CN102151304A - Gastric stasis system of total alkaloids of coptis and evodia rutaecarpa as well as preparation method and application thereof - Google Patents
Gastric stasis system of total alkaloids of coptis and evodia rutaecarpa as well as preparation method and application thereof Download PDFInfo
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Abstract
The invention provides a gastric stasis system of total alkaloids of coptis and evodia rutaecarpa, which has favorable bioavailability and floating performance, as well as a preparation method and application thereof, in particular relates to an intragastric floating sheet and an intragastric adhering sheet. With a famous Chinese medicine prescription, i.e. golden cornus pills as a basis, effective part groups of total alkaloids of coptis and evodia rutaecarpa in medicine materials in the prescription are extracted and purified and mixed with appropriate floating material, adhering material, foaming material, framework material and lubricating agent to obtain a mixture, and the mixture is prepared into the intragastric floating sheet and the intragastric adhering sheet by using routine techniques in the field of pharmacy.
Description
Technical field
Gastric retention system of the company's of the present invention relates to cornel total alkali and its production and application more specifically, relates to the floating in stomach sheet and the gastric adhesion tablet that connect the cornel total alkali, belongs to field of traditional Chinese.
Background technology
Connecting the cornel total alkali is the abbreviation of Rhizoma Coptidis total alkaloids and Fructus Evodiae total alkaloids, and it derives from Chinese medicine name side Zuojin Wan.Zuojin Wan is made up of with 6: 1 prescriptions Rhizoma Coptidis, Fructus Evodiae two flavor medical materials, comes from Yuan Dynasty Zhu Zhen and enjoys " danxi's experiential therapy fire six ", is " the Chinese pharmacopoeia side of recording.The heat of the fiery purgation of spleen excess stomach of Zuojin Wan liver heat removing gallbladder has regulating the stomach and sending down the abnormal ascending QI, antacid preventing or arresting vomiting effect, cures mainly pathogenic fire purging, soothing the liver, stomach function regulating, pain relieving, the pain over the hypochondriac region, and bitter taste is noisy, acid regurgitation, symptom such as desire for hot drinks not.Rhizoma Coptidis nature and flavor bitter cold in the Zuojin Wan, the fire of the clear eliminating pathogen in the liver stomach of energy, six times of consumptions, are equipped with hot Fructus Evodiae warming the liver sending down the abnormal ascending QI, and can alleviate the fraud that the Rhizoma Coptidis bitter cold is upset one's stomach as monarch drug in Fructus Evodiae.The property of two medicines, a Wen Yihan, opposite fully, Fructus Evodiae plays the usefulness of using corrigent; One hardship is fallen a suffering and is opened, and catharsis liver gastric qi machine falls and lets out the contrary gas of liver stomach altogether, works coordinate wonderful.
Modern pharmacological research shows, Rhizoma Coptidis composition pharmacology studies show that berberine has very wide antimicrobial spectrum to laboratory animal in the Rhizoma Coptidis, to dysentery bacterium, Bacillus typhi, bacillus pyocyaneus, escherichia coli, hundred larynx bacillus, bordetella pertussis, tubercule bacillus, staphylococcus, meningococcus, Hemolytic streptococcuss etc. all have than the obvious suppression effect, wherein the inhibitory action to dysentery bacterium is the strongest, and can strengthen leukocytic phagocytic activity, blood pressure lowering is arranged again, analgesic, analgesia, diuresis, abilities such as local anesthesia, in addition, vascular smooth muscle there is relexation, to the uterus, bladder, gastrointestinal smooth muscle is excitation; Berberine type alkaloids such as berberine, palmatine, jateorhizine have the obvious anti-inflammatory and anti effect (Liu Yunxiu, etc. research and development of natural products, 1998,12 (1): 87-93.).Fructus Evodiae contains alkaloid, bitter principle, volatile oil and other composition.Alkaloid comprises indoles alkaloid and quinolone alkaloid.Fructus Evodiae and alkaloid thereof have preventive and therapeutic effect to experimental peptic ulcer, confirm that subsequently the evodol extract also has the effect of tangible anti-water logging stress ulcer.Also have in recent years and discover that rutaecarpin, rutaecarpine have stronger anti-hypoxia, the effect of prolongation poisoning mice life (Zhang Mingfa, etc. natural product research, 1990,2 (4): 59; Zhang Mingfa. Chinese crude drug, 1991,14 (3): 39).Zuojin Wan is made up of above-mentioned two flavor medical materials, and digestive system is had pharmacological action widely, analgesia, antiinflammatory, antibacterial, antiulcer and gastric acid inhibitory secretion significantly.
Studies show that; Zuojin Wan has obvious inhibition helicobacter pylori (Hp), protects gastric mucosa to avoid damaging and treating the effect of gastropathy; its mechanism may be relevant with TNF-α with its inflammation-inhibiting factor IL-8 (Chen Yanfen etc. the Chinese combination of Chinese and Western medicine digests magazine; 2003,11 (3): 133-5.).Therefore, connect the main effective part group that the cornel total alkaloids is the treatment gastrointestinal disease in the Zuojin Wan.
The listing preparation is the Zuojin Wan ordinary preparation at present, mainly contains pill, capsule and tablet.Shortcomings such as these ordinary preparations preparation technology is outmoded, exist that dissolve scattered time limit is long, the effective ingredient dissolution is low, absorb relatively poor and bioavailability is low, these preparations are at the gastric time of staying short (0.5-2h) in addition, cause most of medicine to have little time to contact just being drained the mechanism influence entering intestinal, directly influence medicine and bring into play curative effect at target site with the Gastric Diseases by Spraying position.
But gastric retention system is the drug-supplying system of a kind of prolong drug at gastric transit time, comprises stomach floating system, gastric adhesive systems etc.This type of preparation energy prolong drug can improve bioavailability thereby increase medicine at stomach or duodenal degree of absorption at gastric transit time, reduces toxic and side effects, and the stabilised blood concentration reduces medicining times, improves the new formulation of clinical drug effect.Long (usually＞4h), the effect by polymer in the preparation slowly discharges medicine to the gastric retention type preparation, thereby improves bioavailability of medicament at general preparation of time of staying of gastric.
Compare with common oral preparation, gastric retention system has following advantage: 1), can reduce administration number of times to half-life medicine short or that need frequent drug administration, and easy to use, can improve the compliance that the patient takes medicine greatly; 2) reduce the blood drug level peak valley phenomenon, make blood drug level steady, abirritate and toxic and side effects; 3) improve oral drugs and absorb, avoid some drugs inactivation under the intestinal physiology environment at gastrointestinal; 4) avoid medicine local concentration height, the gastrointestinal irritation that causes improves the incomplete phenomenon of drug absorption that the individual variation gastrointestinal motility causes; 5) improve bioavailability.
Patent documentation CN101190288A discloses the slow releasing preparation of the yellow cornel total alkaloids of treatment gastric ulcer, comprises 2～20 parts of yellow cornel total alkaloidss, discharges 1～5 part of blocker, discharges 0～5 part of promoter, 1～5 part of bleach activator, 0.01～2 part of pharmaceutic adjuvant.Wherein, Rhizoma Coptidis is that solvent extraction liquid concentrates after the macroporous adsorbent resin separation and purification makes content greater than 50% Rhizoma Coptidis total alkaloids with water or sour water or ethanol, and the Fructus Evodiae extracting solution concentrates alkalization with obtaining content behind chloroform or the ethyl acetate extraction greater than 50% Fructus Evodiae total alkaloids.Used macroporous adsorbent resin in this method for extraction and purification, certainly will strengthen operation easier, improve production cost, and organic residual increase in the alkaloid that can cause extracting; Use chloroform or ethyl acetate extraction in the alkali liquor environment, all can cause the residual or organic acid of toxic solvent residual; Simultaneously, said preparation belongs to the gastric slow releasing preparation, and its gastric transit time is very short, and the effect of topical therapeutic or increase drug absorption is subjected to certain limitation.
The extract powder that has also disclosed with Rhizoma Coptidis and Fructus Evodiae among the people such as prior art such as Zhou Yisheng " development of left golden floating slowly releasing sheet " is an active component, is people such as the delay floating slowly releasing sheet of adjuvant preparation and Liu Wen " stomach float type cornel connects the preliminary study of slow releasing tablet " with hydroxypropyl emthylcellulose (HPMC), sodium carboxymethyl cellulose (CMC-Na), octadecanol, polyethylene glycol 6000 (PEG 6000).The alkaloid that these two pieces of articles extract is lower, and owing to do not use foaming agent, causes rising of preparation to be floated the time elongated (about 2min), has obviously influenced the flotation property of preparation, reduces bioavailability of medicament.
Also have, people's such as Xia Yanjiao " connecting the preparation of cornel total alkali gastric patch and the research of release in vitro ", too simple in the literary composition to extraction and purification process, unlikely prepare effective site, do not set forth supplementary product kind and proportioning, only studied the Release Performance of preparation, do not studied the flotation property of preparation, retention performance remains to be investigated.
People's such as Zhao Xinhui " hydroxypropyl emthylcellulose is to the flotation property of the golden intragastric floating tablets in a left side and the influence of drug release characteristics " disclosed the floating in stomach sheet with Rhizoma Coptidis extract and Fructus Evodiae extract preparation, but in the literary composition and undeclared method for extraction and purification and active constituent content, and said preparation to work the time of floating longer, the flotation property (rising among the present invention floated the time less than 5 seconds) that this will have a strong impact on preparation reduces bioavailability of medicament.
In addition, above-mentioned patent and document also have a common shortcoming, from given experimental result, can't realize real Entogastric lingering effect at all, more do not propose the effective interior evaluating method of prepared preparation and prove it in animal or human's body gastrointestinal delay behavior, true effect remains further to be verified.
In order to overcome above defective of the prior art, the present invention proposes by extracting effective part group total alkaloids in the Zuojin Wan prescription---connect the cornel total alkali, adopt the combination of particular excipient, it is prepared into floating in stomach preparation or gastric adhesion preparation, and by its investigation in the delay behavior of dog and human gastrointestinal tract, confirmed that said preparation can be trapped in the gastric juice by the company's of making cornel total alkali for a long time, the company's of avoiding cornel total alkali enters the small intestinal section by metabolism, improve the relative bioavailability that connects the cornel total alkali, further make through focus of medicine and slowly release, guarantee giving full play to of drug effect, effectively treat acute or chronic gastritis, disease of stomach such as peptic gastric ulcer and gastric cancer.
Summary of the invention
The object of the invention provides a kind of gastric retention system with company's cornel total alkali of good biological availability and flotation property, based on Chinese medicine name side Zuojin Wan, company's cornel total alkali effective part group in extraction, the purification prescription medical material, with suitable floating material, adhesion material, expanded material, framework material, mix lubricant, make with the routine techniques of pharmaceutical field.
An object of the present invention is to provide a kind of method that connects the cornel total alkali for preparing, may further comprise the steps:
(1) prepare the method for Rhizoma Coptidis total alkaloids:
Getting the Rhizoma Coptidis coarse powder, is solvent with the 0.1-2.0% dilute acid solution, and described solvent is a kind of or its combination in any from the aqueous solution of hydrochloric acid, sulphuric acid, phosphoric acid preferably; Flood percolation after 24 hours, collect 2～12 times of amounts liquid of filtering, regulating pH value with alkali is 3～6, and standing over night filters, filtrate adds, acid for adjusting pH value to 1～2, and adding sodium chloride is an amount of, and standing over night filters, precipitation washes with water to pH value 5, and drying under reduced pressure is pulverized, and promptly gets Rhizoma Coptidis total alkaloids.
(2) prepare the method for Fructus Evodiae total alkaloids:
Get the Fructus Evodiae coarse powder, add 30～95% alcohol reflux 1～3 time, each 1～3 hour, filter while hot, merge ethanol liquid, concentrating under reduced pressure stirs the adding sodium hydroxide, and making concentration is 0.5～5%, standing over night, filter, precipitation washes with water to neutrality, and drying promptly gets Fructus Evodiae total alkaloids.
(3) Rhizoma Coptidis total alkaloids is mixed by 1: 1～6: 1 with Fructus Evodiae total alkaloids.
Further preferable methods comprises:
(1) prepare the method for Rhizoma Coptidis total alkaloids:
Getting Rhizoma Coptidis powder and be broken into coarse powder, is solvent with 1.0% aqueous hydrochloric acid solution, floods percolation after 24 hours, collects 8 times of amounts liquid of filtering.Percolate is regulated pH value to 5 with sodium hydrate particle, and standing over night filters, and filtrate adds the 1mol/L dilute hydrochloric acid and regulates pH value to 1～2, and it is 10% that adding sodium chloride makes final concentration, and standing over night filters, and precipitation washes with water to pH value 5, and drying under reduced pressure is pulverized, promptly.
(2) prepare the method for Fructus Evodiae total alkaloids:
Get the Fructus Evodiae coarse powder, add 80% alcohol reflux 3 times, each 1.5 hours, for the first time add 6 times of 80% ethanol, second and third time adds 5 times of 80% ethanol, filters while hot, merge ethanol liquid, concentrating under reduced pressure stirs the adding sodium hydroxide, making concentration is 1.5%, standing over night filters, and precipitation washes with water to neutrality, through further refining, promptly.
(3) Rhizoma Coptidis total alkaloids and Fructus Evodiae total alkaloids were pressed 1: 1～6: 1, mixed in preferred 6: 1, promptly get the cornel total alkali that connects of the present invention.
The gastric retention system of the company's of an object of the present invention is to provide cornel total alkali comprises floating in stomach preparation, gastric adhesion preparation etc. further.
The present invention connects the gastric retention system of cornel total alkali, comprises the combination of floating material, adhesion material, expanded material, framework material, also can comprise for example lubricant of pharmaceutically acceptable other excipient.
Floating material is selected from a kind of or its combination in any in octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flava, the Glyceryl Behenate, is preferably stearic acid.
Adhesion material is selected from a kind of or its combination in any in carbopol, carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, dextran sulfate, the polyglutamic acid, is preferably carbopol 934P.
Expanded material is selected to a kind of or its combination in any in carbonate, bicarbonate, citric acid, the tartaric acid, is preferably basic magnesium carbonate.
Framework material is selected from a kind of or its combination in any in hydroxypropyl emthylcellulose, polyvinylpyrrolidone, ethyl cellulose, polyvinyl alcohol, the acrylic resin, be preferably a kind of of hydroxypropyl emthylcellulose or its mixture, the combination of the combination of HPMC E50 and HPMC k4M or HPMC E50 and HPMC K15M more preferably most preferably is weight ratio and is the combination of 4: 3 HPMC E50 and HPMC k4M or HPMC E50 that weight ratio is 25: 14 and the combination of HPMC K15M.
Lubricant is selected from a kind of or its mixture in magnesium stearate, sodium stearate, the Pulvis Talci.
Floating in stomach preparation of the present invention mainly comprises 1～10 part of 1～10 part of 1～20 part of company's cornel total alkali, floating material, framework material, 1～10 part of the expanded material based on the weight portion meter; Further preferably connect 0.2 part of 10 parts of cornel total alkalis, 2 parts of floating materials, 3.5 parts of framework materials, 2 parts of expanded materials and lubricant.
Gastric adhesion preparation of the present invention is 0.1～5 part of 0.1～5 part of 1～20 part of company's cornel total alkali, adhesion material, expanded material, 1～10 part of the framework material that mainly comprises based on the weight portion meter; Further preferably connect 0.1 part of 10 parts of cornel total alkalis, 0.6 part of adhesion material, 0.8 part of expanded material, 7.8 parts of framework materials and lubricant.
Gastric retention system comprises that oral Entogastric lingering capsule such as capsules floating in stomach, gastric adhere to capsule; Oral Entogastric lingering tablet such as floating in stomach sheet, gastric adhesion tablet.
A kind of floating in stomach sheet that connects the cornel total alkali is provided in a preferred embodiment of the invention, has comprised the component of following weight portion:
Connect 100 parts of cornel total alkalis
20 parts of HPMC E50
15 parts of HPMC k4M
20 parts of stearic acid
20 parts of basic magnesium carbonates
1.8 parts of magnesium stearate.
A kind of gastric adhesion tablet that connects the cornel total alkali is provided in a preferred embodiment of the invention, has comprised the component of following weight portion:
Connect 100 parts of cornel total alkalis
50 parts of HPMC E50
28 parts of HPMC K15M
6 parts of carbomer 934 P
8 parts of basic magnesium carbonates
1 part of magnesium stearate.
Another object of the present invention provides a kind of method for preparing the gastric retention system that connects the cornel total alkali, may further comprise the steps that active component connects the cornel total alkali, excipient is crossed 80～100 mesh sieves, and direct compression makes behind the mix homogeneously; Perhaps adopt wet granulation or dry granulation technology tabletting to make.
Studies have shown that the principal element that influences the gastric retention system controlled release preparation is to select suitable floating material, adhesion material, expanded material, framework material.Though instructed the floating in stomach preparation of Rhizoma Coptidis extract and Fructus Evodiae extract in the prior art.But, the combination of different active component and the different concrete compositions of above-mentioned material, be not apparently, the inventor is by performing creative labour and secular selection, obtained the preferred embodiments of the invention, it has better bioavailability and slow release effect than the floating in stomach preparation that discloses in the prior art.
In the gastric controlled release preparation, select HPMC E50 and the suitable proportioning of HPMC K15 for use, the speed of may command hydration and the length that keeps gel time, make said preparation show the shortest rising the time of floating and best lasting flotation time, use the carbomer 934 P of suitable proportioning can strengthen the stick performance of said preparation, can obtain the best flotation time with the HPMC coupling at gastric.Find in the research, in this preparation, use basic magnesium carbonate,, can shorten said preparation and work the time of floating because its proper density is compared with sodium bicarbonate, calcium carbonate commonly used.
Another object of the present invention also provides the gastric retention system that connects cornel total alkali purposes in the medicine of gastroenteropathys such as the stomachache of preparation treatment acute and chronic, gastritis, gastric ulcer and acute chronic enteritis, and the described gastric retention system that connects the cornel total alkali is selected from floating in stomach preparation, gastric adhesion preparation.
Beneficial effect of the present invention
Company's cornel total alkali gastric retention system that the present invention makes shows significant Entogastric lingering in testing in vivo and in vitro, drug slow discharges, can improve the medicine local action time and improve bioavailability, reach expection gastric slow release long-acting purpose, and stable preparation process, quality controllable, favorable reproducibility is fit to large-scale continuous production.
Description of drawings:
Fig. 1: behind the floating tablets and ordinary tablet of oral 99mTc labelling, SPECT human body flat scanning figure.The flat scanning figure of Fig. 1-1 when 1-14 represents that respectively the experimenter takes medicine back 5min, 30min, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h and 6.5h.
Fig. 2: behind the floating tablets and ordinary tablet of oral 99mTc labelling, SPECT human body faulted scanning pattern.The faulted scanning pattern of Fig. 2-1 when 2-9 represents that respectively the experimenter takes medicine back 5min, 1.25h and 6.5h.Fig. 2-1 expression 5min coronalplane figure; Fig. 2-2 expression 5min sagittal view; Fig. 2-3 expression 5min cross-sectional view; Fig. 2-4 expression 1.25h coronalplane figure; Fig. 2-5 expression 1.25h sagittal view; Fig. 2-6 expression 1.25h cross-sectional view; Fig. 2-7 expression 5.5h coronalplane figure; Fig. 2-8 expression 5.5h sagittal view; Fig. 2-9 expression 5.5h cross-sectional view.
Specific embodiment
Below by specific embodiment, further specify the present invention, following embodiment only is used to the present invention is described and to the present invention without limits.
Embodiment 1:
The extraction process of Rhizoma Coptidis total alkaloids
Getting Rhizoma Coptidis powder and be broken into coarse powder, is solvent with 1.0% aqueous hydrochloric acid solution, floods percolation after 24 hours, collects 8 times of amounts liquid of filtering.Percolate is regulated pH value to 5 with sodium hydrate particle, and standing over night filters, and filtrate adds the 1mol/L dilute hydrochloric acid and regulates pH value to 1～2, and it is 10% that adding sodium chloride makes final concentration, and standing over night filters, and precipitation washes with water to pH value 5, and drying under reduced pressure is pulverized, promptly.
Embodiment 2:
The extraction process of Fructus Evodiae total alkaloids
Get the Fructus Evodiae coarse powder, add 80% alcohol reflux 3 times, each 1.5 hours, for the first time add 6 times of 80% ethanol, second and third time adds 5 times of 80% ethanol, filters while hot, merge ethanol liquid, concentrating under reduced pressure stirs the adding sodium hydroxide, making concentration is 1.5%, standing over night filters, and precipitation washes with water to neutrality, through further refining, promptly.
Embodiment 3:
The Fructus Evodiae total alkaloids of embodiment 2 mixed with weight ratio with the Rhizoma Coptidis total alkaloids of embodiment 1 at 6: 1 obtain the used company's cornel total alkali of following examples.
Embodiment 4:
Connect the preparation of cornel total alkali in-stomach floating type patch
Specification: 1000
Prescription:
Connect cornel total alkali 200g
HPMC?E50 40g
HPMC?K4M 30g
Stearic acid 40g
Basic magnesium carbonate 40g
Magnesium stearate 3.6g
Preparation technology: according to the consumption in the above prescription, supplementary material is pulverized, taken by weighing recipe quantity principal agent adjuvant and cross 80 mesh sieves, with the equivalent principal agent adjuvant mix homogeneously that dilution method will be except magnesium stearate that progressively increases, add 95% ethanol system soft material, 24 mesh sieves are granulated, and 50 ℃ of following constant temperature forced air dryings add 1% magnesium stearate at last, mixing, granulate, tabletting, promptly.
Embodiment 5:
Connect the preparation of cornel total alkali gastric adhesive type patch
Specification: 1000
Prescription:
Connect cornel total alkali 100g
HPMC?E50 50g
HPMC?K15M 28g
Carbomer 934 P 6g
Basic magnesium carbonate 8g
Magnesium stearate 1g
Preparation technology: according to the consumption in the above prescription, supplementary material is pulverized, taken by weighing recipe quantity principal agent adjuvant and cross 80 mesh sieves, with the equivalent principal agent adjuvant mix homogeneously that dilution method will be except that magnesium stearate that progressively increases, 95% ethanol is wetting agent, wet granulation, 30 mesh sieves are granulated, drying is one hour under 50 ℃, and 30 mesh sieve granulate add magnesium stearate at last, mixing, granulate, tabletting, promptly.
Embodiment 6:
Connect γ-scintiscan tracer study in the cornel total alkali floating in stomach sheet human body
The ordinary tablet preparation of selecting company's cornel total alkali in-stomach floating type patch of radioelement 99mTc labelling embodiments of the invention 4 for use and connecting the cornel total alkali has radioactivity and connects cornel total alkali in-stomach floating type patch and ordinary tablet for the 3mci/ sheet.
Two volunteers are respectively at being tried unified feed in preceding 30 minutes.Use the floating matrix of company's cornel total alkali and the ordinary tablet of 100ml water delivery service a slice 99mTc labelling behind the full abdomen respectively, logical immediately SPECT monitor is dynamically taken pictures and is observed and write down preparation position under one's belt.In the test, the experimenter can freely walk about and carry out normal activity, can freely intake, and does not allow feed, and unified sitting posture or the stance of keeping forbids couching and aggravating activities.Take medicine in back 7 hours every monitoring and taking pictures once under SPECT in 30 minutes.
Behind the floating tablets and reference plate of oral 99mTc labelling, on the SPECT screen, can clearly observe floating preparation and two bright spots of common reference plate, as shown below, Fig. 1-1～Fig. 1-14 is people's body plane scintigram, and Fig. 2-1～Fig. 2-9 is the human body faulted scanning pattern.
Take medicine the back by the 5min faulted scanning pattern as can be known, tried floating tablets with reference to ordinary tablet all at gastric.Ordinary tablet activity about 1 hour descends and disintegrate becomes seedless cloud shape, and a remaining bright spot shows that floating tablets is still at gastric.Connect cornel total alkali floating tablets and be respectively 330min and 360min two intravital time lags of volunteer.Above result shows, connects cornel total alkali floating tablets and keeps the time of floating state to reach 5.5 hours at gastric, has reached the preparation purpose of design substantially, makes the floating in stomach performance of preparation obtain checking.
Embodiment 7:
The bioavailability of product of the present invention and reference product and flotation property comparative study.
Comparative Examples 5 is from the prescription in people such as Xia Yanjiao " connecting the preparation and the research of release in vitro of cornel total alkali gastric patch " owing to do not provide appropriate proportioning in the literary composition, existing according to the present invention in the ratio of principal agent and adjuvant, select the prescription of the document to be prepared.
Comparative Examples 6 is " stomach float type cornel connects the preliminary study of slow releasing tablet " from people such as Liu Wen, according to the preparation of document prescription proportioning.
Comparative Examples 7 is from the prescription in people such as Zhao Xinhui " hydroxypropyl emthylcellulose is to the flotation property of the golden intragastric floating tablets in a left side and the influence of drug release characteristics ", owing to do not provide appropriate proportioning in the literary composition, the ratio of principal agent and adjuvant in now according to the present invention selects the prescription of the document to be prepared.
Comparative Examples 8 is from the development process of the present invention, garbled preparation condition.
The prescription ratio of components of table 1: embodiment and Comparative Examples
As shown in Table 1, the ratio of adjuvant in this preparation is up to 75% in the Comparative Examples 6, and in this research, the adjuvant ratio only is 42%, and this will help improving the content of principal agent in the preparation, reduces patient's medication dose and number of times, increases patient's compliance.Comparative Examples 5 and Comparative Examples 7 all do not provide recipe ratio, so adopt the ratio among the present invention to prepare, compare flotation property.
Normal experiment technology according to this area, external that has investigated several preparations is respectively floated area (AUC) and relative bioavailability (selecting berberine hydrochloride, palmatine hydrochloride, Jatrorrhizine chloride, rutaecarpine is that index components is measured) under time, the total burst size of external 8h, interior flotation time of body, the time front of blood concentration, the result is as shown in table 2, preparation among the embodiment 4 all obviously is being better than Comparative Examples aspect each index, conclusion proves that the combination of excipient of the present invention and active component has best flotation property and bioavailability degree.
Each evaluation index of table 2: embodiment and Comparative Examples is (n=3, numerical value are mean) relatively
Claims (10)
1. company's cornel total alkali gastric retention system is characterized in that comprising even cornel total alkali, floating material, adhesion material, expanded material, framework material and lubricant.
2. according to company's cornel total alkali gastric retention system of claim 1, it is characterized in that gastric retention system comprises floating in stomach preparation, gastric adhesion preparation etc., comprise that further capsules floating in stomach, gastric adhere to capsule, floating in stomach sheet or gastric adhesion tablet.
3. according to company's cornel total alkali gastric retention system of claim 1 or 2, it is characterized in that floating material is selected from a kind of or its combination in any in octadecanol, hexadecanol, glyceryl monostearate, spermol, stearyl alcohol, stearic acid, Cera Flava, the Glyceryl Behenate, is preferably stearic acid; Adhesion material is selected from a kind of or its combination in any in carbopol, carbopol, sodium carboxymethyl cellulose, hydroxypropyl cellulose, hyaluronic acid, dextran sulfate, the polyglutamic acid, is preferably carbopol 934P; Expanded material is selected to a kind of or its combination in any in carbonate, bicarbonate, citric acid, the tartaric acid, is preferably basic magnesium carbonate; Framework material is selected from a kind of or its combination in any in hydroxypropyl emthylcellulose, polyvinylpyrrolidone, ethyl cellulose, polyvinyl alcohol, the acrylic resin, be preferably a kind of of hydroxypropyl emthylcellulose or its mixture, the combination of the combination of HPMC E50 and HPMC k4M or HPMC E50 and HPMC K15M more preferably most preferably is weight ratio and is the combination of 4: 3 HPMC E50 and HPMC k4M or HPMCE50 that weight ratio is 25: 14 and the combination of HPMC K15M; Lubricant is selected from a kind of or its mixture in magnesium stearate, sodium stearate, the Pulvis Talci.
4. according to company's cornel total alkali gastric retention system of claim 3, it is characterized in that it is the floating in stomach preparation, comprise 1～10 part of 1～10 part of 1～20 part of company's cornel total alkali, floating material, framework material, 1～10 part of expanded material based on the weight portion meter; Further preferably connect 0.2 part of 10 parts of cornel total alkalis, 2 parts of floating materials, 3.5 parts of framework materials, 2 parts of expanded materials and lubricant.
5. according to company's cornel total alkali gastric retention system of claim 3, it is characterized in that it is 0.1～5 part of 0.1～5 part of 1～20 part of company's cornel total alkali, adhesion material, expanded material, 1～10 part of the framework material that comprises based on the weight portion meter for the gastric adhesion preparation; Further preferably connect 0.1 part of 10 parts of cornel total alkalis, 0.6 part of adhesion material, 0.8 part of expanded material, 7.8 parts of framework materials and lubricant.
6. cornel total alkali floating in stomach sheet even is characterized in that comprising the component of following weight portion:
Connect 100 parts of cornel total alkalis
20 parts of HPMC E50
15 parts of HPMC k4M
20 parts of stearic acid
20 parts of basic magnesium carbonates
1.8 parts of magnesium stearate.
7. cornel total alkali gastric adhesion tablet even is characterized in that comprising the component of following weight portion:
Connect 100 parts of cornel total alkalis
50 parts of HPMC E50
28 parts of HPMC K15M
6 parts of carbomer 934 P
8 parts of basic magnesium carbonates
1 part of magnesium stearate.
8. aforesaid right requires each described preparation method that connects the cornel total alkali, it is characterized in that may further comprise the steps:
(1) prepare the method for Rhizoma Coptidis total alkaloids: getting the Rhizoma Coptidis coarse powder, is solvent with 0.1～2.0% dilute acid solution, preferably a kind of or its combination in any from the aqueous solution of hydrochloric acid, sulphuric acid, phosphoric acid, flood percolation after 24 hours, collect 2～12 times of amounts liquid of filtering, regulating pH value with alkali is 3～6, standing over night filters, and filtrate adds, acid for adjusting pH value to 1～2, adding sodium chloride is an amount of, standing over night, filter, precipitation washes with water to pH value 5, drying under reduced pressure, pulverize, promptly get Rhizoma Coptidis total alkaloids;
(2) prepare the method for Fructus Evodiae total alkaloids: get the Fructus Evodiae coarse powder, add 30～95% alcohol reflux 1～3 time, each 1～3 hour, filter while hot, merge ethanol liquid, concentrating under reduced pressure stirs the adding sodium hydroxide, making concentration is 0.5～5%, standing over night filters, and precipitation washes with water to neutrality, drying promptly gets Fructus Evodiae total alkaloids;
(3) Rhizoma Coptidis total alkaloids is mixed by 1: 1～6: 1 with Fructus Evodiae total alkaloids, i.e. the company's of getting cornel total alkali.
9. the preparation method that connects the cornel total alkali according to claim 8 is characterized in that may further comprise the steps:
(1) prepare the method for Rhizoma Coptidis total alkaloids: get Rhizoma Coptidis powder and be broken into coarse powder, the aqueous hydrochloric acid solution with 1.0% is a solvent, floods percolation after 24 hours, collects 8 times of amounts liquid of filtering; Percolate is regulated pH value to 5 with sodium hydrate particle, and standing over night filters, and filtrate adds the dilute hydrochloric acid of 1mol/L and regulates pH value to 1～2, it is 10% that adding sodium chloride makes final concentration, and standing over night filters, and precipitation washes with water to pH value 5, drying under reduced pressure is pulverized, and promptly gets Rhizoma Coptidis total alkaloids;
(2) prepare the method for Fructus Evodiae total alkaloids: get the Fructus Evodiae coarse powder, add 80% alcohol reflux 3 times, each 1.5 hours, for the first time add 6 times of 80% ethanol, second and third time adds 5 times of 80% ethanol, filters while hot, merge ethanol liquid, concentrating under reduced pressure stirs the adding sodium hydroxide, making concentration is 1.5%, standing over night filters, and precipitation washes with water to neutrality, drying promptly gets Fructus Evodiae total alkaloids;
(3) Rhizoma Coptidis total alkaloids and Fructus Evodiae total alkaloids were pressed 1: 1～6: 1, mixed in preferred 6: 1, i.e. the company's of getting cornel total alkali.
10. each described cornel total alkali gastric retention system purposes in the medicine of gastroenteropathys such as the stomachache of preparation treatment acute and chronic, gastritis, gastric ulcer and acute chronic enteritis that connects of above claim.
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