CN110337302B - Horse chestnut extract and linaclotide composition - Google Patents
Horse chestnut extract and linaclotide composition Download PDFInfo
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- CN110337302B CN110337302B CN201880011039.XA CN201880011039A CN110337302B CN 110337302 B CN110337302 B CN 110337302B CN 201880011039 A CN201880011039 A CN 201880011039A CN 110337302 B CN110337302 B CN 110337302B
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- linaclotide
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/10—Peptides having 12 to 20 amino acids
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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
- A61P1/08—Drugs for disorders of the alimentary tract or the digestive system for nausea, cinetosis or vertigo; Antiemetics
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Abstract
Horse chestnut extract and linaclotide composition preparation and its application are provided. The preparation comprises sustained-release pellets, which comprise 10.0-75.0% of horse chestnut extract, 20.0-88.0% of linaclotide, 0.8-3.0% of molding material and 1.0-6.0% of sustained-release material. The preparation can exert synergistic effect of horse chestnut extract and linaclotide, has slow release effect, can improve the treatment effect of irritable bowel syndrome, reduce the dosage of guanylate cyclase-C receptor agonist, reduce the toxic and side effects of guanylate cyclase-C receptor agonist, and improve the compliance of patients.
Description
Technical Field
The invention relates to the technical field of medicines, in particular to a composition of a chestnut tree extract and linaclotide.
Technical Field
Irritable bowel syndrome (irritable bowel syndrome, IBS) is a bowel dysfunction disease mainly manifested by chronic recurrent abdominal pain, diarrhea, constipation, etc., and is clinically manifested by urge to feel endless, constipation, alternate constipation and diarrhea, abdominal pain, diarrhea, abdominal distention, borborygmus and flatulence.
IBS is a global disease, the prevalence of people in the middle-aged 20-40 years is the majority, wherein the prevalence of men is higher, the ratio of men to women is 2:1, and the number of patients with IBS is continuously increasing. Epidemiological examination results in North America show that the incidence of IBS in healthy people is as high as 27%, 10% -20% in European and American countries, the incidence is highest in European and developed countries, and secondly Asians, and the incidence of IBS is lowest in African countries such as south Africa. At present, large-scale epidemiological investigation about IBS has not been carried out in China, but it is quite common that some regional IBS patients account for about 1/3 of those in the digestion clinic.
Human perception of IBS has been 150 years old, but the etiology and pathogenesis of the disease are not completely elucidated, and these complex clinical features are difficult to explain by simple anatomical and biochemical results, so that most students consider that the physiological imbalance of central nervous and intestinal plexus is caused by various reasons, and the abnormal brain-intestinal axis causes the imbalance of neurotransmitter separation, thus causing a series of gastrointestinal symptoms.
The gastrointestinal hormone is closely related to gastrointestinal dynamics abnormality, the regulation and control of the gastrointestinal hormone is closely related to the regulation and control of bidirectional passage between brain and intestinal axes, when various external stimulus factors act on the brain-intestinal axes, the gastrointestinal hormone can generate abnormal secretion, the brain-intestinal interaction balance state is destroyed, and the microcirculation disturbance of the organism is caused, so a series of clinical symptoms such as visceral hypersensitivity, obvious increase of gastrointestinal reactivity, abdominal pain, diarrhea, abdominal distention, constipation and the like are induced. The learner research found that gastrointestinal diseases are accompanied by intestinal microcirculation disturbance, and that the visceral sensitivity of the IBS model rat is increased, and that the intestinal microcirculation disturbance is a main cause of pain. A large number of researches prove that the regulation of bioactive substances such as calcium-reducing gene related peptide, endothelin, vasoactive intestinal peptide, interleukin and the like of the IBS model rat is dysregulated, so that the damage of endothelial cells causes microcirculation disturbance. The occurrence, development and change of IBS are closely related to the microcirculation state.
The horse chestnut Aesculus hippocastanum Linn is a plant of the genus Aesculus of the family Aesculaceae, and is also known as horse chestnut or horse chestnut. The horse chestnut belongs to more than 30 kinds of total plants, and 16 kinds of horse chestnut exist in China. The dried and mature seeds of the aesculus hippocastanum A.chinensis Bun.0ge, the aesculus hippocastanum A.chinensis Bun.0ge var.chekian.0gensis (Hu et fan.0 g) fan.0g and the aesculus hippocastanum A.wilsonii Rehd are traditional qi-regulating traditional Chinese medicines in China, have the effects of regulating qi, regulating middle warmer, regulating stomach, relieving pain and the like, and are used for symptoms such as chest-abdominal distension, choking, gastric and wrist pain and the like. Horse chestnut seeds and barks are traditional folk medicines in Europe and are used for treating hemorrhoids, uterine bleeding, phlebotomy, cholestasis and liver diseases, and aescin extracted from the horse chestnut seeds and barks is a good anti-inflammatory detumescence medicine. The horse chestnut seed extract (alcohol extract) is commonly used in clinical application and comprises tablets and powder injection, mainly comprises aescin sodium for injection and mailing tablets, and the main active ingredient of the horse chestnut seed extract is aescin. The horse chestnut tree seed extract has antioxidant, anti-edema, antiinflammatory and vascular effects. The aescin is widely applied to the clinic for treating chronic venous insufficiency, various oedema, hemorrhoids, asthma, anti-tumor and other diseases, has the functions of antioxidation, permeation resistance, detumescence, anti-tumor and microcirculation improvement.
Aescin is an impermeable dehydrating agent and has the functions of obviously stabilizing vascular endothelial cells and improving microcirculation. Through inhibiting the action of protease in blood, the aescin protects collagen fibers of vein wall, gradually restores the elasticity and contraction functions of lesion vein wall, and improves the tension and strength of the lesion vein wall; meanwhile, aescin also directly acts on vascular endothelial cell receptors to cause venous constriction, increase venous blood reflux speed, reduce venous pressure and improve microcirculation.
In the existing medicines for treating irritable bowel syndrome, linaclotide (Linaclotide) is the first guanylate cyclase-C agonist worldwide, is a polypeptide containing 14 amino acids, can bind and activate guanylate cyclase C receptor on the luminal surface of intestinal epithelial cells, and causes the increase of intracellular and extracellular guanylate. Linaclotide was approved for marketing by the us FDA and the eu EMEA on 8, 30, and 11, 26, 2012, respectively. The most common adverse reactions reported in IBS patients are diarrhea, abdominal pain, bloating and bloating.
The horse chestnut extract and the linaclotide are combined, so that the irritable bowel syndrome can be better treated.
Disclosure of Invention
The object of the present invention is to provide horse chestnut tree extract and linaclotide composition. The application of the horse chestnut extract in preparing the medicine for treating the irritable bowel syndrome can improve the treatment effect of the irritable bowel syndrome, reduce the dosage of guanylate cyclase-C receptor agonist, lighten the treatment toxic and side effects of the guanylate cyclase-C receptor agonist and improve the medication compliance of patients. For this purpose, the present invention provides the following technical solutions.
The invention provides a horse chestnut extract and linaclotide composition, which comprises the horse chestnut extract, linaclotide and pharmaceutically acceptable auxiliary materials.
The preparation form of the composition is sustained-release pellets for oral administration.
The sustained-release pellets comprise the following raw and auxiliary materials in percentage by weight: 10.0 to 75.0 percent of horse chestnut extract, 20 to 88 percent of linaclotide, 0.8 to 3.0 percent of molding material, 1.0 to 6.0 percent of slow release material, 0.2 to 0.8 percent of plasticizer and 0.2 to 0.8 percent of anti-adhesion agent.
Preferably, the sustained-release pellets consist of the following raw and auxiliary materials in percentage by weight: 20.0 to 70.0 percent of horse chestnut extract, 25 to 75 percent of linaclotide, 1.0 to 2.5 percent of molding material, 1.5 to 5.0 percent of slow release material, 0.4 to 0.7 percent of plasticizer and 0.3 to 0.6 percent of anti-adhesion agent.
Preferably, the mass ratio of the horse chestnut extract to the linaclotide is 1:1-1:12.
The invention provides an orally-administrated sustained-release pellet, which is prepared by the following steps:
1) Preparing various raw materials according to the proportion of the sustained-release pellets, firstly uniformly mixing the prepared horse chestnut extract, linaclotide and molding materials, and then preparing a drug-loaded pellet core by a dry-method granulator according to a conventional method;
2) Then mixing the prepared slow-release material, plasticizer and anti-sticking agent to prepare slow-release layer coating liquid;
3) And (3) placing the prepared drug-loaded pellets in a fluidized bed, spraying the prepared coating liquid of the slow-release layer into the fluidized bed, and coating the pellet cores of the drug-loaded pellets according to a conventional method to prepare the slow-release pellets.
The sustained-release pellets for oral administration according to the above, wherein the sustained-release material is selected from any one or more of ethylcellulose, hypromellose, polyacrylic resin, hydroxypropyl cellulose, hydroxyethyl cellulose acetate, cellulose acetate phthalate, shellac, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, jac, hypromellose succinate, polylactic acid and palm wax.
Preferably, the slow release material is selected from polyacrylic resin or ethylcellulose.
The sustained-release pellets for oral administration according to the above, wherein the molding material is selected from any one or more of microcrystalline cellulose, algal polysaccharide, ethylcellulose, hypromellose, hydroxypropyl cellulose, povidone, copovidone, hydrogenated vegetable oil, and glyceryl behenate.
Preferably, the molding material is selected from microcrystalline cellulose or copovidone.
The orally-administrable sustained-release pellets according to the above, wherein the plasticizer is selected from any one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, glyceryl stearate, tributyl citrate, diethyl succinate, oleic acid, rectified coconut oil and propylene glycol;
preferably, the plasticizer is selected from polyethylene glycol or triethyl citrate.
The sustained-release pellet for oral administration according to the above, wherein the anti-sticking agent is selected from any one or more of talc, colloidal silica, lactose, mannitol, povidone, hypromellose and glyceryl monostearate.
Preferably, the anti-sticking agent is selected from talc or hypromellose.
The application of the composition in treating irritable bowel syndrome.
The preparation method of the horse chestnut extract and linaclotide sustained-release pellets comprises the following steps of
(1) Preparing a pill core of the drug-loaded micropill: weighing horse chestnut tree extract, linaclotide and molding materials according to the prescription amount, crushing and sieving with a 80-120 mesh sieve; opening a low-temperature refrigerator, controlling the temperature to be 5-15 ℃, placing the materials into a feed tank after 10min, selecting the vertical speed to be 12-20 r/min, selecting the horizontal speed to be 40-60 r/min, pressing the shaft speed to be 14-20 r/min, extruding and forming raw and auxiliary materials into drug-carrying pellets with uniform particle size by a dry granulator under the action of a finishing knife, sieving, taking the pellets with the particle size of 18-30 meshes, extruding again until all the components are extruded into pellets with the particle size of 18-30 meshes, and obtaining drug-carrying pellet cores;
(2) Preparing sustained-release pellets: firstly, adding a weighed slow-release material into a 95% ethanol solution to dissolve until the slow-release material is clarified, obtaining a slow-release material ethanol solution, then dissolving a weighed plasticizer and an anti-adhesion agent into the slow-release material ethanol solution, and stirring until the slow-release material is clarified, thus obtaining a slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40-45 ℃, drying air flow to 60-70 m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2-3 ml/min in a bottom spraying mode for atomization coating, gradually increasing the pumping rate to 13-20 ml/min until the coating liquid is used up, increasing the fluidization temperature to 45-50 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16-24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
The horse chestnut extract and guanylate cyclase-C receptor agonist composition prepared by the technical scheme of the invention has basically no irritation, less toxic and side effects, is convenient for patients to treat for a long time and improves medication compliance.
The horse chestnut extract and the linaclotide sustained-release pellets prepared by the technical scheme of the invention can ensure the effective drug concentration in a 24-hour body after being taken once a day, and can reduce the gastrointestinal reactions such as nausea, vomiting, diarrhea and the like caused by the gastrointestinal irritation brought by the common preparation.
Drawings
FIG. 1 in vitro release profile of the horse chestnut extract and linaclotide sustained release pellets obtained in example 1 of the present invention.
Detailed Description
Embodiments of the present invention will be described in detail with reference to the following examples, which are only for illustration of the present invention and should not be construed as limiting the scope of the present invention as will be understood by those skilled in the art.
Example 1
(1) Preparing a pill core of the drug-loaded micropill: weighing 50.0g of horse chestnut tree extract, 600.0g of linaclotide and 5.0g of microcrystalline cellulose, crushing and sieving with a 80-mesh sieve; opening a low-temperature refrigerator, controlling the temperature at 5 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 12r/min, a horizontal speed of 40r/min and a shaft pressing speed of 20r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 50.0g of the weighed polyacrylic resin is added into 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain polyacrylic resin ethanol solution, then 5.0g of the weighed polyethylene glycol and 2.0g of talcum powder are dissolved into the polyacrylic resin ethanol solution, and the solution is stirred until the solution is clarified, so as to obtain slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40 ℃, enabling the drying air flow to be 60m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, atomizing the coating liquid at 1.8bar, gradually increasing the pumping rate to 13ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 2
(1) Preparing a pill core of the drug-loaded micropill: weighing 50.0g of horse chestnut tree extract and 50.0g of linaclotide, crushing and sieving with a 120-mesh sieve; starting a low-temperature refrigerator, controlling the temperature at 10 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 15r/min, a horizontal speed of 40r/min and a shaft pressing speed of 15r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, adding 8.0g of weighed ethyl cellulose into 95% ethanol solution to dissolve until the solution is clarified to obtain ethyl cellulose ethanol solution, then dissolving 2.0g of weighed triethyl citrate and 1.0g of hydroxypropyl methylcellulose into the ethyl cellulose ethanol solution, and stirring until the solution is clarified to obtain slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40 ℃, controlling the drying air flow to 65m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 3ml/min in a bottom spraying mode, atomizing the coating liquid at 1.9bar, gradually increasing the pumping rate to 15ml/min until the coating liquid is used up, increasing the fluidization temperature to 46 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 3
(1) Preparing a pill core of the drug-loaded micropill: weighing 200.0g of horse chestnut extract, 400.0g of linaclotide and 2.0g of copovidone, crushing and sieving with a 80-mesh sieve; opening a low-temperature refrigerator, controlling the temperature at 5 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 20r/min, a horizontal speed of 40r/min and a shaft pressing speed of 20r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 50.0g of weighed hypromellose is added into a 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain a hypromellose ethanol solution, then 5.0g of weighed diethyl succinate and 4.0g of talcum powder are dissolved into the hypromellose ethanol solution, and the solution is stirred until the solution is clarified, so as to obtain a slow-release coating liquid; taking the pill core of the drug-loaded micropill, regulating the fluidization temperature to 40 ℃ and drying air flow to 60m 3 * h-1, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber for atomization coating by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, and atomizing pressureThe force is 1.8bar, the pumping speed is gradually increased to 13ml/min until the coating liquid is used up, the fluidization temperature is increased to 45 ℃, the coating liquid is continuously fluidized and dried in a fluidized bed for 30 minutes and then taken out, the pellets with 16-24 meshes are selected, and the slow-release pellets are obtained after the pellets are inspected to be qualified.
Example 4
(1) Preparing a pill core of the drug-loaded micropill: weighing 150.0g of horse chestnut extract, 525.0g of linaclotide and 5.0g of hydrogenated vegetable oil, crushing and sieving with a 80-120 mesh sieve; opening a low-temperature refrigerator, controlling the temperature to be 5-15 ℃ and placing the materials into a feed tank after 10min, selecting a vertical speed of 20r/min, a horizontal speed of 50r/min and a pressing shaft speed of 20r/min, extruding and forming raw materials and auxiliary materials by a dry granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with a particle size of 18-30 meshes, extruding again with a particle size of less than 30 meshes until all components are extruded into pellets with a particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 60.0g of weighed hydroxypropyl cellulose is added into 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain hydroxypropyl cellulose ethanol solution, then 5.0g of weighed glyceryl triacetate and 5.0g of colloidal silicon dioxide are dissolved into the hydroxypropyl cellulose ethanol solution, and the solution is stirred until the solution is clarified, so as to obtain slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40 ℃, enabling the drying air flow to be 60m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, atomizing the coating liquid at an atomization pressure of 2.5bar, gradually increasing the pumping rate to 20ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 5
(1) Preparing a pill core of the drug-loaded micropill: weighing 200.0g of horse chestnut extract, 500.0g of linaclotide and 5.0g of hypromellose, crushing and sieving with a 80-mesh sieve; starting a low-temperature refrigerator, controlling the temperature at 10 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 15r/min, a horizontal speed of 40r/min and a shaft pressing speed of 15r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, adding the weighed cellulose acetate phthalate into a 95% ethanol solution to dissolve until the solution is clarified to obtain a cellulose acetate phthalate ethanol solution, then dissolving the weighed acetyl triethyl citrate and mannitol into the cellulose acetate phthalate ethanol solution, and stirring the solution until the solution is clarified to obtain a slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40 ℃, enabling the drying air flow to be 60m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, atomizing the coating liquid at 1.8bar, gradually increasing the pumping rate to 13ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 6
(1) Preparing a pill core of the drug-loaded micropill: weighing 180.0g of horse chestnut extract, 720.0g of linaclotide and 8.0g of hydroxypropyl cellulose, crushing and sieving with a 80-mesh sieve; opening a low-temperature refrigerator, controlling the temperature to be 5 ℃, placing the materials in a feed tank after 10min, selecting the vertical speed to be 12r/min, the horizontal speed to be 40r/min, the shaft pressing speed to be 14r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 60.0g of weighed ethyl cellulose is added into a 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain an ethyl cellulose ethanol solution, and then 5.0g of weighed acetyl tributyl citrate is dissolved into the ethyl cellulose ethanol solution and stirred until the solution is clarified, so as to obtain a slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40 ℃, enabling the drying air flow to be 60m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, atomizing the coating liquid at an atomization pressure of 2.5bar, gradually increasing the pumping rate to 15ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 7
(1) Preparing a pill core of the drug-loaded micropill: weighing 120.0g of horse chestnut tree extract and 840.0g of linaclotide, crushing and sieving with a 100-mesh sieve; starting a low-temperature refrigerator, controlling the temperature at 10 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 15r/min, a horizontal speed of 40r/min and a pressing shaft speed of 14r/min, extruding and forming raw materials and auxiliary materials by a dry granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, adding 100.0g of weighed cellulose acetate phthalate into 95% ethanol solution to dissolve until the mixture is clarified to obtain cellulose acetate phthalate ethanol solution, then dissolving 5.0g of weighed dibutyl phthalate and 2.0g of talcum powder into the cellulose acetate phthalate ethanol solution, and stirring the mixture until the mixture is clarified to obtain slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 45 ℃, enabling the drying air flow to 70m < 3 > h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 3ml/min in a bottom spraying mode, atomizing the coating liquid at the atomization pressure of 2.0bar, gradually increasing the pumping rate to 16ml/min until the coating liquid is used up, increasing the fluidization temperature to 50 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 8
(1) Preparing a pill core of the drug-loaded micropill: weighing 80.0g of horse chestnut extract, 480.0g of linaclotide and 5.0g of ethylcellulose, crushing and sieving with a 120-mesh sieve; starting a low-temperature refrigerator, controlling the temperature at 15 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 20r/min, a horizontal speed of 40r/min and a shaft pressing speed of 20r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 50.0g of weighed hydroxypropyl methylcellulose is added into a 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain a hydroxypropyl methylcellulose ethanol solution, and then 5.0g of weighed tributyl citrate and 2.0g of hydroxypropyl methylcellulose are dissolved into the hydroxypropyl methylcellulose ethanol solution and stirred until the solution is clarified, so as to obtain a slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 45 ℃, enabling the drying air flow to 70m < 3 > h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 3ml/min in a bottom spraying mode, atomizing the coating liquid at 1.8bar, gradually increasing the pumping rate to 13ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 9
(1) Preparing a pill core of the drug-loaded micropill: weighing 50.0g of horse chestnut extract, 600.0g of linaclotide and 5.0g of povidone, crushing and sieving with a 80-mesh sieve; starting a low-temperature refrigerator, controlling the temperature at 15 ℃ for 10min, placing the materials into a feed tank, selecting a vertical speed of 12r/min, a horizontal speed of 40r/min and a pressing shaft speed of 14r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, 50.0g of the weighed polyacrylic resin is added into 95% ethanol solution to be dissolved until the solution is clarified, so as to obtain polyacrylic resin ethanol solution, then 5.0g of the weighed oleic acid and 2.0g of lactose are dissolved into the polyacrylic resin ethanol solution, and the solution is stirred until the solution is clarified, so as to obtain slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 45 ℃, enabling the drying air flow to 70m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2ml/min in a bottom spraying mode, atomizing the coating liquid at 1.8bar, gradually increasing the pumping rate to 13ml/min until the coating liquid is used up, increasing the fluidization temperature to 45 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16 and 24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 10
(1) Preparing a pill core of the drug-loaded micropill: weighing 80.0g of horse chestnut extract, 400.0g of linaclotide and 1.0g of microcrystalline cellulose, crushing and sieving with a 80-mesh sieve; opening a low-temperature refrigerator, controlling the temperature to be 5 ℃, placing the materials in a feed tank after 10min, selecting the vertical speed to be 12r/min, the horizontal speed to be 40r/min, the shaft pressing speed to be 14r/min, extruding and forming raw materials and auxiliary materials by a dry-method granulator, forming drug-carrying pellets with uniform particle size under the action of a finishing knife, sieving, taking pellets with the particle size of 18-30 meshes, extruding again with the particle size of less than 30 meshes until all components are extruded into pellets with the particle size of 18-30 meshes, and obtaining a drug-carrying pellet core;
(2) Preparing sustained-release pellets: firstly, adding the weighed hydroxyethyl cellulose acetate into a 95% ethanol solution to dissolve until the solution is clarified to obtain a hydroxyethyl cellulose acetate ethanol solution, then dissolving the weighed propylene glycol and hydroxypropyl methylcellulose into the hydroxyethyl cellulose acetate ethanol solution, and stirring the solution until the solution is clarified to obtain a slow-release coating liquid; taking pill cores of drug-loaded pellets, regulating the fluidization temperature to 40-45 ℃, drying air flow to 60-70 m < 3 > -h < -1 >, taking the obtained slow-release coating liquid, pumping the slow-release coating liquid into an atomization chamber by a peristaltic pump at a flow rate of 2-3 ml/min in a bottom spraying mode for atomization coating, gradually increasing the pumping rate to 13-20 ml/min until the coating liquid is used up, increasing the fluidization temperature to 45-50 ℃, continuously carrying out fluidization drying in a fluidized bed for 30 minutes, taking out, selecting pellets between 16-24 meshes, and checking to obtain the slow-release pellets after the inspection is qualified.
Example 11 Release degree determination
The sustained release pellets prepared in example 1 were used as test samples, and the release degree test method was as follows:
taking the product obtained in the example 1, taking a device of a dissolution rate measurement method (an annex XD first method) according to the dissolution rate measurement method (an annex XC second method), taking 900ml of water as a solvent, rotating at 50 revolutions per minute, performing normal operation, filtering the solution for 1, 2, 4, 6, 8 and 12 hours, supplementing the medium with the same temperature and the same volume, discarding at least 10ml of primary filtrate, precisely measuring the proper amount of secondary filtrate, and adding water to dilute the solution to prepare a solution with 0.67mg in each 1ml as a test solution. YMC ProTM C18 column (size: 3.0x 150mm,3.5um,Waters Corp, milford, mass.) or equivalent column was used and maintained at 40 ℃. Mobile Phase A (MPA) consisted of water containing 0.1% trifluoroacetic acid, while Mobile Phase B (MPB) consisted of 95% acetonitrile: 5% water containing 0.1% trifluoroacetic acid. The amount of release was calculated as peak area by the external standard method.
The experimental results are shown in figure 1, and the products obtained in examples 2-9 all meet the requirements under the same test conditions, and the experimental results are the same as those in example 1.
Example 12 Effect on IBS model rats
The newborn Wistar rats were divided into a normal group (n=6) and a model group (n=48) at random according to body weight, 6 control groups were randomly left after molding, and the remaining groups were the therapeutic drug group of the present invention (examples 1, 3, 5, 7, 8, 9, n=6) and linaclotide control drug group (n=6), respectively.
An IBS rat model was prepared by mother-child separation and acetic acid enema. For young mice of 2-21 days old, the mice are separated from the female mice for 2 hours every day, and are stimulated with intrarectal acetic acid, i.e. a central venous catheter (diameter 1 mm) lubricated with paraffin oil is inserted into the anus for 2cm, and 0.5ml of 0.5% acetic acid is injected. The visceral sensitivity evaluation was performed on normal and model rats by the method described by Al-Chaer et Al, and the IBS model was successful with model rats having significantly lower abdominal recoil reflection (AWR) capacity threshold than normal rats, and with 48 rats molded, without any experimental procedure, by the end of week 5. Treatment was initiated at week 6 with 2 μg/kg of the drug of groups 1, 3, 5, 7, 8, 9 of examples, respectively, and 2 μg/kg of linaclotide of the control group.
Visceral sensitivity evaluation index
The visceral sensitivity of each group of rats was assessed according to AWR on day 2 after the end of treatment, the rats were placed in a specially made transparent plastic cage, and were allowed to move back and forth only, and were not turned around, and a paraffin lubricated 2F double lumen catheter was inserted through the anus of the rat, with the balloon tip 1cm from the anus. The catheter and the tail root of the rat are wound together by using adhesive tape, and the air bag is fixed. After the rats are adapted to the environment, the air sac is gradually injected with water to expand the intestinal tract for 20s. The capacity threshold (number of ml of water injected) of each group of rats with abdominal lifting (abdominal contraction and lifting) and dorsal arching (arching and lifting of pelvis) caused by AWR was observed separately.
To obtain accurate evaluation results, each threshold measurement was repeated 3 times, the data was averaged, and the results are shown in table 1.
Table 1 comparison of abdominal lifting and dorsal arching values for rats of each group
Comparison with normal group P <0.01, comparison with model group P <0.01
Compared with the normal group, the abdomen lifting value and the back arching value of the model group are reduced, and the difference is extremely significant (P < 0.01); compared to the model group, the linaclotide groups, examples 1, 3, 5, 7, 8, 9, all had elevated abdominal lifting values and back arching values, with very significant differences (P < 0.01). The example group had better effect than the comparative group.
Mesenteric microcirculation detection
On day 2 after the end of treatment, rats were anesthetized by intramuscular injection of 20% uratam (0.7 ml/100.0 g), the abdomen was opened along the normal midline of the abdomen, the lower ileum was pulled out, the mesentery was tiled and fixed on a constant temperature perfusion box of a microcirculation microscope stage, physiological saline maintained a constant temperature environment of 37 ℃, and the microscope was connected to an image analysis system. The mesenteric microvasculature is carefully searched, the tube diameter and the blood flow state of the same microvasculature of the mesentery of each animal under the endoscope (x 40) are continuously observed for 30 minutes, and the image changes of 10 minutes, 20 minutes and 30 minutes are recorded. The blood flow state is classified into 4 grades according to the characteristics of the semi-quantitative flow rate grading measurement method of the field cattle combined with the experiment: level 0, fast blood flow, smooth rope shape, no or micro particle feeling; level I, the blood flow is faster, and obvious granular sensation is achieved; stage II, the blood flow is slow, sediment is formed, and the flow is slow or swings back and forth; class III, stagnant or invisible blood flow. Statistical analysis was performed by taking measured values at 10min, 20min, and 30min of observation. To obtain accurate evaluation results, each measurement was repeated 3 times and the data averaged.
The effect on the diameter of the mesenteric microvasculature and the results are shown in Table 2.
TABLE 2 microvascular diameter variation for rats of each group
Comparison with normal group P <0.05, comparison with model group P <0.05, P <0.01
The microvascular tube diameters of the model group were significantly contracted compared to the normal group, the differences were statistically significant (P < 0.05), and the differences of the comparative groups, examples 1, 3, 5, 7, 8, 9, were statistically significant (P <0.05 or P < 0.01) compared to the model group. The example group had better effect than the comparative group.
The effect on the state of mesenteric microvascular blood flow is shown in table 3.
Table 3 changes in the state of the rat mesenteric microcirculation blood flow in each group
Note) P <0.01 compared to normal group
The model group had a slow or stopped blood flow, more of class ii to iii, and significant statistical significance of the difference (P < 0.01) compared to the normal group, and the comparative group, examples 1, 3, 5, 7, 8, 9, had significantly faster blood flow, all recovered to class 0 to class i. The example group had better effect than the comparative group.
Claims (15)
1. A chestnut extract and linaclotide composition, characterized in that the composition comprises a chestnut extract, linaclotide and pharmaceutically acceptable excipients.
2. The horse chestnut extract and linaclotide composition according to claim 1, wherein the composition is in the form of a sustained release pellet for oral administration.
3. The composition according to claim 2, wherein the sustained-release pellets consist of the following raw and auxiliary materials in percentage by weight: 10.0 to 75.0 percent of horse chestnut extract, 20 to 88 percent of linaclotide, 0.8 to 3.0 percent of molding material, 1.0 to 6.0 percent of slow release material, 0.2 to 0.8 percent of plasticizer and 0.2 to 0.8 percent of anti-adhesion agent.
4. The composition according to claim 3, wherein the sustained-release pellets consist of the following raw and auxiliary materials in percentage by weight: 20.0 to 70.0 percent of horse chestnut seed extract, 25 to 75 percent of linaclotide, 1.0 to 2.5 percent of molding material, 1.5 to 5.0 percent of slow release material, 0.4 to 0.7 percent of plasticizer and 0.3 to 0.6 percent of anti-adhesion agent.
5. Composition according to any one of claims 1 to 4, characterized in that the mass ratio of horse chestnut extract to linaclotide is 1:1 to 1:12.
6. The composition according to any one of claims 2 to 4, characterized in that it is prepared by the process of:
1) Preparing various raw materials according to the proportion of the sustained-release pellets as claimed in claim 3 or 4, firstly uniformly mixing the prepared horse chestnut extract, linaclotide and molding materials, and then preparing a drug-loaded pellet core by a dry granulator according to a conventional method;
2) Then mixing the prepared slow-release material, plasticizer and anti-sticking agent to prepare slow-release layer coating liquid;
3) And (3) placing the prepared drug-loaded pellets in a fluidized bed, spraying the prepared coating liquid of the slow-release layer into the fluidized bed, and coating the pellet cores of the drug-loaded pellets according to a conventional method to prepare the slow-release pellets.
7. The composition according to any one of claims 3 or 4, wherein the slow release material is selected from any one or more of ethylcellulose, hypromellose, polyacrylic resin, hydroxypropyl cellulose, hydroxyethyl cellulose acetate ester, cellulose acetate phthalate, shellac, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, jac, hypromellose succinate, polylactic acid, and palm wax.
8. The composition of claim 7, wherein the slow release material is selected from the group consisting of polyacrylic resin or ethylcellulose.
9. The composition according to any one of claims 3 and 4, wherein the molding material is selected from any one or more of microcrystalline cellulose, algal polysaccharide, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copovidone, hydrogenated vegetable oil, and glyceryl behenate.
10. The composition of claim 9, wherein the molding material is selected from microcrystalline cellulose or copovidone.
11. The composition according to any one of claims 3 or 4, wherein the plasticizer is selected from any one or more of triethyl citrate, acetyl tributyl citrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, glyceryl stearate, tributyl citrate, diethyl succinate, oleic acid, rectified coconut oil and propylene glycol.
12. The composition of claim 11, wherein the plasticizer is selected from polyethylene glycol or triethyl citrate.
13. The composition according to any one of claims 3 or 4, wherein the anti-sticking agent is selected from any one or more of talc, colloidal silica, lactose, mannitol, povidone, hypromellose, and glyceryl monostearate.
14. The composition of claim 13, wherein the anti-sticking agent is selected from talc or hypromellose.
15. Use of the composition of claim 1 for the preparation of a medicament for the treatment of irritable bowel syndrome.
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| CN101023952A (en) * | 2006-02-20 | 2007-08-29 | 张丽娟 | Use of aesin in releasing abdominal distention and astriction |
| CN105412904A (en) * | 2014-06-17 | 2016-03-23 | 深圳翰宇药业股份有限公司 | Linaclotide enteric controlled-release pellet capsule preparation and preparing method and application thereof |
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| CN104667259A (en) * | 2015-03-26 | 2015-06-03 | 深圳市健元医药科技有限公司 | Medicinal composition capsule for treating chronic constipation and preparation method thereof |
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| CN105412904A (en) * | 2014-06-17 | 2016-03-23 | 深圳翰宇药业股份有限公司 | Linaclotide enteric controlled-release pellet capsule preparation and preparing method and application thereof |
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