inhibitor and gastric mucosa protectant is 1-2:1-2, the matter
Sub- pump inhibitor is selected from Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Iprazole, esomeprazole, left-handed dissolved
Support draws azoles, Dexlansoprazole or dextral-rabeprazole；The gastric mucosa protectant be selected from prostanoid medicine, Teprenone,
Ulcerlmin or CBS.
Further to improve, the gastric mucosa protectant is prostaglandin or Teprenone.
Further to improve, the proton pump inhibitor is L-pantoprazole, Dexlansoprazole or dextrorotation Lei Beila
Azoles.
Further to improve, the gastric mucosa protectant is Teprenone, and the proton pump inhibitor is dextrorotation Lei Beila
Azoles.
Further to improve, proton pump inhibitor and gastric mucosa protectant are connected by Hydrogenbond.
Further to improve, above-mentioned compound is cocrystallization sodium-salt hydrate, and the cocrystallization sodium-salt hydrate formula is
(dextral-rabeprazole-hydrogen bond-Teprenone) ﹒ 2Na ﹒ 1H2O, the cocrystallization sodium-salt hydrate is spread out with the 2 θ X-rays represented
Penetrate has characteristic peak at 7.5 °, 12.4 °, 18.4 °, 22.3 °, 25.8 ° and 33.7 °.
Another aspect of the present invention provides the preparation method of cocrystallization sodium-salt hydrate, and this method comprises the following steps：
S1：It is 1 that 1mol dextral-rabeprazoles and 1mol Teprenones are dissolved in into 50mL volume ratios:2.5 water and ethanol
In mixed liquor, the concentration of caustic alcohol is 0.15mol/mL in the mixed liquor；
S2：In being stood at -10 DEG C, crystallization is spontaneously dried, produced.
Another aspect of the present invention provides a kind of microsphere tablet, and the microsphere tablet includes compound provided by the present invention and auxiliary
Material, the wherein ratio of weight and number of compound and auxiliary material are 1:1-2.5；The auxiliary material includes each composition of following parts by weight：
Polylactic-co-glycolic acid 5-10
Pregelatinized starch particulate 1-2.5.
The present invention can be with compound group by addition polylactic-co-glycolic acid and pregelatinized starch particulate in microsphere tablet
Into microballoon, the stability of microsphere tablet is remarkably improved, and the microsphere tablet prepared is slowly discharged in 24h,
Play long-acting effect.
Further to improve, the auxiliary material also includes each composition of following parts by weight：
Polypropylene glucan 3-8
Sodium alginate 0.5-1.
The present invention further adds the mixture of polypropylene glucan and sodium alginate in auxiliary material, and it can further be wrapped
Include in microsphere surface, and then improve the drugloading rate and envelop rate of microsphere tablet.
Further to improve, the pregelatinized starch particulate is prepared from by following parts by weight composition：
Pregelatinized starch 7-8
Macrogol 600 0.5-1.
Another aspect of the present invention provides the preparation method of pregelatinized starch particulate, and this method comprises the following steps：
S11：It is 1 that 7-8g pregelatinized starch is dissolved in into 50mL volume ratios:1 water and the mixed liquor of ethanol, are made mixed liquor；
S12：By mixed liquor made from step S11 in 5000rmin-1Stirring, forms emulsion；
S13：The formalin of addition 3.7% into emulsion made from step S12, solidifies, and centrifuges, and distillation is washed to
Formaldehydeless taste, suction filtration is dried, and the pregelatinized starch particulate that particle size range is 5-10 μm is made.
Another aspect of the present invention provides the preparation method of microsphere tablet, and this method comprises the following steps：
1) it is the pregelatinized starch particulate of polylactic-co-glycolic acid and 3/4 parts by weight is soluble in water, the aqueous solution is made；
2) the pregelatinized starch particulate of compound and residuals weight part is dissolved in ethanol, ethanol solution is made；
3) ethanol solution made from step S2 is added in the aqueous solution made from step S1,1600rmin-1Stirring, shape
Into emulsion；
4) control emulsion temperature is less than at 20 DEG C, continues to stir, and ethanol is evaporated into microballoon solidification, microballoon is made；
5) it is polypropylene glucan and sodium alginate is soluble in water, the aqueous solution is made；
6) by step 4) made from microballoon be dissolved in step 5) made from the aqueous solution, stirred in 20 DEG C, 50 turns/min of rotating speed
30min is mixed, 2min is centrifuged through 500 turns/min, bilayer microballoon is made in solidification；
7) by double-deck microballoon tabletting, tablet is made.
Another aspect of the present invention provides the purposes of the compound, and it is being prepared for treating peptic ulcer, alimentary canal
Application in the medicine of bleeding.
The beneficial effects of the present invention are what a kind of proton pump inhibitor of offer and gastric mucosa protectant of the invention were constituted answers
Compound and application thereof, by the way that proton pump inhibitor is combined with gastric mucosa protectant, combination is directly to mix
Close, or be indirectly connected with by hydrogen bond, it is more stable to connect the cocrystallization sodium hydrate property to be formed by hydrogen bond, and medicine generation is dynamic
Mechanical property is significantly provided；Although both mechanism of action are different, the compound that both form has unexpected
Synergy, has positive application prospect in peptic ulcer, the therapy field of hemorrhage of digestive tract.
The compound being indirectly connected with by hydrogen bond, also overcomes the various of existing proton pump inhibitor on drug effect pharmacokinetics
Deficiency, with good clinical landscapes.
Brief description of the drawings
Fig. 1 is the x-ray diffraction pattern of cocrystallization sodium-salt hydrate；
Fig. 2 is the vitro release result of the test of microsphere tablet.
Specific embodiment mode
The compound of a kind of proton pump inhibitor of embodiment 1 and gastric mucosa protectant composition
The compound includes 1mol dextral-rabeprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 2 and gastric mucosa protectant composition
The compound includes 1mol Dexlansoprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 3 and gastric mucosa protectant composition
The compound includes 1mol L-pantoprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 4 and gastric mucosa protectant composition
The compound includes 1mol dextral-rabeprazole and 1mol prostaglandin.
The compound of a kind of proton pump inhibitor of embodiment 5 and gastric mucosa protectant composition
The compound includes 1mol Dexlansoprazole and 2mol ulcerlmin.
The compound of a kind of proton pump inhibitor of embodiment 6 and gastric mucosa protectant composition
The compound includes 1mol Dexlansoprazole and 1mol CBS.
The compound of a kind of proton pump inhibitor of embodiment 7 and gastric mucosa protectant composition
The compound includes 1mol dextral-rabeprazole and 1mol Misoprostol.
The compound of a kind of proton pump inhibitor of embodiment 8 and gastric mucosa protectant composition
The compound includes 1mol dextral-rabeprazole and 1mol enprostil.
The compound of a kind of proton pump inhibitor of embodiment 9 and gastric mucosa protectant composition
The compound includes 1mol esomeprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 10 and gastric mucosa protectant composition
The compound includes 1mol L-pantoprazole and 1mol prostaglandin.
The compound of a kind of proton pump inhibitor of embodiment 11 and gastric mucosa protectant composition
The compound includes 1mol Iprazole and 2mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 12 and gastric mucosa protectant composition
The compound includes 1mol esomeprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 13 and gastric mucosa protectant composition
The compound includes 1mol Iprazole and 1mol Teprenone.
The compound of a kind of proton pump inhibitor of embodiment 14 and gastric mucosa protectant composition
The compound is cocrystallization sodium-salt hydrate, and the cocrystallization sodium-salt hydrate formula is (dextral-rabeprazole-hydrogen
Key-Teprenone) ﹒ 2Na ﹒ 1H2O, the X-ray diffraction that the cocrystallization sodium-salt hydrate is represented with 2 θ 7.5 °, 12.4 °,
There is characteristic peak at 18.4 °, 22.3 °, 25.8 ° and 33.7 °, as shown in figure 1, the relative intensity of each characteristic peak is as follows above：
| 2θ | Relative intensity (%) |
| 7.5° | 42 |
| 12.4° | 25 |
| 18.4° | 100 |
| 22.3° | 68 |
| 25.8° | 34 |
| 33.7° | 82 |
The microsphere tablet of embodiment 15
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 1
Polylactic-co-glycolic acid 7.5g
Pregelatinized starch particulate 2.5g.
The microsphere tablet of embodiment 16
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 2
Polylactic-co-glycolic acid 11.25g
Pregelatinized starch particulate
Pregelatinized starch 3.5g
Macrogol 600 0.25g.
The microsphere tablet of embodiment 17
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 14
Polylactic-co-glycolic acid 16.5g
Pregelatinized starch particulate
Pregelatinized starch 3.2g
Macrogol 600 0.4g.
The microsphere tablet of embodiment 18
The consumption of each composition of microsphere tablet is：
The microsphere tablet of embodiment 19
The consumption of each composition of microsphere tablet is：
The microsphere tablet of embodiment 20
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 14
Polylactic-co-glycolic acid 11.2g
Pregelatinized starch particulate
The compound of a kind of proton pump inhibitor of reference examples 1 and gastric mucosa protectant composition
The compound includes 1mol dextral-rabeprazole and 1mol allantoin.
The microsphere tablet of reference examples 2
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 1
Polyvinyl alcohol 7.5g
Pregelatinized starch particulate 2.5g.
The microsphere tablet of reference examples 3
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 1
Polylactic-co-glycolic acid 7.5g
Pregelatinized starch 2.5g.
The microsphere tablet of reference examples 4
The consumption of each composition of microsphere tablet is：
The compound 10g of embodiment 14
Polylactic-co-glycolic acid 11.2g
Pregelatinized starch particulate
The stability test of test example 1
1.1 accelerated test
The microsphere tablet of the embodiment of the present invention 16, embodiment 20 and reference examples 2-4 is taken, it is relatively wet at 40 DEG C ± 2 DEG C
Spend to place 6 months under conditions of 75% ± 5%, 1 month during testing, 2 months, 3 months, 6 the end of month separately sampled one
It is secondary, by the regulation in Chinese Pharmacopoeia, detect the character, the content (labelled amount %) of dextral-rabeprazole, envelop rate of microsphere tablet
(%), the results are shown in Table 1.
The accelerated test result of the microsphere tablet of table 1
The microsphere tablet that the embodiment of the present invention 16 and embodiment 20 are provided as can be seen from the table, accelerated result of the test can
Know, after placing 6 months, obvious change does not occur for the character of the microsphere tablet, the amount containing dextral-rabeprazole, envelop rate
Change；And reference examples 2-4 microsphere tablet place 6 months after, microsphere tablet jaundice, and dextral-rabeprazole content it is notable under
Drop, envelop rate is significantly reduced；Show the microsphere tablet of the present invention compared with reference examples 2-4, stability is significantly improved；And from
It can be seen that the envelop rate of embodiment 20 is apparently higher than embodiment 16 and reference examples 4 in upper table, and the envelop rate of embodiment 16 is bright
It is aobvious to be higher than reference examples 2 and 3, it follows that polypropylene glucan is added in auxiliary material and sodium alginate is remarkably improved the bag of microballoon
Envelope rate, adds other mixtures, to the raising DeGrain of envelop rate.
1.2 long term test
The microsphere tablet of the embodiment of the present invention 16, embodiment 20 and reference examples 2-4 is taken, at 25 DEG C ± 2 DEG C of temperature, phase
To humidity be 60% ± 10% under conditions of place 12 months, every 3 months sampling once, respectively at 0 month, 3 months, 6 months,
Sample within 9 months, 12 months, 24 months, detect the character, the content (labelled amount %) of dextral-rabeprazole and encapsulating of microsphere tablet
Rate (%), the results are shown in Table 2.
The long-term test results of the microsphere tablet of table 2
The microsphere tablet that the embodiment of the present invention 16 and embodiment 20 are provided as can be seen from the table, can through long-term test results
Know, after placing 24 months, obvious change does not occur for the character of the microsphere tablet, the amount containing dextral-rabeprazole, envelop rate
Change；And after reference examples 2-4 microsphere tablet is placed 24 months, microsphere tablet jaundice, and the content of dextral-rabeprazole is notable
Decline, envelop rate reduction；Show the microsphere tablet of the present invention compared with reference examples 2-4 microsphere tablet, stability is significantly improved；
And it can be seen that the envelop rate of embodiment 20 is apparently higher than embodiment 16 and reference examples 4 from upper table, and embodiment 16
Envelop rate is apparently higher than reference examples 2 and 3, it follows that add polypropylene glucan in auxiliary material and sodium alginate is remarkably improved
The envelop rate of microballoon, adds other mixtures, to the raising DeGrain of envelop rate.
The vitro release determination test of test example 2
Drug release rate is detected:With reference to 2010 editions《Chinese Pharmacopoeia》Annex XIXD vitro drug releases degree is checked.
Take above example 16 and reference examples 2-3 microsphere tablet respectively, put in medicament dissolution instrument, in 1h, 2h, 4h, 6h,
12h, 16h, 24h are separately sampled, detect dissolution percentage with high performance liquid chromatography, and calculate the cumulative release percentage of medicine
Rate, is as a result shown in Fig. 2.
As can be seen from the figure the microsphere tablet of embodiment 16, slowly discharges in 24h.
The pharmacokinetic studies of test example 3
Inhibitory action of 3.1 compounds to mouse absolute ethyl alcohol Ulceration
1. the foundation and packet of Ulcer Models
90 ICR mouse are chosen, male and female half and half are randomly divided into 9 groups：Physiological saline group (giving isometric physiological saline),
Model group (giving isometric physiological saline), 1 group of administration (gavage gives dextral-rabeprazole, dosage 10mg/kg), administration
2 groups (gavage gives the compound of embodiment 1, dosage 10mg/kg), 3 groups of administration (gavage gives the compound of embodiment 2,
Dosage 10mg/kg), administration 4 groups (gavage gives the compound of embodiment 3, dosage 10mg/kg), 5 groups of administration (fill
Stomach gives the compound of embodiment 4, dosage 10mg/kg), administration 6 groups (gavage gives the compound of embodiment 14, administration
Dosage 10mg/kg), administration 7 groups (gavage gives the compound of reference examples 1, dosage 10mg/kg)；Successive administration 7d, Yu Mo
1h after secondary administration, in addition to physiological saline group, remaining equal gavage absolute ethyl alcohol 1ml/20g.Cervical vertebra is all taken off after 1h to put to death, and is cut open the belly,
Ligation orifice of the stomach, pylorus take out stomach behind end respectively, and 10% formaldehyde 6ml is injected into stomach, full stomach are placed in formalin fixed
30min, cuts off along greater curvature, normal saline flushing, uses filter paper suck dry moisture.The maximum in gastric ulcer face is determined using slide measure
Major diameter and maximum wide footpath, using the product of the two as ulcer index, calculate ulcer inhibition rate, ulcer inhibition rate (%)=(model
The routed index of group ulcer index-administration group)/model group ulcer index × 100%.
2. data processing：Data are with mean ± standard deviationRepresent.The comparison of each group difference is examined using t.
3. result
Each group the results are shown in Table 3 to absolute ethyl alcohol cause mouse gastric ulcer.
The each group of table 3 causes the result of mouse gastric ulcer to absolute ethyl alcohol
Compared with 1 group of administration, p#＜ 0.01, p%＜ 0.05, compared with 7 groups of administration, p* ＜ 0.05, p@＜ 0.01, with administration
2 groups are compared, p*＜ 0.05, p&＜ 0.05.
Compared with 7 groups of 1 group of administration and administration, the compound that the present invention is provided can significantly reduce the ulcer index of mouse, by
This show that, with individually giving proton pump inhibitor or proton pump inhibitor compared with the compound that allantoin is constituted, the present invention is carried
Therapeutic action of the compound of confession to mouse gastric ulcer is significantly improved, and the present invention provide by dextral-rabeprazole and for general
The compound of auspicious ketone composition to the inhibiting rate of gastric ulcer apparently higher than other compounds, and the cocrystallization sodium water that the present invention is provided
Therapeutic action of the compound to gastric ulcer is higher than other compounds.
Inhibitory action of 3.2 compounds to Rat Experimental duodenal ulcer
1. the foundation and packet of Ulcer Models
The SD rats that 90 body weight are 160-200g are chosen, water 24h is can't help in male and female half and half, the preceding fasting of experiment；Weigh mark
Afterwards, 9 groups are randomly divided into：Blank control group (giving isometric carboxymethyl cellulose), model control group (give isometric carboxymethyl
Cellulose), administration 1 group (gavage gives dextral-rabeprazole, dosage 10mg/kg), (gavage gives embodiment 1 for 2 groups of administration
Compound, dosage 10mg/kg), administration 3 groups (gavage gives the compound of embodiment 2, dosage 10mg/kg), give
(gavage gives the compound of embodiment 4 for 4 groups of medicine (gavage gives the compound of embodiment 3, dosage 10mg/kg), 5 groups of administration
Thing, dosage 10mg/kg), administration 6 groups (gavage gives the compound of embodiment 14, dosage 10mg/kg), 7 groups of administration
(gavage gives the compound of reference examples 1, dosage 10mg/kg)；1h is administered or, 10% cysteamine is subcutaneously injected respectively, uses
Measure as 280mg/kg.After 24h, side arteria carotis communis is separated under etherization, takes blood about 3ml blood supplies Gastrin to detect.So
Take off cervical approach afterwards and put to death rat, cut open the belly, ligation orifice of the stomach and pyloric ring takes out stomach and duodenum, collected after gastric juice, along greater curvature and
Mesoduodenum offside cuts off sample, observes duodenal ulcer formational situation, and measure ulcer area.
2. data processing：Data are with mean ± standard deviationRepresent.The comparison of each group difference is examined using t.
3. result
Each group the results are shown in Table 4 to experimental duodenal ulcer.
Result of each group of table 4 to Rat Experimental duodenal ulcer
Compared with 1 group of administration, p%＜ 0.01, compared with 7 groups of administration, p#＜ 0.05, p*＜ 0.01, compared with 2 groups of administration,
p&＜ 0.05, p#＜ 0.05.
Compared with 7 groups of 1 group of administration and administration, the compound that the present invention is provided can significantly reduce the duodenal ulcer of mouse
Area, it follows that, with individually giving proton pump inhibitor or proton pump inhibitor compared with the compound that allantoin is constituted, this
Therapeutic action of the compound to mouse duodenal ulcer provided is invented to significantly improve, and the present invention provide by dextrorotation thunder
Shellfish draws the compound that azoles and Teprenone are constituted to the therapeutic action of duodenal ulcer apparently higher than other compounds, and this
Therapeutic action of the cocrystallization sodium hydrate provided to duodenal ulcer is provided and is higher than other compounds.
Influence of 3.3 compounds to mouse hemorrhage of digestive tract
1. method：Mouse 90, male and female half and half, body weight 20g is randomly divided into 9 groups, every group 90, respectively blank control
Group, model control group and administration 1-7 groups.Before experiment, indocin is injected intraperitoneally by 0.1mL/10g in mouse fasting 24h.After 0.5h,
Be administered 1 group (gavage gives dextral-rabeprazole, dosage 5mg/kg), administration 2 groups (gavage gives the compound of embodiment 1,
Dosage 5mg/kg), 3 groups of administration (gavage gives the compound of embodiment 2, dosage 5mg/kg), 4 groups of (gavages of administration
Give the compound of embodiment 3, dosage 5mg/kg), administration 5 groups (gavage gives the compound of embodiment 4, dosage
5mg/kg), 6 groups (gavage gives the compound of embodiment 14, dosage 5mg/kg) are administered, (gavage, which is given, to be compareed for 7 groups of administration
The compound of example 1, dosage 5mg/kg).Above-mentioned gavage is repeated after 3h 1 time, after the 2nd gavage 2.5h, each group mouse is pressed
After the ethanol of 0.1mL/10kg gavages 50%, 1h, take off cervical vertebra and put to death mouse, solution takes stomach, with physiological saline that its gastric content is clear
Wash clean, it is fixed in 10% formalin solution, gastrointestinal tissue is taken out after 1h, bleeding area is calculated.
2. data processing：Data are with mean ± standard deviationRepresent.The comparison of each group difference is examined using t.
3. result
Each group the results are shown in Table 5 to hemorrhage of digestive tract therapeutic action.
Result of each group of table 5 to mouse hemorrhage of digestive tract therapeutic action
Compared with 1 group of administration, p%＜ 0.01, compared with 7 groups of administration, p#＜ 0.05, p*＜ 0.01, compared with 2 groups of administration,
p&＜ 0.01, p#＜ 0.01.
Compared with 7 groups of 1 group of administration and administration, the compound that the present invention is provided can significantly reduce the hemorrhage of digestive tract face of mouse
Product, it follows that, with individually giving proton pump inhibitor or proton pump inhibitor compared with the compound that allantoin is constituted, this hair
Therapeutic action of the compound of bright offer to mouse hemorrhage of digestive tract is significantly improved, and the present invention provide by dextrorotation Lei Beila
Therapeutic action of the compound of azoles and Teprenone composition to hemorrhage of digestive tract is carried apparently higher than other compounds, and the present invention
Therapeutic action of the cocrystallization sodium hydrate of confession to hemorrhage of digestive tract is higher than other compounds.
Claims (10)
1. the compound that a kind of proton pump inhibitor is constituted with gastric mucosa protectant, it is characterised in that the compound includes matter
Sub- pump inhibitor and gastric mucosa protectant, the mol ratio of the proton pump inhibitor and gastric mucosa protectant is 1-2:1-2, it is described
Proton pump inhibitor is selected from Omeprazole, Pantoprazole, Lansoprazole, Rabeprazole, Iprazole, esomeprazole, left-handed
Pantoprazole, Dexlansoprazole or dextral-rabeprazole；The gastric mucosa protectant is selected from prostanoid medicine, for Puri
Ketone, ulcerlmin or CBS.
2. compound as claimed in claim 1, it is characterised in that the gastric mucosa protectant is for prostaglandin or for Puri
Ketone.
3. compound as claimed in claim 1, it is characterised in that the proton pump inhibitor is L-pantoprazole, dextrorotation
Lansoprazole or dextral-rabeprazole.
4. compound as claimed in claim 2 or claim 3, it is characterised in that the gastric mucosa protectant is Teprenone, the matter
Sub- pump inhibitor is dextral-rabeprazole.
5. compound as claimed in claim 4, it is characterised in that the proton pump inhibitor and gastric mucosa protectant pass through hydrogen
Bond closes connection.
6. compound as claimed in claim 5, it is characterised in that the compound is cocrystallization sodium-salt hydrate, described common
It is (dextral-rabeprazole-hydrogen bond-Teprenone) ﹒ 2Na ﹒ 1H to crystallize sodium-salt hydrate formula2O, the cocrystallization sodium salt hydration
The X-ray diffraction that thing is represented with 2 θ has characteristic peak at 7.5 °, 12.4 °, 18.4 °, 22.3 °, 25.8 ° and 33.7 °.
7. a kind of microsphere tablet, including the compound described in claim any one of 1-6, it is characterised in that the microsphere tablet
Also include auxiliary material, the ratio of weight and number of the compound and auxiliary material is 1:1-2.5；The auxiliary material include following parts by weight it is each into
Point：
Polylactic-co-glycolic acid 5-10
Pregelatinized starch particulate 1-2.5.
8. microsphere tablet as claimed in claim 7, it is characterised in that the auxiliary material also includes each composition of following parts by weight：
Polypropylene glucan 3-8
Sodium alginate 0.5-1.
9. microsphere tablet as claimed in claim 8, it is characterised in that the pregelatinized starch particulate is by following parts by weight
Composition is prepared from：
Pregelatinized starch 7-8
Macrogol 600 0.5-1.
10. a kind of compound described in any one of claim 1-6 is used to treating peptic ulcer, hemorrhage of digestive tract preparing
Application in medicine.
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Cited By (2)
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| WO2023165619A1 (en) * | 2022-03-04 | 2023-09-07 | 丽珠医药集团股份有限公司 | Use of ilaprazole in regulating intestinal microecology |
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| CN107174662B (en) | 2020-12-08 |
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