WO2019136744A1 - Composition d'extrait d'hippocastanum et de linaclotide - Google Patents

Composition d'extrait d'hippocastanum et de linaclotide Download PDF

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Publication number
WO2019136744A1
WO2019136744A1 PCT/CN2018/072588 CN2018072588W WO2019136744A1 WO 2019136744 A1 WO2019136744 A1 WO 2019136744A1 CN 2018072588 W CN2018072588 W CN 2018072588W WO 2019136744 A1 WO2019136744 A1 WO 2019136744A1
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sustained
release
pellets
linaclotide
pellet
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PCT/CN2018/072588
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English (en)
Chinese (zh)
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刘庭福
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深圳市星银医药有限公司
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Priority to CN201880011039.XA priority Critical patent/CN110337302B/zh
Priority to PCT/CN2018/072588 priority patent/WO2019136744A1/fr
Publication of WO2019136744A1 publication Critical patent/WO2019136744A1/fr

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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
    • 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

Definitions

  • the invention relates to the technical field of medicine, in particular to a composition of horse chestnut extract and linaclotide.
  • IBS Irritable bowel syndrome
  • IBS As a global disease, IBS accounts for the majority of young people aged 20-40, and the incidence of men is higher. The ratio of male to female is 2:1, and the number of IBS patients is increasing.
  • the epidemiological survey in North America shows that the incidence of IBS in healthy people is as high as 27%, and in European and American countries is 10%-20%. In terms of ethnicity, the incidence rate is highest in developed countries in Europe and America, followed by Asians. The incidence of IBS is lowest in African countries such as South Africa. At present, China has not conducted a large-scale epidemiological survey on IBS, but it is also quite common. In some areas, IBS patients account for about one-third of digestive outpatients.
  • IBS patients have visceral paresthesia, which is characterized by long-term hypersensitivity of the gastrointestinal tract and gastrointestinal responsiveness.
  • the abnormalities of gastrointestinal kinetics are most prominent, and studies show that gastrointestinal hormones It is closely related to gastrointestinal motility abnormalities, and its regulation is closely related to the regulation of bidirectional pathway between the brain and the intestine axis.
  • various external stimulating factors act on the brain-gut axis, the secretion of gastrointestinal hormones will be abnormal, brain- The balance of intestinal interaction was destroyed, leading to microcirculatory disturbances in the body, which induced a series of clinical symptoms such as high visceral hypersensitivity, marked increase in gastrointestinal responsiveness, abdominal pain, diarrhea, abdominal distension, and constipation.
  • IBS model rats have increased visceral sensitivity, and mesenteric microcirculation disturbance is the main cause of pain.
  • a large number of studies have confirmed that the biological activity substances such as calcitonin-related peptide, endothelin, vasoactive intestinal peptide, and interleukin in IBS model are dysregulated, which leads to microcirculatory disorders caused by endothelial cell damage. Therefore, the occurrence, development and change of IBS are closely related to the state of microcirculation.
  • European horse chestnut tree Aesculus hippocastanum Linn. is a horse chestnut, a horse chestnut plant, alias Omar chestnut, horse chestnut tree. There are more than 30 species of plants in the genus Aesculus, and there are 16 species in China. Dry and mature of the genus A. chinensis Bun.0ge, A.chinensis Bun.0ge var.chekian.0gensis (Hu et Fan.0g) Fan.0g and A. wilsonii Rehd. Seeds are traditional qi and traditional Chinese medicines in China. They have the effects of wide qi and qi and pain in the stomach. They are used for chest and abdomen bloating and stomach wrist pain.
  • Horse chestnut seeds and bark are traditional folk medicines used in Europe to treat acne, uterine bleeding, venous tumors, biliary stasis and liver disease.
  • the aescin extracted from it is a good anti-inflammatory and swelling drug.
  • the horse chestnut seed extract (alcohol extract) is commonly used in clinical applications as tablets and powder injections, mainly sodium aescinate and maizhiling tablets for injection, and its main active ingredient is escin.
  • the horse chestnut seed extract has antioxidant, anti-edema, anti-inflammatory and vascular effects.
  • Aescin is widely used in the treatment of chronic venous insufficiency, various edema, hemorrhoids, asthma and anti-tumor diseases. It has anti-oxidation, anti-seepage and anti-tumor effects, anti-tumor effect and microcirculation.
  • Aescin is a non-permeable dehydrating agent that significantly stabilizes vascular endothelial cells and improves microcirculation. Aescin inhibits the collagen fibers in the venous wall by inhibiting the action of proteases in the blood, gradually restores the elasticity and contraction function of the venous wall, and increases its tension and strength. At the same time, Aescin also acts directly on vascular endothelial cell receptors. Causes venous contraction, increases venous blood reflux rate, reduces venous pressure, and improves microcirculation.
  • Linaclotide is the world's first guanylate cyclase-C agonist, a 14 amino acid peptide that binds and activates The guanylate cyclase C receptor on the surface of the intestinal epithelial cell leads to an increase in intracellular and extracellular cyclic guanosine monophosphate. Linalotide was approved by the US FDA and EU EMEA on August 30, 2012 and November 26, 2012, respectively. The most common adverse reactions reported in patients with IBS are diarrhea, abdominal pain, flatulence and bloating.
  • the invention combines the extract of horse chestnut with linaclotide to better treat irritable bowel syndrome.
  • the application of horse chestnut extract in the preparation of medicine for treating irritable bowel syndrome can improve the therapeutic effect of irritable bowel syndrome, reduce the dosage of guanylate cyclase-C receptor agonist, and reduce guanylate
  • the toxic side effects of cyclase-C receptor agonists improve the compliance of patients with medication.
  • the present invention provides the following technical solutions.
  • the present invention provides a horse chestnut extract and a linaclotide composition, the composition comprising horse chestnut extract, linaclotide and a pharmaceutically acceptable adjuvant.
  • the formulation is in the form of a sustained release pellet for oral administration.
  • the sustained-release pellets are composed of the following weight percentages of raw materials: horse chestnut extract 10.0-75.0%, linaclotide 20-88%, molding material 0.8-3.0%, sustained-release material 1.0-6.0%, increase
  • the plasticizer is 0.2 to 0.8%
  • the anti-adhesive agent is 0.2 to 0.8%.
  • the sustained-release pellets are composed of the following weight percentages of raw materials: horse chestnut extract 20.0-70.0%, linaclotide 25-75%, molding material 1.0-2.5%, sustained-release material 1.5-5.0 %, plasticizer 0.4-0.7%, anti-adhesive agent 0.3-0.6%.
  • the mass ratio of the horse chestnut extract to linaclotide is 1:1 to 1:12.
  • sustained-release pellets for oral administration are prepared by:
  • the prepared drug-loaded pellets are placed in a fluidized bed, and the prepared sustained-release layer coating liquid is sprayed into the fluidized bed, and the drug-loaded pellet core is coated according to a conventional method, and is prepared. Sustained release pellets.
  • the sustained-release material is selected from the group consisting of ethyl cellulose, hypromellose, polyacryl resin, hydroxypropyl cellulose, hydroxyethyl cellulose cellulose acetate, Cellulose acetate phthalate, shellac, cellulose acetate phthalate, vinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, yakeyi, hypromellose succinate, polylactic acid Any one or more of palm wax and palm wax.
  • the sustained release material is selected from the group consisting of polyacrylic resins or ethylcellulose.
  • the molding material is selected from the group consisting of microcrystalline cellulose, seaweed polysaccharide, ethyl cellulose, hypromellose, hydroxypropyl cellulose, povidone, copovidone Any one or more of hydrogenated vegetable oil and glyceryl behenate.
  • the molding material is selected from the group consisting of microcrystalline cellulose or copovidone.
  • the plasticizer is selected from the group consisting of triethyl citrate, triethyl acetyl citrate, acetyl tributyl citrate, dibutyl sebacate, and triacetic acid.
  • Glyceryl ester polyethylene glycol, diethyl phthalate, dibutyl phthalate, glyceryl stearate, tributyl citrate, diethyl succinate, oleic acid, rectified coconut oil And one or more of propylene glycol;
  • the plasticizer is selected from the group consisting of polyethylene glycol or triethyl citrate.
  • the anti-adherent agent is selected from the group consisting of talc, colloidal silica, lactose, mannitol, povidone, hypromellose and glyceryl monostearate. Any one or more of them.
  • the anti-adherent agent is selected from the group consisting of talc or hypromellose.
  • composition in the treatment of irritable bowel syndrome.
  • the dry granulator will extrude the original auxiliary material and Under the action of the finishing knife, the drug-loaded pellets with uniform particle size are formed, sieved, and the pellets between 18 and 30 mesh are taken, and the pellets are pressed again less than 30 mesh until all the components are extruded to 18 to 30 mesh. Between the pellets, that is, the drug-loaded pellets;
  • sustained-release pellets Preparation of sustained-release pellets: firstly, the weighed sustained-release material is dissolved in a 95% ethanol solution to be clarified to obtain a slow-release material ethanol solution, and then the weighed plasticizer and anti-adhesive agent are dissolved. The slow-release material in ethanol solution is stirred until clarified to obtain a sustained-release coating liquid; the drug-loading pellet core is taken, the fluidization temperature is adjusted to 40-45 ° C, and the dry air flow rate is 60-70 m 3 * h -1 , and the sustained release is obtained.
  • the coating liquid is pumped into the atomization chamber by a peristaltic pump at a flow rate of 2 to 3 ml/min, and the atomization pressure is 1.8 to 2.5 bar, and the pumping rate is gradually increased to 13 to 20 ml/min to the package.
  • the fluidization temperature is increased to 45-50 ° C, and the fluidized bed is continuously fluidized and dried for 30 minutes, and then taken out, and the pellets between 16 and 24 mesh are selected, and the sustained release pellets are obtained after the inspection.
  • the horse chestnut extract and the guanylate cyclase-C receptor agonist composition prepared by the technical scheme of the invention are substantially non-irritating, have less toxic and side effects, are convenient for long-term treatment of patients, and improve medication compliance.
  • the horse chestnut extract and the linaclotide sustained-release pellet prepared by adopting the technical scheme of the present invention can ensure the effective drug concentration in the body for 24 hours and can reduce the gastrointestinal irritation caused by the common preparation. Gastrointestinal reactions such as nausea, vomiting, and diarrhea.
  • Fig. 1 shows the in vitro release degree of the horse chestnut extract and the linaclotide sustained-release pellet obtained in Example 1 of the present invention.
  • the sustained-release coating liquid was pumped into the atomization chamber by a peristaltic pump at a flow rate of 2 ml/min, and the atomization pressure was 1.8 bar, and the pumping rate was gradually increased to 13 ml/min until the coating liquid was used up. , increase the fluidization temperature to 45 ° C, continue to fluidize and dry in a fluidized bed for 30 minutes, take out, select 16 to 24 mesh between the pellets, after the test is the sustained release pellets.
  • the drug-loaded pellets with uniform particle size are sieved, and the pellets between 18 and 30 mesh are taken, and the pellets are pressed again less than 30 mesh until all the components are extruded into pellets between 18 and 30 mesh, that is, Drug-loaded pellets;
  • 60m3*h-1 take the obtained slow-release coating liquid, pump it into the spray chamber atomization coating with a peristaltic pump at a flow rate of 2ml/min.
  • the atomization pressure is 1.8bar, and gradually increase the pumping rate to 13ml. /min until the coating liquid is used up, increase the fluidization temperature to 45 ° C, continue to fluidize and dry in a fluidized bed for 30 minutes, take out, select 16 to 24 mesh between the pellets, after the test is the sustained release pellets.
  • the atomization pressure was 2.5 bar, and the pumping rate was gradually increased. 20ml / min to the coating liquid is used up, increase the fluidization temperature to 45 ° C, continue to fluidize and dry in a fluidized bed for 30 minutes, remove, select 16 to 24 mesh between the pellets, after the test is the sustained release pellets .
  • the atomization pressure is 1.8 bar, and the pump is gradually increased.
  • the infusion rate is up to 13ml/min until the coating liquid is used up, the fluidization temperature is increased to 45 ° C, and the fluidized bed is continuously fluidized and dried for 30 minutes, and then taken out, and the pellets between 16 and 24 mesh are selected. Release the pellets.
  • the sustained-release coating liquid was pumped into the spray chamber by a peristaltic pump at a flow rate of 2 ml/min, and the atomization pressure was 2.5 bar, and the pumping rate was gradually increased to 15 ml/min until the coating liquid was used up. , increase the fluidization temperature to 45 ° C, continue to fluidize and dry in a fluidized bed for 30 minutes, take out, select 16 to 24 mesh between the pellets, after the test is the sustained release pellets.
  • the dry air flow rate is 70m3*h-1, and the obtained slow-release coating liquid is taken, and pumped into the atomization chamber by a peristaltic pump at a flow rate of 3 ml/min, and the atomization pressure is 2.0 bar, and the pump is gradually increased.
  • the infusion rate is up to 16ml/min until the coating liquid is used up, the fluidization temperature is increased to 50 ° C, and the fluidized bed is continuously fluidized and dried for 30 minutes, and then taken out, and the pellets between 16 and 24 mesh are selected. Release the pellets.
  • the drug-loaded pellets having uniform particle size are formed, sieved, and the pellets between 18 and 30 mesh are taken, and the pellets are pressed again less than 30 mesh until all the components are extruded into pellets between 18 and 30 mesh. That is, the drug-loading pellet core is obtained;
  • the atomization pressure is 1.8 bar, and the pumping rate is gradually increased. After 13ml/min to the coating liquid, increase the fluidization temperature to 45 ° C, continue to fluidize and dry in a fluidized bed for 30 minutes, take out, select 16 to 24 mesh between the pellets, after the test is the sustained release micro pill.
  • the drug-loaded pellets with uniform particle size are sieved, and the pellets between 18 and 30 mesh are taken, and the pellets are pressed again less than 30 mesh until all the components are extruded into pellets between 18 and 30 mesh, that is, Drug-loaded pellets;
  • the pumping rate was gradually increased to 13 ml/min until the coating liquid was used up, and the flow was increased.
  • the drug-loaded pellets having uniform particle size are formed, sieved, and the pellets between 18 and 30 mesh are taken, and the pellets are pressed again less than 30 mesh until all the components are extruded into pellets between 18 and 30 mesh. That is, the drug-loading pellet core is obtained;
  • sustained-release pellets firstly, the weighed hydroxyethyl cellulose acetate cellulose ester is added to a 95% ethanol solution to dissolve to clarify, thereby obtaining a hydroxyethyl cellulose cellulose acetate ester ethanol solution, and then The weighed propylene glycol and hypromellose are dissolved in hydroxyethyl cellulose acetate cellulose solution and stirred until clarified to obtain a sustained-release coating liquid; the drug-loading pellet core is taken to adjust the fluidization temperature to 40 ⁇ 45 ° C, dry air flow 60 ⁇ 70m3 * h-1, take the resulting slow-release coating liquid, pumped into the spray chamber atomization coating with a peristaltic pump at a flow rate of 2 ⁇ 3ml / min, the atomization pressure is 1.8 ⁇ 2.5bar, gradually increase the pumping rate to 13 ⁇ 20ml / min until the coating liquid is used up, increase the fluidization temperature to 45 ⁇ 50 ° C, continue
  • the sustained-release pellets prepared in Example 1 were used as test samples, and the release test method was as follows:
  • Example 1 Take the product obtained in Example 1, according to the release method (Appendix XD first method), using the dissolution test method (Appendix XC second method), using 900ml of water as solvent, the rotation speed is 50 rpm, according to the law. After 1, 2, 4, 6, 8 and 12 hours, take the appropriate amount of the solution and add the same volume of medium at the same time, discard at least 10ml of the initial filtrate, accurately measure the amount of the filtrate, and dilute with water to make each 1ml. A solution containing 0.67 mg was used as a test solution. A YMC ProTM C18 column (size: 3.0 x 150 mm, 3.5 um, Waters Corp., Milford, MA) or equivalent column was used and maintained at 40 °C.
  • Mobile phase A consisted of water containing 0.1% trifluoroacetic acid
  • mobile phase B consisted of 95% acetonitrile: 5% water containing 0.1% trifluoroacetic acid. Calculate the release amount by peak area according to the external standard method.
  • the IBS rat model was prepared by mother-child separation and acetic acid enema. The 2 to 21 day old pups were separated from the mother for 2 h every day, and stimulated with acetic acid in the rectum. The central venous catheter (diameter 1 mm) lubricated with paraffin oil was inserted into the anus 2 cm, and 0.5 ml of 0.5% acetic acid was injected. Within 2 weeks from the 22nd day of the experiment, no experimental operation was performed, and by the end of the 5th week, the visceral sensitivity assessment was performed on the rats in the normal group and the model group according to the method described by Al-chaer et al.
  • the threshold of retraction reflex (AWR) was significantly lower than that of the normal group, and the 48 rats were modeled.
  • the therapeutic drug group was given 2 ⁇ g/kg of the drugs of the groups 1, 3, 5, 7, 8, and 9, respectively, and the control drug group was given linaclotide 2 ⁇ g/kg.
  • each threshold measurement is repeated 3 times, and the data is averaged. The results are shown in Table 1.
  • rats were given 20% urethane intramuscular injection (0.7ml/100.0g) anesthesia, laparotomy along the midline of the abdomen, pulling the lower ileum, and laying the mesentery on the microcirculation microscope stage.
  • the physiological saline is maintained at a constant temperature of 37 ° C, and the microscope is connected with an image analysis system.
  • the mesenteric microvessels were carefully searched, and the diameter and blood flow of the same microvessel in the mesenteric of each animal under endoscope (x40) were observed continuously for 30 min. The images were recorded at 10 min, 20 min, and 30 min.
  • the blood flow state is divided into four grades according to the semi-quantitative flow rate grading method of Tian Niu combined with the characteristics of this experiment: grade 0, blood flow is fast, smooth strips, no or micro-grain; grade I, blood flow is fast, There is obvious graininess; Grade II, slow blood flow, silt-like, slow flow or swinging back and forth; Grade III, blood flow stagnant or blood flow is invisible.
  • grade 0 blood flow is fast, smooth strips, no or micro-grain
  • grade I blood flow is fast, There is obvious graininess
  • Grade II slow blood flow, silt-like, slow flow or swinging back and forth
  • Grade III blood flow stagnant or blood flow is invisible.
  • the measured values were observed for 10 min, 20 min, and 30 min for statistical analysis. In order to obtain an accurate evaluation result, each measurement value was repeated 3 times, and the data was averaged.
  • the microvessel diameter of the model group was significantly contracted, and the difference was statistically significant (P ⁇ 0.05).
  • the difference between the control group and the first, third, fifth, seventh, eighth, and ninth groups was statistically significant. Significance (P ⁇ 0.05 or P ⁇ 0.01). The effect of the example group was better than that of the control group.

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Abstract

L'invention concerne une préparation de composition d'un extrait d'hippocastanum et de linaclotide et son utilisation. La préparation comprend des pastilles à libération prolongée comprenant 10,0 % à 75,0 % de l'extrait d'hippocastanum, 20,0 % à 88,0 % de linaclotide, 0,8 % à 3,0 % de matériaux de moulage, et 1,0 % à 6,0 % de matériaux à libération prolongée. La préparation peut exercer un rôle synergique de l'extrait d'hippocastanum et du linaclotide, présente des effets de libération prolongée, et peut améliorer l'effet thérapeutique du syndrome du côlon irritable, réduire la quantité de l'agoniste du récepteur de la guanylate cyclase-C, réduire les effets toxiques et secondaires dans le traitement avec l'agoniste du récepteur de la guanylate cyclase-C, et améliorer la conformité du patient à des médicaments.
PCT/CN2018/072588 2018-01-15 2018-01-15 Composition d'extrait d'hippocastanum et de linaclotide WO2019136744A1 (fr)

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CN201880011039.XA CN110337302B (zh) 2018-01-15 2018-01-15 一种马栗树提取物和利那洛肽组合物
PCT/CN2018/072588 WO2019136744A1 (fr) 2018-01-15 2018-01-15 Composition d'extrait d'hippocastanum et de linaclotide

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101023952A (zh) * 2006-02-20 2007-08-29 张丽娟 七叶皂苷在缓解腹胀和便秘的用途
US20140242124A1 (en) * 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of Guanylate Cyclase and Their Uses
CN104667259A (zh) * 2015-03-26 2015-06-03 深圳市健元医药科技有限公司 治疗慢性便秘的药物组合物胶囊及其制备方法
CN105412904A (zh) * 2014-06-17 2016-03-23 深圳翰宇药业股份有限公司 利那洛肽肠溶缓释微丸胶囊制剂及其制备方法和用途

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA2745499A1 (fr) * 2008-12-05 2010-06-10 Angiochem Inc. Conjugues therapeutiques peptidiques et leurs applications

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN101023952A (zh) * 2006-02-20 2007-08-29 张丽娟 七叶皂苷在缓解腹胀和便秘的用途
US20140242124A1 (en) * 2013-02-25 2014-08-28 Synergy Pharmaceuticals Inc. Agonists of Guanylate Cyclase and Their Uses
CN105412904A (zh) * 2014-06-17 2016-03-23 深圳翰宇药业股份有限公司 利那洛肽肠溶缓释微丸胶囊制剂及其制备方法和用途
CN104667259A (zh) * 2015-03-26 2015-06-03 深圳市健元医药科技有限公司 治疗慢性便秘的药物组合物胶囊及其制备方法

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