CN116077609B - Yellow thick antidiarrheal quick-release pellet for treating IBD and IBS and preparation method thereof - Google Patents
Yellow thick antidiarrheal quick-release pellet for treating IBD and IBS and preparation method thereof Download PDFInfo
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- CN116077609B CN116077609B CN202211508376.4A CN202211508376A CN116077609B CN 116077609 B CN116077609 B CN 116077609B CN 202211508376 A CN202211508376 A CN 202211508376A CN 116077609 B CN116077609 B CN 116077609B
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- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940126673 western medicines Drugs 0.000 description 1
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- A—HUMAN NECESSITIES
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Abstract
The invention relates to the field of pharmaceutical preparations, in particular to a yellow thick antidiarrheal quick-release pellet for treating IBD and IBS and a preparation method thereof. The yellow-thick antidiarrheal quick-release pellets comprise active ingredients and auxiliary materials, wherein the active ingredients comprise: the auxiliary materials comprise coptis chinensis extract, magnolia bark extract, costustoot oil and dried ginger oil: adsorbents, fillers, disintegrants, and binders. The preparation method comprises the following steps: 1) Mixing cortex Magnolia officinalis extract with oleum aucklandiae and Zingiberis rhizoma oil, adding adsorbent, and making into microencapsulated oil; 2) Adding the coptis extract into the microencapsulated oil obtained in the step (1), uniformly mixing, and adding an adsorbent to prepare a solidified product; 3) Mixing the solidified material obtained in the step (2) with a filler and a disintegrating agent, and adding an adhesive to prepare a soft material; 4) Preparing the soft material obtained in the step (3) into pellets; 5) Drying the pellets obtained in the step (4), and sieving to obtain the product. The quick release yellow thick antidiarrheal pellets have quicker effect and better treatment effect than the conventional yellow thick antidiarrheal pellets.
Description
Technical Field
The invention relates to the field of pharmaceutical preparations, in particular to a yellow thick antidiarrheal quick-release pellet for treating IBD and IBS and a preparation method thereof.
Background
Inflammatory Bowel Disease (IBD) refers to the manifestation of chronic non-specific intestinal inflammation caused by unknown causes, the type of disease being ulcerative enteritis and crohn's disease, the clinical symptoms being diarrhea, abdominal pain, mucous hematochezia, etc. Inflammatory bowel disease is closely related to lifestyle habits such as high fat, high protein and high sugar diets.
At present, biological agents such as infliximab, adalimumab, tozumab and the like are mainly used for treating inflammatory bowel diseases, and the biological agents can play a role in treating inflammatory bowel diseases through different targets and mechanisms, but can relieve inflammatory bowel disease symptoms, but can generate adverse reactions such as rash, headache and the like.
Chinese patent CN113613640a discloses a new use of optically pure R-enantiomer of adrenergic β2 receptor agonist (including R-salbutamol, R-terbutaline, R-clenbuterol and R-banbuterol) for the treatment of inflammatory bowel disease and parenteral diseases including skin diseases. The patent establishes a dextran sodium sulfate-induced colonitis model, and carries out treatment by administering R-salbutamol, and a histopathological result shows that the colorectal shortening rate is reduced after the treatment of the R-salbutamol, the mucosal distortion or erosion is reduced, the inflammatory reaction of a mucous membrane and submucosa is obviously reduced, and the epithelium lining of a colonic mucosa is obviously recovered. The present invention discloses that the R-enantiomer of an adrenergic beta 2 receptor agonist for the treatment of IBD, while having fewer side effects than the racemic and other marketed drugs, still produces adverse effects.
Irritable Bowel Syndrome (IBS) is a condition associated with altered gastrointestinal function, associated with or associated with bowel movement, such as frequency and/or altered stool characteristics. Irritable bowel syndrome is divided into 4 subtypes, with diarrhea type irritable bowel syndrome being the most common. Western medicines are mainly used for treating irritable bowel syndrome by adopting comprehensive therapies such as taking antibiotics, probiotics, anxiolytic medicines and the like, but the curative effect is not outstanding and has side effects.
Chinese patent CN109310719a relates to the use of a composition based on bacteria and/or yeasts and/or other microorganisms, alone or in combination, for the treatment of symptoms of irritable bowel syndrome. The bacterial composition of this application is capable of increasing the bacterial population of lactobacillus at the intestinal microbiota level while significantly reducing the bacterial population of pathogens associated with IBS, an increased intestinal concentration of short chain fatty acids, a reduced pro-inflammatory cytokine, demonstrating that bacteria based on lactobacillus, in particular probiotic compositions comprising the species lactobacillus paracasei, can alleviate symptoms associated with IBS, in particular by ameliorating abdominal pain and discomfort associated therewith. But the therapeutic effect of using probiotics to treat IBS is not prominent.
Therefore, in order to better treat IBD and IBS, the development of a drug with small toxic and side effects, good safety and remarkable curative effect is extremely important for treating IBD and IBS. The main components of the yellow magnolia bark antidiarrheal dripping pill are coptis root extract, magnolia bark extract, dried ginger oil and costustoot oil, the main effects of the yellow magnolia bark antidiarrheal dripping pill are clearing heat, drying dampness and relieving diarrhea, and the yellow magnolia bark antidiarrheal dripping pill has remarkable treatment effects on treating acute diarrhea of damp-heat symptoms, such as diarrhea of stool or watery stool. The invention develops the yellow thick antidiarrheal quick-release pellets, which have better treatment effect and quicker treatment effect compared with the yellow thick antidiarrheal pellets.
Disclosure of Invention
Aiming at the problems, the invention aims to provide a yellow thick antidiarrheal quick-release pellet for treating IBD and IBS and a preparation method thereof, which has quick response and remarkable effect.
In order to achieve the above object, the present invention has the following technical scheme:
in one aspect, the invention provides a quick-release yellow-thickness antidiarrheal pellet for treating IBD and IBS, which comprises active ingredients and auxiliary materials, wherein the active ingredients comprise coptis chinensis extract, magnolia officinalis extract, costustoot oil and dried ginger oil, and the auxiliary materials comprise an adsorbent, a filler, a disintegrating agent and an adhesive.
Preferably, the yellow thick antidiarrheal quick release pellets comprise the following components in parts by weight: 5-93 parts of coptis extract, 5-93 parts of magnolia bark extract, 1-45 parts of costustoot oil, 1-45 parts of dried ginger oil, 5-70 parts of adsorbent, 10-50 parts of filler, 1-11 parts of disintegrating agent and 1-10 parts of adhesive.
Further preferably, the yellow thick antidiarrheal quick release pellets comprise, by weight: 30-60 parts of coptis extract, 30-60 parts of magnolia bark extract, 5-20 parts of costustoot oil, 5-20 parts of dried ginger oil, 15-60 parts of adsorbent, 10-30 parts of filler, 4-8 parts of disintegrating agent and 1-5 parts of adhesive.
Still more preferably, the yellow thick antidiarrheal quick release pellets comprise, by weight: 36 parts of coptis extract, 36 parts of magnolia bark extract, 9 parts of costustoot oil, 11 parts of dried ginger oil, 18 parts of adsorbent, 10 parts of filler, 8 parts of disintegrating agent and 2 parts of adhesive.
Preferably, the adsorbent is selected from one or more of micropowder silica gel, calcium phosphate, aluminum hydroxide, aluminum oxide, mesoporous silicon and chitosan.
Further preferably, the adsorbent is mesoporous silicon.
Still more preferably, the mesoporous silicon has a particle size of 100nm and a pore size of 4-7nm.
Preferably, the filler is selected from one or more of microcrystalline cellulose, sucrose, starch, lactose, dextrin.
Further preferably, the filler is microcrystalline cellulose.
Preferably, the disintegrating agent is selected from one or more of hydroxypropyl cellulose, hypromellose, and carboxymethyl starch sodium.
Further preferably, the disintegrant is sodium carboxymethyl starch.
Preferably, the binder is selected from one or more of polyvinylpyrrolidone, sodium carboxymethylcellulose, hydroxypropyl cellulose, ethanol, methylcellulose, ethylcellulose, sodium dodecyl sulfate.
Further preferably, the binder is sodium dodecyl sulfate.
On the other hand, the invention provides a preparation method of the yellow thick antidiarrheal quick release pellets, which comprises the following steps:
(1) Mixing cortex Magnolia officinalis extract with oleum aucklandiae and Zingiberis rhizoma oil, adding adsorbent, and making into microencapsulated oil;
(2) Adding the coptis extract into the microencapsulated oil obtained in the step (1), uniformly mixing, and adding an adsorbent to prepare a solidified product;
(3) Mixing the solidified material obtained in the step (2) with a filler and a disintegrating agent, and adding an adhesive to prepare a soft material;
(4) Preparing the soft material obtained in the step (3) into pellets;
(5) Drying the pellets obtained in the step (4), and sieving to obtain the product.
In the step (1), the microencapsulated grease is prepared by stirring, shaking, ultrasonic treatment and other modes after the adsorbent is added, preferably stirring, wherein the stirring modes include but are not limited to conventional stirring modes such as stirrer stirring, glass rod stirring, rotor stirring and the like.
In the step (2), the mixing means is selected from grinding, ball milling, mashing, homogenizing and the like, preferably grinding.
In the step (3), the mixture is stirred and the binder is added.
Preferably, in step (4), the method of making pellets is prepared using an extrusion spheronizer.
Further preferably, the rotational speed of the extrusion spheronizer is 20-50 rpm, the spheronizer frequency is 40-60Hz, and the spheronization time is 5-10 minutes.
Still more preferably, the spheronizer frequency is 50Hz.
Preferably, the drying temperature in the step (5) is 50-80 ℃ and the time is 1-4 hours, and the mixture is sieved by a 32-40 mesh sieve.
Further preferably, the drying temperature in step (5) is 65 ℃.
In still another aspect, the invention also provides the application of the yellow thick antidiarrheal quick-release pellets or the yellow thick antidiarrheal quick-release pellets prepared by the preparation method in preparing medicines for treating IBD and IBS.
Compared with the prior art, the invention has the beneficial effects that:
the invention improves the preparation process of the yellow thick antidiarrheal dripping pill, and provides a novel preparation method of the yellow thick antidiarrheal quick-release pellet, and the yellow thick antidiarrheal quick-release pellet prepared by the method has more obvious effect on treating damp-heat type inflammatory bowel disease and damp-heat diarrhea type irritable bowel syndrome, has quicker effect and has obvious curative effect superior to the conventional yellow thick antidiarrheal dripping pill.
Drawings
FIG. 1 is a diagram showing the classification of the stool characteristics of Bristol in Experimental example 3.
Detailed Description
In order to make the technical means, the creation features, the achievement of the purpose and the effect of the present invention easy to understand, the present invention will be further elucidated with reference to the specific embodiments, but the following embodiments are only preferred embodiments of the present invention, not all of them. Based on the examples in the embodiments, those skilled in the art can obtain other examples without making any inventive effort, which fall within the scope of the invention. In the following examples, unless otherwise specified, the methods of operation used were conventional, the equipment used was conventional, and the materials used in the examples were the same.
Raw material component purchasing manufacturer and model
Mesoporous silicon: purchased from the Raschi organism under the number 43244334 (particle size 100nm, pore size 4-7 nm);
chitosan nanoparticles: purchased from the Raschi organism under the number 43247962 (particle size 100nm, pore size 10-18 nm);
nano aluminum oxide: purchased from Wuhan Haishan technology, with a product number of 1344281 (particle size 100nm, pore diameter 10-20 nm);
microcrystalline cellulose: purchased from alaa Ding Shiji under the designation C104843;
sodium carboxymethyl starch: purchased from alaa Ding Shiji under the designation C105666;
sodium dodecyl sulfate: purchased from alaa Ding Shiji under the number S118592;
artificial gastric juice (no enzyme): purchased from Shanghai source leaf Biotechnology Co., ltd, cat No. R30387;
artificial intestinal fluid (no enzyme): purchased from Shanghai Seiyaku Biotechnology Co., ltd., product number R24021.
The preparation method of the coptis extract comprises the following steps:
(1) Screening rhizoma Coptidis, removing impurities, and cleaning with clear water;
(2) Drying the cleaned rhizoma coptidis at a low temperature of 40-60 ℃;
(3) Crushing the dried coptis chinensis into 20-mesh powder;
(4) Reflux-extracting Coptidis rhizoma with ethanol, drying, and refining with hydrochloric acid to obtain refined product.
The preparation method of the magnolia bark extract comprises the following steps:
(1) Screening magnolia officinalis, removing impurities, and cleaning with clear water;
(2) Drying cleaned cortex Magnolia officinalis at 40-60deg.C;
(3) Crushing dried magnolia officinalis into 20 mesh powder;
(4) Extracting effective active substances from cortex Magnolia officinalis by supercritical carbon dioxide fluid extraction device, wherein extraction pressure of cortex Magnolia officinalis extract is 21-25MPa, benzene extraction temperature is 35-40deg.C, and benzene extraction time is 3-5 hr.
The preparation method of the costustoot oil comprises the following steps:
(1) Screening and removing impurities from the costustoot oil, and cleaning the costustoot oil with clear water;
(2) Drying the cleaned costustoot oil at a low temperature of 40-60 ℃;
(3) Crushing the dried costustoot oil into 20 mesh powder;
(4) Extracting the active substances from the costus root by using a supercritical carbon dioxide fluid extraction device, wherein the extraction pressure of the costus root is 24-28MPa, the extraction temperature is 35-40 ℃, and the extraction time is 3-5 hours.
The preparation method of the dried ginger oil comprises the following steps:
(1) The dried ginger oil is screened to remove impurities, and is cleaned by clean water;
(2) Drying the cleaned rhizoma Zingiberis oil at 40-60deg.C;
(3) Crushing the dried ginger oil into 20 mesh powder;
(4) Extracting effective active substances from the dried ginger oil by using a supercritical carbon dioxide fluid extraction device, wherein the extraction pressure of the dried ginger oil is 25-29MPa, the extraction temperature is 38-42 ℃, and the extraction time is 3-5 hours.
The yellow thick antidiarrheal quick release pellets are prepared according to the following method:
(1) Fully and uniformly mixing the magnolia bark extract, the costustoot oil and the dried ginger oil in the step 1, adding mesoporous silicon into the oil phase mixture for a small amount for many times, and fully stirring until the powder microencapsulated grease with better fluidity is obtained; adding Coptidis rhizoma total alkaloids into microencapsulated oil for multiple times, grinding to mix them uniformly, and adding appropriate amount of mesoporous silica nanoparticle, chitosan nanoparticle, and nanometer aluminum oxide respectively until forming cured product with good mobile phase;
(2) Mixing the above two solidified materials with appropriate amount of microcrystalline cellulose and sodium carboxymethyl starch, stirring, adding ethanol containing sodium dodecyl sulfate as binder, and preparing soft material;
(3) Extruding the soft material in a spheronizer with the rotation speed of 20-50 r/min, the frequency of 50Hz and the spheronizing time of 5-10 min, drying the obtained pellets at 65 ℃ for 1-4h, and sieving with a 32-40 mesh sieve to obtain the mesoporous silicon pellets of the yellow thick antidiarrheal dripping pills and the alumina pellets of the yellow thick antidiarrheal dripping pills.
Example 1 preparation of yellow-thick antidiarrheal immediate-release mesoporous silicon pellets
The formulation of example 1 is as follows:
comparative example 1 preparation of yellow-thick antidiarrheal quick-release chitosan pellets
Unlike example 1, mesoporous silicon was replaced with the same amount of chitosan, and the rest was the same. The formulation of comparative example 1 is as follows:
comparative example 2 preparation of antidiarrheal quick-release alumina pellets
Unlike example 1, the mesoporous silicon was replaced with the same amount of alumina, and the rest was the same.
The formulation of comparative example 2 is as follows:
comparative example 3
Unlike example 1, no mesoporous silicon was added. The remainder are the same.
In comparative example 3, the dilution effect was achieved without adding mesoporous silicon as a component carrier, and the diluted system could not be obtained.
Experimental example 1 dissolution test of quick-release yellow-thick antidiarrheal pellets
1. Test method
Respectively using artificial gastric juice (without enzyme) and artificial intestinal juice (without enzyme) as dissolution medium, rotating at 75r/min, and operating according to the third method (small cup method) of dissolution rate measurement method 0931 of four general rules of the year 2020 of Chinese pharmacopoeia of dissolution rate measurement method; taking 15 pills of the yellow thick antidiarrheal dripping pill, weighing the pills, putting the pills into a dissolution cup, immediately starting a dissolution instrument and timing, wherein the artificial gastric juice (without enzyme) in the dissolution cup is 150mL, and the artificial intestinal juice (without enzyme) in the dissolution cup is 150mL. Sampling at 5, 10, 30, 40, 60, 90 and 120min respectively, 1.5mL each time, and simultaneously supplementing artificial gastric juice (without enzyme) and artificial intestinal juice (without enzyme) with the same temperature, and rapidly filtering the dissolved solution at each time point to obtain the sample to be detected.
Taking 10 grains of the product, precisely weighing the quality, placing the grains into a 50mL measuring flask, adding 40mL of methanol, then fixing the volume to 50mL, performing ultrasonic treatment (500W, 40 kHz) for 30 minutes, cooling, adding methanol to dilute to a scale, shaking uniformly, filtering, and taking the subsequent filtrate as a content measuring solution.
HPLC experimental conditions:
chromatographic conditions: thermo C18 column (4.6 mm. Times.250 mm,5 μm);
mobile phase: acetonitrile-0.1% phosphoric acid water, gradient elution (0-45 min,37% -77% acetonitrile; 45-48min,77% -37% acetonitrile; 48-60min,37% acetonitrile);
flow rate: 1.0mL/min;
detection wavelength: 230nm;
column temperature: 30 ℃;
sample injection amount: 10 mu L.
Sample injection is carried out on the sample to be detected respectively, the peak area is recorded, and the sample dissolution rate is calculated.
The dissolution rate was calculated as follows:
Q t ＝(1.5A t m b /A n m a )×100％
qt is the dissolution rate of a component at time t, coefficient=volume of solution in cuvette (150 ml)/volume of assay solution (50 ml) =1.5; at is the peak area At a point in time in the cuvette; an is the area of each peak in the content measuring solution; ma is the mass of the detector placed in the small cup; mb is mass of 10-grain detection object for content measurement.
The index components detected are respectively as follows: berberine hydrochloride, magnolol and magnolol, 6-gingerol, and costustoot oil are used as index components of Coptidis rhizoma extract and costunolide.
2. Test results
(1) Artificial gastric juice (no enzyme) dissolution
The artificial gastric juice (no enzyme) dissolution data are shown in the following table:
note that: g1: a yellow thick antidiarrheal dripping pill group; and G2: yellow thick antidiarrheal quick release mesoporous silicon pellet group; and G3: a yellow thick antidiarrheal quick release chitosan pellet group; and G4: yellow thick antidiarrheal quick release aluminum oxide micropill group.
The data in the table show that the dissolution rate of the components of berberine hydrochloride, magnolol, 6-gingerol, costunolide and dehydrocostuslactone in 5min is higher than that of the yellow thick antidiarrheal quick-release mesoporous silicon pellet group, the yellow thick antidiarrheal quick-release chitosan pellet group, the yellow thick antidiarrheal quick-release alumina pellet group and the yellow thick antidiarrheal pellet group, and the dissolution rate reaches 20-25min earlier than that of the yellow thick antidiarrheal pellet group.
(2) Artificial intestinal juice (without enzyme) dissolution
The data for the dissolution of artificial intestinal fluid (no enzyme) are shown in the following table:
note that: g1: a yellow thick antidiarrheal dripping pill group; and G2: yellow thick antidiarrheal quick release mesoporous silicon pellet group; and G3: a yellow thick antidiarrheal quick release chitosan pellet group; and G4: yellow thick antidiarrheal quick release aluminum oxide micropill group.
The data in the table show that the dissolution rate of the components of berberine hydrochloride, magnolol, honokiol, 6-gingerol, costunolide and dehydrocostuslactone in 5min of the yellow thick antidiarrheal quick release mesoporous silicon pellet group is higher than that of the yellow thick antidiarrheal quick release chitosan pellet group, the yellow thick antidiarrheal quick release alumina pellet group and the yellow thick antidiarrheal dripping pellet group, and the dissolution rate is 10-20min earlier than that of the yellow thick antidiarrheal dripping pellet group.
The dissolution test shows that the yellow thick antidiarrheal immediate release mesoporous silicon pellet process can effectively improve the dissolution speed of index components of the formula, improve the peak time of the index components, and lead the dissolution of partial components such as costunolide and dehydrocostuslactone to be non-progressive rising due to instability after dissolution, but the dissolution rate of each group is sequenced as follows in the whole analysis: yellow thick antidiarrheal quick release mesoporous silicon pellet group > yellow thick antidiarrheal quick release chitosan pellet group > yellow thick antidiarrheal quick release alumina pellet group > yellow thick antidiarrheal dripping pellet group.
Experimental example 2 study of the efficacy of the quick Release yellow-thick antidiarrheal pellets for treating damp-heat Inflammatory Bowel Disease (IBD)
1. Moulding and method
60 clean grade healthy male SD rats, 12-18 weeks old, weighing 200+ -20 g, were adapted to 1 week. Randomly selecting 10 blank control groups, and carrying out ordinary feed feeding and normal drinking; the remaining 50 animals were subjected to modeling of Ulcerative Colitis (UC) due to damp-heat: (1) the rats are given high-fat and high-sugar diet (common feed+200 g/L honey water is freely drunk), and the rats are alternately filled with grease (15 g/kg) and white spirit (20 ml/kg) every other day for 20 days; (2) the rats in each group were fasted on day 21 without water for 24h and were anesthetized with 3% pentobarbital sodium (1 ml/kg) by intraperitoneal injection after weighing. 50 model rats were lavage with 125mg/kg (3.75 m L/kg) of trinitrobenzene sulfonic acid (TNBS) solution; the same volume of 0.9% sodium chloride injection enema was administered to 10 rats in the placebo group. The enema (2 mm external diameter intravenous infusion tube) is inserted into anus about 6-8cm, and enema is injected. Then the tail of the rat is lifted and inverted for 1 minute, so that TNBS fully acts on the intestinal cavity to prevent the liquid from overflowing.
Model animals are randomly divided into a model control group, a yellow thick antidiarrheal dripping pill group, a yellow thick antidiarrheal quick-release mesoporous silicon pellet group, a yellow thick antidiarrheal quick-release chitosan pellet group and a yellow thick antidiarrheal quick-release alumina pellet group according to the weight after 24 hours of molding, and are continuously dosed for 14 days. The specific groupings and dosing are shown in Table 1.
Table 1 test animal grouping and administration
2. Detection index
(1) Disease Activity Index (DAI) scoring
Body weight changes, stool consistency, and fecal occult blood were recorded on days 3, 7, 10, and 14 after dosing. Dai= (weight loss + stool consistency + stool occult blood)/3, scoring table as table 2:
TABLE 2DAI scoring Table
| Weight loss rate (%) | Stool characteristics | Fecal occult blood/macroscopic hematochezia | Scoring device |
| 0 | Normal state | Normal state | 0 |
| 1-5 | Loosening | Fecal occult blood | 1 |
| 5-10 | Loosening | Fecal occult blood | 2 |
| 10-15 | Thin stool | Blood of the naked eye | 3 |
| ＞15 | Thin stool | Blood of the naked eye | 4 |
(2) Colonic mucosa injury (CMDI) scoring
After animal sacrifice, the colon was taken, cut along the mesentery, the colonic specimen was flushed with normal saline and the intestinal mucosa layer was spread upward on a white porcelain plate, the length of the colon was measured, the extent of colonic mucosa injury was observed with a magnifying glass and CMDI scoring was performed, and the scoring criteria were as shown in table 3:
TABLE 3CMDI score Table
| Scoring of | Symptoms of colon |
| 0 point | No damage |
| 1 minute | Localized congestion, edema but no ulcers |
| 2 minutes | Has ulcers but no obvious inflammation |
| 3 minutes | With ulcers and inflammation in only one place |
| 4 minutes | Has multiple ulcers and inflammations, and the size of the ulcers is less than 1cm |
| 5 minutes | Has multiple ulcers and inflammations, at least one of which has a size of > 1cm |
3. Experimental results
(1) Disease Activity Index (DAI) scoring
Compared with a blank group, DAI indexes are obviously increased (p is less than 0.001) before administration after molding is finished, which indicates that molding is successful; compared with the model group, the yellow thick antidiarrheal dripping pill group, the yellow thick antidiarrheal quick release mesoporous silicon pellet group, the yellow thick antidiarrheal quick release chitosan pellet group and the yellow thick antidiarrheal quick release alumina pellet group have obviously reduced DAI indexes (p is less than 0.05-0.001) after 3 days of treatment, which indicates that the yellow thick formula has the effect of rapidly improving the weight and the excrement of model animals; compared with the model group, and after different pellet groups are treated, the yellow thick antidiarrheal quick-release mesoporous silicon pellet group is obviously better than the yellow thick antidiarrheal dripping pill group in 3 days of administration, and the treatment effect of the yellow thick antidiarrheal quick-release chitosan pellet group and the alumina pellet group is also obviously better than that of the dripping pill group after 14 days of treatment; compared with the yellow thick antidiarrheal dripping pill group, the DAI index of the yellow thick antidiarrheal immediate release mesoporous silicon micro pill group is obviously better (p is less than 0.05), and the quick release effect of the yellow thick antidiarrheal immediate release chitosan micro pill group and the yellow thick antidiarrheal immediate release alumina micro pill group is obviously different from that of the yellow thick antidiarrheal dripping pill group only after 14 days of treatment (p is less than 0.05); compared with the yellow thick antidiarrheal quick release mesoporous silicon pellet group, the yellow thick antidiarrheal quick release chitosan pellet group and the yellow thick antidiarrheal quick release alumina pellet group have obviously weaker DAI activity index improvement degree (p is less than 0.05) after 3 days of treatment, but the curative effect after 7 days of treatment is not obviously different from that of the yellow thick antidiarrheal quick release mesoporous silicon pellet group, and the results are shown in Table 4.
The results show that each pellet group of the yellow thick antidiarrheal dripping pill and the yellow thick antidiarrheal quick release dripping pill can obviously improve the DAI score of damp-heat type IBD rats and improve the symptoms of the rats. DAI score improving effect yellow thick antidiarrheal quick release mesoporous silicon pellet group > yellow thick antidiarrheal quick release chitosan pellet group ≡yellow thick antidiarrheal quick release alumina pellet group > yellow thick antidiarrheal pellet group.
Table 4 the DAI index of each group of rats (n=10,)
in comparison with the set of models, * p＜0.05， ** p＜0.01， *** p＜0.001；
compared with the yellow thick antidiarrheal dripping pill group, # p＜0.05， ## p＜0.01， ### p＜0.001；
compared with the medium-pore silicon micropill group of the yellow thick antidiarrheal dripping pill, △ p＜0.05， △△ p＜0.01， △△△ p＜0.001；
(2) Colonic mucosa injury (CMDI) scoring
Compared with the blank group, the colon length of the rats in the model group is obviously shortened (p < 0.001), the colon tissue has obvious ulcers, and the CMDI score is obviously increased (p < 0.001); compared with a model group, the yellow-thick antidiarrheal dripping pill, the yellow-thick antidiarrheal quick-release mesoporous silicon pellet, the chitosan pellet and the alumina pellet can obviously reduce the CMDI score (p is less than 0.05-0.001), improve colon shortening (p is less than 0.05-0.001) caused by modeling, and show that the yellow-thick prescription has obvious effect of protecting colon mucous membrane injury; compared with the yellow thick antidiarrheal dripping pill group, the CMDI score and the colon length of the yellow thick antidiarrheal immediate release mesoporous silicon pellet group after treatment are obviously superior to those of the dripping pill group, and the curative effects of the yellow thick antidiarrheal immediate release chitosan pellet group and the yellow thick antidiarrheal immediate release alumina pellet group are not obviously different from those of the yellow thick antidiarrheal dripping pill group; compared with the yellow thick antidiarrheal quick release mesoporous silicon pellet group, the yellow thick antidiarrheal quick release chitosan pellet group and the yellow thick antidiarrheal quick release alumina pellet group have no significant difference in CMDI scores, but the colon length mesoporous silicon pellet group is significantly higher than the chitosan pellet group and the alumina pellet group. The results are shown in Table 5.
The results show that each pellet group of the yellow thick antidiarrheal dripping pill and the yellow thick antidiarrheal quick release dripping pill can obviously reduce the CMDI score of damp-heat type IBD rats and protect the colonic mucosa from damage. The colon protection effect is that the yellow thick antidiarrheal quick release mesoporous silicon pellet group is equal to the yellow thick antidiarrheal quick release chitosan pellet group, the yellow thick antidiarrheal quick release alumina pellet group is equal to the yellow thick antidiarrheal drop pill group, the colon mucous membrane injury (CMDI) score improving effect is that the yellow thick antidiarrheal quick release mesoporous silicon pellet group is equal to the yellow thick antidiarrheal quick release chitosan pellet group, the yellow thick antidiarrheal quick release alumina pellet group is equal to the yellow thick antidiarrheal drop pill group.
Table 5 colon length and CMDI score (n=10,)
| colon length (cm) | CMDI scoring | |
| Blank control group | 17.70±1.13 | 0.40±0.52 |
| Model control group | 14.44±1.42 | 3.10±0.99 |
| Yellow thick antidiarrheal drop pill group | 15.84±1.13 * | 2.00±0.67 ** |
| Yellow thick antidiarrheal quick-release mesoporous silicon pellet group | 17.46±1.63 ***# | 1.30±0.48 ***# |
| Yellow thick antidiarrheal quick release chitosan pellet group | 16.10±1.17 *△ | 1.60±0.52 *** |
| Yellow thick antidiarrheal quick release alumina pellet group | 16.03±10.04 *△ | 1.60±0.70 *** |
In comparison with the set of models, * p＜0.05， ** p＜0.01， *** p＜0.001；
compared with the yellow thick antidiarrheal dripping pill group, # p＜0.05， ## p＜0.01， ### p＜0.001；
compared with the medium-pore silicon micropill group of the yellow thick antidiarrheal dripping pill, △ p＜0.05， △△ p＜0.01， △△△ p＜0.001；
4. conclusion of the test
The research adopts a traditional Chinese medicine damp-heat syndrome modeling method to combine with a classical Morris method to construct an inflammatory bowel disease model, the Morris method is commonly used for researching the efficacy of various inflammatory bowel diseases such as ulcerative colitis, crohn disease and the like which are mainly pathologically expressed by colon lesions, and the efficacy of the traditional Chinese medicine is evaluated by observing the efficacy of the yellow thick antidiarrheal dropping pill and the yellow thick antidiarrheal quick-release micropill, and the efficacy of the traditional Chinese medicine is compared. By combining various indexes, the yellow thick antidiarrheal quick release mesoporous silicon pellet, the yellow thick antidiarrheal quick release chitosan pellet and the yellow thick antidiarrheal quick release alumina pellet can effectively improve the symptoms of a model rat, reduce DAI score of the model rat, inhibit colon shortening, reduce damage score of colon mucous membrane and improve colon mucous membrane pathology, but comprehensive data show that the curative effect of each group on damp-heat type inflammatory bowel disease is ordered as yellow thick antidiarrheal quick release mesoporous silicon pellet group > yellow thick antidiarrheal quick release chitosan pellet group approximately equal to yellow thick antidiarrheal quick release alumina pellet group.
Experimental example 3 research on efficacy of Huangshu anti-diarrhea quick-release pellets for treating damp-heat diarrhea type Irritable Bowel Syndrome (IBS)
1. Moulding and method
60 SPF-class SD male rats weighing 180-210g were adaptively kept for 1 week. 10 animals are randomly selected as blank control groups, and fed normally in a normal environment, fed with water and fed for 21 days. The other 50 are subjected to modeling of chronic multifactorial stress spleen and stomach damp-heat diarrhea type IBS rat model: rats were kept in the normal environment and given normal feed, chronic stress 21d. Randomly giving (1) water inhibition for 24 hours; (2) clamping the tail for 1min (placing the animal in a fixed cage, exposing the tail, clamping the tail 1cm away from the tail tip with hemostatic forceps, and making the animal give out grignard sound with strength for 1 min); (3) in a 45℃environment for 5min (placing the animals in an oven at 45℃for 5 min); (4) swimming with ice water at 4deg.C for 3min (placing the animal in a barrel containing ice water at 4deg.C for 15cm and 3min, and taking out); (5) 12h-12h day-night reversal (the lamp is not turned on in the early 8 days to make the animal in the dark state, and the lamp is turned on in the late 8 days to make the animal in the illumination state at night); (6) fasted for 24 hours; (7) horizontal oscillation for 45min (horizontal oscillation by manual force of cart, frequency 150 times/min, amplitude 10 cm). Only 1 treatment was given to the rats per day, the sequence was random, but any two consecutive days of treatment were not identical, and the rats were not expected to be stimulated for a total of 3 weeks.
After the molding is completed, the model animals are randomly divided into a model control group, a yellow thick antidiarrheal dripping pill group, a yellow thick antidiarrheal quick-release mesoporous silicon micro pill group, a yellow thick antidiarrheal quick-release chitosan micro pill group and a yellow thick antidiarrheal quick-release alumina micro pill group according to the weight, and the administration is continued for 14 days. The specific groupings and dosing are shown in Table 6.
Table 6 test animal grouping and administration
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2. Detection index
(1) Rat fecal shape scoring
Fecal trait scoring was performed prior to dosing, 7 days of dosing, and 14 days of dosing when there was more faeces in animals 6-8 morning, according to roman iv: the model rats were scored for the Bristol fecal trait classification from functional gastroenteropathy, and the scores were recorded as shown in FIG. 1.
(2) Vasoactive peptide (VIP) content assay
Serum vasoactive peptides: after the administration of the drug for 14 days, the rats were anesthetized with 3% sodium pentobarbital (10 ml/kg), the chest was opened to expose the heart, 2ml of blood was collected by a syringe, and the rats were placed in a test tube containing EDTA and centrifuged for 10min (3000 r/min), and the supernatant was collected for use.
Colonography vasoactive peptide: taking animal colon tissue to detect serum vasoactive peptide, placing a section of colon tissue with the weight of about 100mg above anus into a homogenizing tube, respectively adding 2mL of physiological saline and 0.5mL of glacial acetic acid (1 mol/L), manually homogenizing plant obvious tissue fragments, adding 0.5mL of sodium hydroxide solution (1 mol/L), uniformly mixing, taking out the tissue homogenate, centrifuging for 15min (3000 r/min), and taking the supernatant for later use.
And (3) measuring absorbance (OD value) by adopting an ELISA method according to ELISA kit instruction manual operation, and calculating the contents of the vasoactive peptides in the rat serum and colon tissues.
3. Test results
(1) Rat fecal shape scoring
Compared with a blank control group, the animal fecal scores of the model control group after molding are obviously increased (p is less than 0.001), the molding is successful, and the animal fecal character scores of the model animals of each group before administration have no obvious difference, so that the model is stable; compared with the model group, all groups with yellow thick antidiarrheal effect after treatment for 7 days and 14 days have obvious improvement on fecal characteristics (p < 0.001), which indicates that the yellow thick prescription has obvious antidiarrheal effect; compared with the yellow thick antidiarrheal dripping pill group, the fecal property score of the yellow thick antidiarrheal quick release mesoporous silicon pellet group is obviously superior to that of the dripping pill group (p is less than 0.05) after 7 days and 14 days of treatment, and the fecal typing score average value of the yellow thick antidiarrheal quick release chitosan pellet group and the yellow thick antidiarrheal quick release alumina pellet group has a descending trend but has no obvious difference compared with the dripping pill group; compared with the yellow thick antidiarrheal quick release mesoporous silicon pellet group, the fecal typing score of the yellow thick antidiarrheal quick release chitosan pellet group and the yellow thick antidiarrheal quick release alumina pellet group after 7 days of treatment are not significantly different from those of the mesoporous silicon pellet group, but are obviously higher than those of the Yu Jiekong silicon pellet group after 14 days, and the results are shown in Table 7.
The results show that each pellet group of the yellow thick antidiarrheal dripping pill and the yellow thick antidiarrheal quick release dripping pill can obviously improve the diarrhea condition of damp-heat diarrhea type IBS model animals, and the effect of improving the yellow thick antidiarrheal quick release mesoporous silicon pellet group > the yellow thick antidiarrheal quick release chitosan pellet group is approximately equal to the yellow thick antidiarrheal quick release alumina pellet group.
TABLE 7 rat fecal shape scoring
| Administration of drugsFront part | Administration is carried out for 7 days | Administration is carried out for 14 days | |
| Blank control group | 3.70±0.48 | 3.60±0.52 | 3.60±0.52 |
| Model control group | 6.10±0.74 | 6.40±0.52 | 6.60±0.52 |
| Yellow thick antidiarrheal drop pill group | 6.20±0.79 | 5.20±0.79 *** | 4.70±0.95 *** |
| Yellow thick antidiarrheal quick-release mesoporous silicon pellet group | 6.40±0.52 | 4.40±0.84 ***# | 3.90±0.74 ***# |
| Yellow thick antidiarrheal quick release chitosan pellet group | 6.40±0.70 | 4.90±0.74 *** | 4.70±0.82 ***△ |
| Yellow thick antidiarrheal quick release alumina pellet group | 6.20±0.79 | 5.00±1.05 ** | 4.60±0.70 ***△ |
In comparison with the set of models, * p＜0.05， ** p＜0.01， *** p＜0.001；
compared with the yellow thick antidiarrheal dripping pill group, # p＜0.05， ## p＜0.01， ### p＜0.001；
compared with the medium-pore silicon micropill group of the yellow thick antidiarrheal dripping pill, △ p＜0.05， △△ p＜0.01， △△△ p＜0.001；
(2) Vasoactive peptide (VIP) content
Compared with a blank group, the serum VIP and the colonic tissue VIP of the model group are obviously increased, which indicates that the VIP in the animal body of the damp-heat diarrhea type IBS model is obviously reduced; serum VIP and colonic tissue VIP were significantly improved (p < 0.001) for each treatment group compared to the model group; compared with the yellow thick antidiarrheal dripping pill group, the yellow thick antidiarrheal quick-release mesoporous silicon pellet group has obviously better effect (p is less than 0.05), and the yellow thick antidiarrheal quick-release chitosan pellet group and the yellow thick antidiarrheal quick-release alumina pellet group have no obvious difference; the results are shown in Table 8, without significant differences between the yellow thick antidiarrheal immediate release chitosan pellet group and the yellow thick antidiarrheal immediate release alumina pellet group, as compared to the yellow thick antidiarrheal immediate release mesoporous silicon pellet group.
The results show that each pellet group of the yellow thick antidiarrheal dripping pill and the yellow thick antidiarrheal quick release dripping pill can obviously improve the serum and colon VIP level in an IBS model body, the curative effect of the yellow thick antidiarrheal quick release mesoporous silicon pellet group is approximately equal to that of the yellow thick antidiarrheal quick release chitosan pellet group, and the yellow thick antidiarrheal quick release alumina pellet group is approximately equal to that of the yellow thick antidiarrheal dripping pill group.
TABLE 8 vasoactive peptide content
In comparison with the set of models, *** p＜0.001；
compared with the yellow thick antidiarrheal dripping pill group, # p＜0.05；
the experimental results of the inventor show that the yellow thick antidiarrheal dropping pill and the yellow thick antidiarrheal quick release pellets can effectively improve the stool characters of rats with damp-heat diarrhea type irritable bowel syndrome, reduce stool scores, and simultaneously reduce the concentration of serum vasoactive peptide and colon tissue vasoactive peptide caused by a model. The effect of the yellow thick antidiarrheal quick-release mesoporous silicon pellet group on improving the fecal characteristics is obviously better than that of the yellow thick antidiarrheal dripping pill in 7 days and 14 days after administration, which shows that the yellow thick antidiarrheal quick-release mesoporous silicon pellet can exert the drug effect more quickly; meanwhile, compared with the yellow thick antidiarrheal quick-release chitosan pellet group and the yellow thick antidiarrheal quick-release alumina pellet group, the yellow thick antidiarrheal quick-release mesoporous silicon pellet group has obviously better effect on reducing the vasoactive peptide in serum and colon tissues than the yellow thick antidiarrheal dripping pill. In conclusion, the yellow-thick antidiarrheal prescription has good treatment effect on rats with diarrhea-type irritable bowel syndrome due to damp-heat, and the yellow-thick antidiarrheal quick-release mesoporous silicon pellets have quicker and more obvious effects and better curative effects than the yellow-thick antidiarrheal dripping pills.
The foregoing description of the preferred embodiments of the invention is not intended to be limiting, but rather is intended to cover all modifications, equivalents, alternatives, and improvements that fall within the spirit and scope of the invention.
Claims (4)
1. The quick-release yellow-thick antidiarrheal pellets for treating inflammatory bowel disease and irritable bowel syndrome are characterized by comprising effective components and auxiliary materials, wherein the effective components consist of coptis chinensis extract, magnolia officinalis extract, costustoot oil and dried ginger oil, and the auxiliary materials comprise an adsorbent, a filling agent, a disintegrating agent and an adhesive;
the yellow thick antidiarrheal quick-release pellets comprise the following components in parts by weight: 36 parts of coptis chinensis extract, 36 parts of magnolia officinalis extract, 9 parts of costustoot oil, 11 parts of dried ginger oil, 18 parts of adsorbent, 10 parts of filler, 8 parts of disintegrating agent and 2 parts of adhesive;
the preparation method of the coptis extract comprises the following steps: screening coptis chinensis to remove impurities, and cleaning with clear water; (2) drying the cleaned coptis at a low temperature of 40-60 ℃; (3) crushing the dried coptis into 20-mesh powder; (4) Reflux-extracting Coptidis rhizoma with ethanol, drying, and refining with hydrochloric acid to obtain refined product;
the preparation method of the magnolia bark extract comprises the following steps: (1) screening magnolia officinalis to remove impurities, and cleaning with clear water; (2) drying the cleaned magnolia officinalis at a low temperature of 40-60 ℃; (3) crushing the dried magnolia officinalis into 20 mesh powder; (4) Extracting cortex Magnolia officinalis with supercritical carbon dioxide fluid extraction device at 35-40deg.C under 21-25MPa for 3-5 hr;
the preparation method of the costustoot oil comprises the following steps: screening and removing impurities from the costustoot oil, and cleaning the costustoot oil with clear water; (2) drying the cleaned costustoot oil at a low temperature of 40-60 ℃; (3) crushing the dried costustoot oil into 20 mesh powder; (4) Extracting the active substances from the costus root oil by using a supercritical carbon dioxide fluid extraction device, wherein the extraction pressure of the costus root oil is 24-28MPa, the extraction temperature is 35-40 ℃, and the extraction time is 3-5 hours;
the preparation method of the dried ginger oil comprises the following steps: (1) the dried ginger oil is screened to remove impurities, and is cleaned by clean water; (2) drying the cleaned dried ginger oil at a low temperature of 40-60 ℃; (3) crushing the dried ginger oil into 20 mesh powder; (4) Extracting effective active substances from the dried ginger oil by using a supercritical carbon dioxide fluid extraction device, wherein the extraction pressure of the dried ginger oil is 25-29MPa, the extraction temperature is 38-42 ℃, and the extraction time is 3-5 hours;
the filler is microcrystalline cellulose, the disintegrating agent is sodium carboxymethyl starch, and the adhesive is sodium dodecyl sulfate; the adsorbent is mesoporous silicon, the particle size of the mesoporous silicon is 100nm, and the pore diameter is 4-7nm.
2. The method for preparing the yellow thick antidiarrheal immediate release pellets according to claim 1, which comprises the following steps:
(1) Mixing cortex Magnolia officinalis extract with oleum aucklandiae and Zingiberis rhizoma oil, adding adsorbent, and making into microencapsulated oil;
(2) Adding the coptis extract into the microencapsulated oil obtained in the step (1), uniformly mixing, and adding an adsorbent to prepare a solidified product;
(3) Mixing the solidified material obtained in the step (2) with a filler and a disintegrating agent, and adding an adhesive to prepare a soft material;
(4) Preparing the soft material obtained in the step (3) into pellets;
(5) Drying the pellets obtained in the step (4), and sieving to obtain the product.
3. The method of claim 2, wherein the micropellet-forming process in step (4) is performed using an extrusion spheronizer.
4. Use of a yellow thick antidiarrheal immediate release pellet according to claim 1 or prepared by a method according to any one of claims 2-3 in the preparation of a medicament for the treatment of inflammatory bowel disease and irritable bowel syndrome.
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