CN113616619A - Oral colon positioning preparation for preventing and treating ulcerative colitis - Google Patents
Oral colon positioning preparation for preventing and treating ulcerative colitis Download PDFInfo
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/70—Polygonaceae (Buckwheat family), e.g. spineflower or dock
- A61K36/708—Rheum (rhubarb)
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- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/88—Liliopsida (monocotyledons)
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
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- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
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- A—HUMAN NECESSITIES
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
The invention provides an oral colon-specific preparation for preventing and treating ulcerative colitis and a preparation method thereof. The invention uses enzymatic coating material bletilla striata polysaccharide extract and pH sensitive coating material acrylic resin to coat the core layer by layer of the drug-carrying pill to form a layer-by-layer coated pellet. In an in-vitro release test, the coated pellets prepared by the method can not be released basically in a gastric acid simulating environment for 2 hours, release less in a small intestinal juice simulating environment for 3 hours, only about 10 percent, and release more than 90 percent in a colonic juice simulating environment for 7 hours.
Description
Technical Field
The invention relates to the field of traditional Chinese medicine preparations, in particular to an oral colon-specific preparation for preventing and treating ulcerative colitis, a preparation method and application thereof.
Background
Ulcerative Colitis (UC) is a chronic nonspecific inflammatory disease of colon and rectum with unclear pathogenesis, the onset age period is mostly concentrated near 20-50 years, generally, UC is clinically manifested by diarrhea, abdominal pain, tenesmus, mucopurulent bloody stool and the like, some patients can have extra-intestinal complications such as joint and liver and bile duct diseases and eye and skin injuries and the like, and even can be accompanied by systemic symptoms of different degrees, most importantly, the pathological changes are easy to repeat, the chance of canceration is 5-10 times higher than that of normal people, the disease is called cancer which is not cancer, great influence is brought to the daily life of the patients, even the life safety is threatened, and the disease is classified as one of the difficult diseases by the world health organization modern times.
Ulcerative colitis, whose pathogenesis is complex, is that multiple factors interact with each other to cause immune system disorder in vivo, and then cytokine network balance is destroyed, and a large number of inflammatory cells are activated and chemotactic and recruited to inflammation sites, and release multiple inflammatory factors, thereby causing inflammatory response of intestinal tissues. At present, the medicines for western medicine clinical treatment are mainly amino salicylic acid (5-amino-salicylic acid, 5-ASA), Glucocorticoids (GCS) and immunosuppressants, wherein sulfasalazine and mesalamine account for a large proportion, and some olsalazine and balsalazide sodium are also used. However, the curative effect is not stable enough, certain adverse reaction exists in the using process of the medicine, the long-term persistence treatment is needed, the repeated treatment is easy, the patient usually stops taking the medicine midway to cause a long course of disease, the light and medium patients usually do not easily accept the medicine, meanwhile, the problems of certain hepatorenal toxicity, medicine dependence and the like are also accompanied to bring great trouble to the patient, and the medicine has certain limitation.
UC belongs to the categories of diarrhea, intestinal weakness, dysentery, intestinal wind, visceral toxin and the like in traditional Chinese medicine, the main causes of UC are weakness of spleen and stomach, deficiency of kidney yang, retention of damp-heat in the interior, blood stasis and intestinal collaterals and the like, and the spleen and the stomach can be damaged by external infection of six excesses, improper diet and emotional disorders to induce the UC. Clinical application finds that the traditional Chinese medicine has unique advantages in UC treatment, has strong correction effect on immune disorder of patients, can realize multi-link, multi-azimuth and multi-target effects, particularly has comprehensive effects and fewer adverse reactions, becomes the key point of research of broad scholars, and shows wide application prospects. The clinical medicine for treating UC mainly comprises the prescriptions of white atractylodes rhizome, white peony root powder, ginseng, radix scutellariae, white atractylodes rhizome powder, rhubarb, peony decoction and the like, which are reduced and cut, has obvious effect and difficult recurrence, but has certain limitation, the effective administration method mainly comprises enema and suppository administration, if the prescriptions are long-term and conventional, most patients are not easy to accept and comply, great inconvenience is brought to the treatment of UC patients, and the commonly used oral Chinese patent medicines on the market, such as intestine-securing and diarrhea-relieving pills, foundation-securing and intestine-benefiting pills, intestine and stomach-calming capsules (tablets), Hudi enteric-coated capsules and the like, lack certain colon positioning performance, and the curative effect needs to be improved.
The rhubarb and bletilla tuber powder is a proved prescription which is added or reduced clinically, and has a very good effect on clinically treating gastrointestinal ulcer bleeding. The traditional Chinese medicine composition is composed of rheum officinale, bletilla striata and other medicines, and has a simple formula, wherein the rheum officinale in the formula can clear heat, purge fire, remove stagnation and relax bowels; rhizoma Bletillae has effects of clearing heat, relieving swelling, astringing, arresting hemorrhage, promoting granulation, and healing wound; the two medicines are used together to play the efficacies of clearing away heat and toxic material, removing putrefaction and promoting tissue regeneration, promoting blood circulation and removing blood stasis so as to heal ulcer, and clinical practices show that the rhubarb and the rhubarb powder have definite curative effect on gastrointestinal ulcer diseases, low recurrence rate and better development prospect.
The UC focus is mainly in the colon, and the sigmoid colon is the most common focus, and the pathological expression of the UC focus is that intestinal mucosa is infiltrated by inflammatory cells such as neutrophils for a long time to cause epithelial cell apoptosis, thereby causing damage of the intestinal mucosa and further causing phenomena such as bleeding, so that the medicine is accurately delivered to a diseased part, the retention time of the medicine is prolonged, and the repair of an ulcer surface is the key of treatment. The clinical application is mainly suppository or enema, although the curative effect is obvious, the compliance of patients is not high, the conventional common oral preparation lacks colon positioning characteristics, the focus part is difficult to reach perfectly, and the dosage is remained almost even if the conventional common oral preparation can reach the focus part, so the treatment aim is difficult to achieve.
An oral colon-targeted drug delivery system (OCTDDS) refers to a novel drug delivery system in which a drug preparation is not released in the upper gastrointestinal tract after being orally administered, so that the preparation smoothly passes through the stomach and small intestine and reaches the ileocecal part or colon part to achieve localized release of the drug so as to exert local or systemic therapeutic effect, and can be classified into pH-dependent type, time-lag dependent type, enzyme-triggered type, bioadhesive type and the like, and has wide significance in application to colonic diseases.
Disclosure of Invention
In order to solve the technical problems, the embodiment of the invention provides an oral colon-specific preparation for preventing and treating ulcerative colitis, which comprises a drug-loaded pill core, wherein an enzymatic inner layer and a pH-dependent outer layer are sequentially wrapped outside the drug-loaded pill core, wherein: the content of the raw material medicine in the drug-carrying pill core is 20-40% of the weight of the drug-carrying pill core; the weight of the enzymatic inner layer is 15-20% of the weight of the drug-loaded pellet core; the weight of the pH-dependent outer layer is 20-30% of the sum of the weight of the enzymatic inner layer and the weight of the drug-loaded pellet core; and the raw material medicines in the medicine-carrying pill core comprise effective components of rhubarb and bletilla powder, namely rhubarb total anthraquinone extract and rhubarb polysaccharide extract, which have the function of preventing and treating ulcerative colitis.
Preferably, the dosage ratio of the rhubarb total anthraquinone extract to the rhubarb polysaccharide extract is 1: 2.
Preferably, the total anthraquinone extract of rhubarb of the present invention is extracted by the method disclosed in the following chinese patent CN201711324744.9 (a method for extracting and purifying total anthraquinone of rhubarb and its application in improving cerebral ischemia-reperfusion injury) which has been applied by the present applicant. The preparation of the rhubarb polysaccharide extract of the invention comprises the following steps: the method comprises the steps of taking a rhubarb medicinal material obtained by extracting total anthraquinone of rheum officinale with the method disclosed in CN201711324744.9 as a raw material, extracting by a microwave-assisted water extraction and alcohol precipitation method, taking water as an extraction solvent, carrying out extraction at the material-liquid ratio of 1:50 and the extraction power of 500W and the extraction temperature of 80 ℃ for 15min, and carrying out decoloration and purification by S-8 macroporous resin to obtain the rhubarb extract.
Preferably, the enzymatic medicament-carrying inner layer comprises an enzymatic coating material, a plasticizer and an antisticking agent, and the dosage of the enzymatic medicament-carrying inner layer is 3-5%, 40-55% and 20-30% of the weight of the pill core respectively; the pH-dependent outer layer comprises a pH-dependent coating material, a plasticizer and an antisticking agent, and the dosage of the pH-dependent outer layer is respectively 90-110%, 10-30% and 25-50% of the weight of the pellet core.
Preferably, the enzymatic coating material is a bletilla polysaccharide extract. More preferably, the bletilla striata polysaccharide extract of the present invention is prepared by the preparation method disclosed in the following chinese patent CN201910217453.2 and the preparation method thereof, which have been filed by the applicant. The purity of the bletilla polysaccharide in the final extract is 50-70%.
Preferably, the weight of the coating of the enzymatic drug-loaded inner layer is increased by 0-20%.
Preferably, the plasticizer of the enzymatic drug-loading inner layer is triethyl citrate, and the dosage of the plasticizer is 5-10 times of the weight of the enzymatic coating material; the anti-sticking agent of the enzymatic drug-loading inner layer is micropowder silica gel, and the dosage of the anti-sticking agent is 3-5 times of the weight of the enzymatic coating material.
Preferably, the pH-dependent coating material is an acrylic resin S100.
Preferably, the coating weight gain of the pH-dependent outer layer is 20% to 50%.
Preferably, the plasticizer in the pH-dependent outer layer is triethyl citrate, and the weight of the plasticizer is 10-30% of the pH-dependent coating material; the antisticking agent in the pH-dependent outer layer is talcum powder, and the weight of the antisticking agent is 20-40% of that of the pH-dependent coating material.
In order to solve the above technical problems, an embodiment of the present invention further provides a method for preparing an oral colon-specific preparation for preventing and treating ulcerative colitis, the method comprising the steps of:
(1) preparing a drug-loaded pill core: mixing the radix et rhizoma Rhei total anthraquinone extract and radix et rhizoma Rhei polysaccharide extract with medicinal adjuvants, and making into pill core by extrusion and spheronization method;
(2) preparation of the enzymatic inner layer: dissolving an enzymatic coating material in a 2% aqueous acetic acid solution; under continuous stirring, sequentially and slowly adding a plasticizer and a lubricant in a formula amount, fully stirring to obtain an enzymatic inner-layer coating solution, and coating the drug-loaded pellet core prepared in the step (1) by using the enzymatic inner-layer coating solution to obtain an enzymatic inner-layer coated pellet;
(3) preparation of the pH-dependent outer layer: and (3) adding the pH-dependent coating material into ethanol under stirring, sequentially adding a plasticizer and a lubricant according to the formula amount after the pH-dependent coating material is completely dissolved, fully stirring to obtain a pH-dependent outer coating solution, and coating and aging the enzymatic inner-layer coated pellets prepared in the step (2) by using the pH-dependent outer coating solution to obtain the colon-specific preparation for preventing and treating ulcerative colitis.
Compared with the prior art, the preparation has the advantages that the drug-loaded pill core is sequentially coated with the enzymatic inner layer and the pH-dependent outer layer, and the enzymatic inner layer is also used in the process of loading the drug, so that the preparation has the drug auxiliary uniformity. The colon-specific preparation has strong targeting property, good stability and good curative effect, thereby achieving the purpose of preventing and treating ulcerative colitis. The preparation is convenient to take and has small side effect.
Drawings
In order to more clearly explain the technical solution of the present application, the drawings needed to be used in the embodiments will be briefly described below.
FIG. 1 is an in vitro release profile of an oral colon-specific formulation for the prevention and treatment of ulcerative colitis provided in the examples herein; in the figure, A: example 1; b: example 2; c: example 3.
FIG. 2 is an appearance diagram of a pill core of the oral colon-specific preparation for preventing and treating ulcerative colitis provided by the embodiment of the application;
FIG. 3 is an appearance diagram of an enzymatic coated pellet of an oral colon positioning preparation for preventing and treating ulcerative colitis provided in the examples of the present application.
Fig. 4 is an appearance diagram of a pH-dependent layer coated pellet of an oral colon positioning preparation for preventing and treating ulcerative colitis provided in the examples of the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail below with reference to the accompanying drawings. However, it will be appreciated by those of ordinary skill in the art that numerous technical details are set forth in order to provide a better understanding of the present application in various embodiments of the present invention. However, the technical solution claimed in the present application can be implemented without these technical details and various changes and modifications based on the following embodiments.
The oral colon targeted drug delivery system is a novel drug delivery system which is not released in the upper digestive tract after the drug preparation is orally administered, so that the preparation smoothly passes through the stomach and the small intestine and reaches the ileocecal part or the colon part to position and release the drug, thereby playing the local or systemic therapeutic effect. Can be divided into pH dependent type, time lag dependent type, enzyme trigger type, biological adhesion type and the like, and has the following advantages: (1) can prolong the action time of the medicine in vivo, reduce the administration times and improve the compliance of patients; (2) unnecessary high blood concentration is reduced, and toxic and side effects are reduced; (3) the targeting property of the medicine is increased, the medicine is convenient to take, and the curative effect is improved; (4) improving bioavailability.
The following examples simulate the gastrointestinal environment in humans for in vitro release assays. The test is carried out according to the first method of dissolution and release determination of four 0931 parts in the four parts of the Chinese pharmacopoeia (2015 edition) in 2015 edition, the dissolution media are 750ml of artificial gastric juice (pH is 1.2), artificial small intestine juice (pH is 6.8) and artificial colon juice (pH is 7.4) respectively at 37 ℃ +/-0.5 ℃ and 50rpm in 2h of artificial gastric juice, 3h of artificial small intestine juice and 7h of artificial colon juice, the determination is carried out according to the dissolution content determination method established in the earlier stage, and the average cumulative release degree is calculated.
Artificial gastric juice (ph 1.2): weighing 16.4ml of dilute hydrochloric acid, adding ultrapure water to a constant volume of 1000ml, and fully and uniformly mixing to obtain the pure hydrochloric acid. (Dilute hydrochloric acid preparation: taking 234ml hydrochloric acid, adding water to 1000ml and mixing uniformly.)
Artificial intestinal juice (ph 6.8): taking 250ml of 0.2mol/L potassium dihydrogen phosphate solution, adding 118ml of 0.2mol/L sodium hydroxide solution, diluting with water to 1000ml, and shaking up to obtain the potassium dihydrogen phosphate.
Artificial colon liquid (ph 7.6): 27.22g of monopotassium phosphate is weighed, water is added to dissolve the monopotassium phosphate into 1000ml, 50ml of monopotassium phosphate is taken, 42.4ml of 0.2mol/L sodium hydroxide solution is added, and water is added to dilute the mixture to 200ml, so that the potassium phosphate is obtained.
Example 1
Preparing raw material medicines: 1) preparing the rhubarb total anthraquinone: preparing the extract of the total anthraquinone in rhubarb according to the method disclosed in CN 201711324744.9; 2) preparation of rhizoma bletillae polysaccharide extract: preparing bletilla striata polysaccharide extract according to the method disclosed in CN 201910217453.2; 3) preparation of rhubarb polysaccharide extract: the method comprises the steps of taking a rhubarb medicinal material obtained by extracting total anthraquinone of rheum officinale with the method disclosed in CN201711324744.9 as a raw material, extracting by a microwave-assisted water extraction and alcohol precipitation method, taking water as an extraction solvent, carrying out extraction at the material-liquid ratio of 1:50 and the extraction power of 500W and the extraction temperature of 80 ℃ for 15min, and carrying out decoloration and purification by S-8 macroporous resin to obtain the rhubarb extract.
Prescription of drug-loaded pill core: comprises raw material medicines and auxiliary materials.
The raw material medicines are effective components of rhubarb which account for 20 percent of the weight of the drug-loaded pill core, wherein the total anthraquinone extract of rhubarb: the mass ratio of the rhubarb polysaccharide extract is 1: 2.
The auxiliary materials comprise: the filler microcrystalline cellulose accounts for 50% of the weight of the drug-loaded pill core, and the wetting agent water accounts for 30% of the weight of the drug-loaded pill core. However, the present embodiment should not be limited thereto, and the filler includes but is not limited to microcrystalline cellulose, and may also be one or more of lactose, pregelatinized starch, and microcrystalline cellulose; the wetting agent includes but is not limited to ultrapure water, and can be one of 10% ethanol and 20% ethanol.
Enzymatic inner layer formulation: the bletilla polysaccharide extract is a coating medicine material, the weight percentage of triethyl citrate is 25%, the micropowder silica gel accounts for 5 times of the weight of the bletilla polysaccharide extract, and the coating weight is increased by 16%.
pH-dependent outer layer recipe: methacrylic resin S100(Eudragit S100) is coating material, triethyl citrate accounts for 25% of the weight of Eudragit S100, talcum powder accounts for 25% of the weight of Eudragit S100, and the coating weight is increased by 25%.
The preparation process comprises the following steps:
1) preparing a drug-loaded pill core: uniformly mixing the effective components of the rhubarb, microcrystalline cellulose and the like according to the formula amount in advance, adding a wetting agent, preparing a soft material by a wet method, extruding and rolling to prepare 20-40-mesh pellets, and drying at 60 ℃; the appearance of the pill core is shown in figure 2;
2) preparing an enzymatic inner coating solution: dissolving rhizoma bletilla polysaccharide extract in 2% acetic acid solution, stirring continuously, sequentially adding triethyl citrate and silica gel micropowder, and stirring thoroughly to obtain enzymatic inner layer coating solution;
3) enzymatic inner coating: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; the fluidization amount is: 25-30m3H; spraying pressure: 0.8-1.2 bar; inlet temperature: 4, spraying and coating an enzymatic inner layer at 0-46 ℃, and activating at 40 ℃ for 2h after coating to obtain a bletilla striata polysaccharide coated pellet, wherein the appearance is shown in figure 3;
4) preparing a pH-dependent outer coating solution: adding Eudragit S100 into ethanol under magnetic stirring, dissolving completely, sequentially adding triethyl citrate and talcum powder, and stirring to obtain pH-dependent outer coating solution;
5) pH dependent outer coating: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; the fluidization amount is: 25-30m3H; spraying pressure: 0.8-1.2 bar; inlet temperature: spraying at 4,0-46 deg.C to coat enzyme promoting layer, and activating at 40 deg.C for 2 hr to obtain final coated pellet, with appearance shown in figure 4.
6) The in vitro release results are shown in table 1:
table 1: in vitro release results of coated pellets in different pH media (example 1)
Example 2
Preparation of total anthraquinone extract of rhubarb, polysaccharide extract of rhubarb and polysaccharide extract of bletilla striata according to the prescription of the drug-carrying pill core in example 1: comprises raw material medicines and auxiliary materials.
The effective components of the rhubarb account for 25 percent of the weight of the drug-loaded pill core, wherein the total anthraquinone of the rhubarb: rhubarb polysaccharide is 1: 2.
The auxiliary materials comprise: the filler microcrystalline cellulose accounts for 60 percent of the weight of the drug-loaded pill core, and the wetting agent water accounts for 15 percent of the weight of the drug-loaded pill core. However, the present embodiment should not be limited thereto, and the filler includes but is not limited to microcrystalline cellulose, and may also be one or more of lactose, pregelatinized starch, and microcrystalline cellulose; the wetting agent includes but is not limited to ultrapure water, and can be one of 10% ethanol and 20% ethanol.
Enzymatic inner layer formulation: the bletilla polysaccharide extract is a coating medicine material, the weight percentage of triethyl citrate is 25%, the micropowder silica gel accounts for 4 times of the weight of the bletilla polysaccharide extract, and the coating weight is increased by 10%.
pH-dependent outer layer recipe: methacrylic resin S100(Eudragit S100) as coating material, citric acid triethyl ester
The weight percentage of the ester in the Eudragit S100 is 20%, the weight percentage of the talcum powder in the Eudragit S100 is 20%, and the weight of the coating is increased by 20%.
The preparation process comprises the following steps:
1) preparing a drug-loaded pill core: uniformly mixing the effective components of the rhubarb, microcrystalline cellulose and the like according to the formula amount in advance, adding a wetting agent, preparing a soft material by a wet method, extruding and rolling to prepare 20-40-mesh pellets, and drying at 60 ℃;
2) preparing an enzymatic inner coating solution: dissolving rhizoma bletilla polysaccharide extract in 2% acetic acid solution, stirring continuously, sequentially adding triethyl citrate and silica gel micropowder, and stirring thoroughly to obtain enzymatic inner layer coating solution;
3) coating the inner layer with time lag: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; the fluidization amount is: 25-30m 3/h; spraying pressure: 0.8-1.2 bar; inlet temperature: spraying and coating an enzymatic inner layer at the temperature of 4,0-46 ℃, and activating at the temperature of 40 ℃ for 2 hours after coating to obtain a bletilla striata polysaccharide coated pellet;
4) preparing a pH-dependent outer coating solution: adding Eudragit S100 into ethanol under magnetic stirring, dissolving completely, sequentially adding triethyl citrate and talcum powder, and stirring to obtain pH-dependent outer coating solution;
5) pH dependent outer coating: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; the fluidization amount is: 25-30m 3/h; spraying pressure: 0.8-1.2 bar; inlet temperature: spraying enzyme-coated inner layer at 4,0-46 deg.C, and activating at 40 deg.C for 2 hr to obtain final coated pellet.
6) The in vitro release results are shown in table 2:
table 2: in vitro release results of coated pellets in different pH media (example 2)
Example 3
Preparation of total anthraquinone extract of rhubarb, polysaccharide extract of rhubarb and polysaccharide extract of bletilla striata according to the prescription of the drug-carrying pill core in example 1: comprises raw material medicines and auxiliary materials.
The effective components of the rhubarb account for 15 percent of the weight of the drug-loaded pill core, wherein the total anthraquinone of the rhubarb: rhubarb polysaccharide is 1: 2.
The auxiliary materials comprise: the filler microcrystalline cellulose accounts for 60 percent of the weight of the drug-loaded pill core, and the wetting agent water accounts for 25 percent of the weight of the drug-loaded pill core. However, the present embodiment should not be limited thereto, and the filler includes but is not limited to microcrystalline cellulose, and may also be one or more of lactose, pregelatinized starch, and microcrystalline cellulose; the wetting agent includes but is not limited to ultrapure water, and can be one of 10% ethanol and 20% ethanol.
Enzymatic inner layer formulation: the bletilla polysaccharide extract is a coating medicine material, the weight percentage of triethyl citrate is 20%, the micropowder silica gel accounts for 6 times of the weight of the bletilla polysaccharide extract, and the coating is increased by 20%.
pH-dependent outer layer recipe: methacrylic resin S100(Eudragit S100) as coating material, citric acid triethyl ester
The weight percentage of the ester is 30 percent of that of the Eudragit S100, the weight percentage of the talcum powder is 30 percent of that of the Eudragit S100, and the weight of the coating is increased by 30 percent.
The preparation process comprises the following steps:
1) preparing a drug-loaded pill core: mixing the rhubarb active component, microcrystalline cellulose and the like according to the prescription amount in advance, adding 30% ethanol water solution, preparing soft materials by a wet method, performing an extrusion spheronization method to obtain 20-40-mesh pellets, and drying at 60 ℃;
2) preparing an enzymatic inner coating solution: dissolving rhizoma bletilla polysaccharide extract in 2% acetic acid solution, stirring continuously, sequentially adding triethyl citrate and silica gel micropowder, and stirring thoroughly to obtain enzymatic inner layer coating solution;
3) coating the inner layer with time lag: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; the fluidization amount is: 25-30m3H; spraying pressure: 0.8-1.2 bar; inlet temperature: spraying and coating an enzymatic inner layer at the temperature of 4,0-46 ℃, and activating at the temperature of 40 ℃ for 2 hours after coating to obtain a bletilla striata polysaccharide coated pellet;
4) preparing a pH-dependent outer coating solution: adding Eudragit S100 into ethanol under magnetic stirring, dissolving completely, sequentially adding triethyl citrate and talcum powder, and stirring to obtain pH-dependent outer coating solution;
5) pH dependent outer coating: in the fluidized bed, 20g of pills are added, and the coating is carried out by a Glatt fluidized bed under the following coating conditions: bottom spray coating, flow rate: 1-1.5ml/77 s; material temperature: 33-35 ℃; amount of fluidization：25-30m3H; spraying pressure: 0.8-1.2 bar; inlet temperature: spraying enzyme-coated inner layer at 4,0-46 deg.C, and activating at 40 deg.C for 2 hr to obtain final coated pellet.
6) The in vitro release results are shown in table 3:
table 3: in vitro release results of coated pellets in different pH media (example 3)
The invention uses enzymatic coating material bletilla striata polysaccharide extract and pH sensitive coating material acrylic resin to coat the drug-carrying pill core layer by layer to form a layer-by-layer coated pellet. According to the characteristics of the micro environment of stomach, small intestine and colon when the human body is empty, firstly, the pH of different parts is different, the pH of gastric juice is about 1.0-1.2, the pH of small intestine liquid is about 6.5-7.0, and the pH of colon liquid is about 7.0-7.6; secondly, the medicine is retained for 0 to 2 hours in the stomach, 2 to 4 hours in the small intestine and 5 to 12 hours in the colon according to different retention time of the medicine in different parts. Referring to fig. 1, the coated pellets prepared by the present application can be released in vitro in a gastric acid-simulated environment for 2 hours substantially without release, in a small intestinal fluid-simulated environment for 3 hours with less release of about 10%, and in a colonic fluid-simulated environment for 7 hours with release of more than 90%.
The outermost layer of the oral colon positioning preparation-coated pellets prepared by the invention is the pH sensitive coating material acrylic resin S100 which is basically not corroded too much in the environment with the pH value less than 7, so the coated pellets are not released or basically not released in gastric juice and small intestinal juice; when in colonic fluid environment, due to the alkalescent environment more than 7 and rich flora, not only the outer pH sensitive coating layer can be corroded, but also the inner bletilla polysaccharide coating layer can be enzymolyzed, so that the medicine is exposed in the microenvironment of the colon, thereby achieving positioning and quick release and improving the curative effect. The invention is different from common oral preparations, has colon positioning performance, is different from common rectal administration and enema preparations, and has convenient administration.
The above-mentioned embodiments only express several embodiments of the present invention, and the description thereof is more specific and detailed, but not construed as limiting the scope of the present invention. It should be noted that, for a person skilled in the art, several variations and modifications can be made without departing from the inventive concept, which falls within the scope of the present invention. Therefore, the protection scope of the present invention should be subject to the appended claims.
Claims (10)
1. The utility model provides an oral colon of prevention and cure ulcerative colitis fixes a position preparation which characterized in that, includes medicine carrying pill core, enzymatic medicine carrying inner layer and pH dependence skin are wrapped up in proper order to medicine carrying pill core's outside, wherein:
the content of the raw material medicine in the medicine-carrying pill core is 20-40% of the weight of the medicine-carrying pill core;
the weight of the enzymatic drug-loaded inner layer is 15-20% of the weight of the drug-loaded pellet core;
the weight of the pH-dependent outer layer is 20-30% of the sum of the weight of the enzymatic drug-loaded inner layer and the weight of the drug-loaded pill core;
and the bulk drugs in the drug-loaded pill core are rhubarb total anthraquinone extract and rhubarb polysaccharide extract.
2. The oral colon positioning preparation for preventing and treating ulcerative colitis according to claim 1, wherein the ratio of the total anthraquinone extract and polysaccharide extract is 1: 2.
3. The oral colon positioning preparation for preventing and treating ulcerative colitis according to claim 1, wherein the enzymatic drug-loaded inner layer comprises an enzymatic coating material, a plasticizer and an antisticking agent, and the dosage of the enzymatic drug-loaded inner layer is 3-5%, 40-55% and 20-30% of the weight of the pill core respectively; the pH-dependent outer layer comprises a pH-dependent coating material, a plasticizer and an antisticking agent, and the dosage of the pH-dependent outer layer is respectively 90-110%, 10-30% and 25-50% of the weight of the pellet core.
4. The oral colon positioning preparation for preventing and treating ulcerative colitis according to claim 3, wherein the enzymatic coating material is bletilla striata polysaccharide extract.
5. The oral colon positioning preparation for preventing and treating ulcerative colitis according to claim 3, wherein the coating weight gain of the enzymatic drug-loaded inner layer is 0-20%.
6. The oral colon positioning preparation for preventing and treating ulcerative colitis according to claim 5, wherein the plasticizer of the enzymatic drug-loaded inner layer is triethyl citrate, and the amount of the plasticizer is 5-10 times of the weight of the enzymatic coating material; the anti-sticking agent of the enzymatic drug-loading inner layer is micropowder silica gel, and the dosage of the anti-sticking agent is 3-5 times of the weight of the enzymatic coating material.
7. The oral colon-specific formulation for preventing and treating ulcerative colitis according to claim 3, wherein the pH-dependent coating material is acrylic resin S100.
8. The colon-specific formulation for preventing and treating ulcerative colitis according to claim 7, wherein the weight increase of the coating of the pH-dependent outer layer is 20-50%.
9. The oral colon positioning formulation for the prevention and treatment of ulcerative colitis according to claim 8, wherein the plasticizer in the pH-dependent outer layer is triethyl citrate, the weight of the plasticizer is 10-30% of the pH-dependent coating material; the antisticking agent in the pH-dependent outer layer is talcum powder, and the weight of the antisticking agent is 20-40% of that of the pH-dependent coating material.
10. The method for preparing an oral colon-specific formulation for the prevention and treatment of ulcerative colitis according to any one of claims 1 to 9, comprising the steps of:
(1) preparing a drug-loaded pill core: mixing the radix et rhizoma Rhei total anthraquinone extract and radix et rhizoma Rhei polysaccharide extract with medicinal adjuvants, and making into pill core by extrusion and spheronization method;
(2) preparation of the enzymatic inner layer: dissolving an enzymatic coating material in a 2% aqueous acetic acid solution; under continuous stirring, sequentially and slowly adding a plasticizer and a lubricant in a formula amount, fully stirring to obtain an enzymatic inner-layer coating solution, and coating the drug-loaded pellet core prepared in the step (1) by using the enzymatic inner-layer coating solution to obtain an enzymatic inner-layer coated pellet;
(3) preparation of the pH-dependent outer layer: and (3) adding the pH-dependent coating material into ethanol under stirring, sequentially adding a plasticizer and a lubricant according to the formula amount after the pH-dependent coating material is completely dissolved, fully stirring to obtain a pH-dependent outer coating solution, and coating and aging the enzymatic inner-layer coated pellets prepared in the step (2) by using the pH-dependent outer coating solution to obtain the colon-specific preparation for preventing and treating ulcerative colitis.
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| CN101214229A (en) * | 2007-12-29 | 2008-07-09 | 天津大学 | Colon-targeted orally-administered preparation with double-layer coatings and preparation thereof |
| US20170258869A1 (en) * | 2016-03-11 | 2017-09-14 | Gateway Pharmaceutical LLC | Pharmaceutical Compositions for Colon-Specific Delivery |
| US20180000740A1 (en) * | 2016-03-11 | 2018-01-04 | Gateway Pharmaceutical LLC | Pharmaceutical compositions for colon-specific delivery |
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| CN101214229A (en) * | 2007-12-29 | 2008-07-09 | 天津大学 | Colon-targeted orally-administered preparation with double-layer coatings and preparation thereof |
| US20170258869A1 (en) * | 2016-03-11 | 2017-09-14 | Gateway Pharmaceutical LLC | Pharmaceutical Compositions for Colon-Specific Delivery |
| US20180000740A1 (en) * | 2016-03-11 | 2018-01-04 | Gateway Pharmaceutical LLC | Pharmaceutical compositions for colon-specific delivery |
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