CN110337302A - A kind of hippocastanum extract and Linaclotide composition - Google Patents
A kind of hippocastanum extract and Linaclotide composition Download PDFInfo
- Publication number
- CN110337302A CN110337302A CN201880011039.XA CN201880011039A CN110337302A CN 110337302 A CN110337302 A CN 110337302A CN 201880011039 A CN201880011039 A CN 201880011039A CN 110337302 A CN110337302 A CN 110337302A
- Authority
- CN
- China
- Prior art keywords
- pellet
- sustained release
- linaclotide
- cellulose
- slow
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
Classifications
-
- 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
Abstract
A kind of hippocastanum extract and Linaclotide composite preparation and its application.Said preparation includes sustained release pellet, including hippocastanum extract 10.0-75.0%, Linaclotide 20.0-88.0%, moulding material 0.8-3.0%, slow-release material 1.0-6.0%.Said preparation can play the synergistic effect of hippocastanum extract and Linaclotide, with slow release effect, the therapeutic effect of intestinal irritable syndrome can be improved, reduce the dosage of guanylate cyclase-C receptor stimulating agent, the treatment toxic side effect for reducing guanylate cyclase-C receptor stimulating agent, improves the compliance of patient medication.
Description
The present invention relates to pharmaceutical technology fields, are specifically related to the composition of a kind of hippocastanum extract and Linaclotide.
Irritable bowel syndrome (irritable bowel syndrome, it IBS be) with abdominal pain, diarrhea, constipation of chronic recurrent exerbation etc. is the function of intestinal canal disorder disease mainly showed, clinical manifestation is that stool is urgently felt not to the utmost, constipation, constipation replace with diarrhea, abdominal pain, diarrhea, abdominal distension, borborygmus and flatus.
IBS is in the great majority as a kind of global disease, morbidity crowd with 20-40 years old the young and the middle aged, wherein, male to female ratio 2:1 higher with the disease incidence of male again, and the patient numbers of IBS are increasing.IBS disease incidence is up to 27% to north America region epidemiology tune Check in healthy population as the result is shown, it is then 10%-20% in American-European countries, in race's comparison, with European and American developed countries' disease incidence highest, followed by Asian, and the disease incidence of IBS is minimum in the African countries such as South Africa.China not yet carries out the extensive epidemiological survey in relation to IBS at present, but also fairly common, and the regional IBS patient having accounts for about the 1/3 of Gastroenterology Clinic patient.
Understanding about 150 year history of the mankind to IBS, but the cause of disease and pathogenesis of this disease do not illustrate completely yet, these complicated clinical characters are difficult to be explained with results such as simple dissection biochemistry, most scholars are considered caused by the Imbalance of nervous centralis caused by a variety of causes, enteric plexus, the exception of brain intestines axis causes point pine of neurotransmitter unbalance, so as to cause gastrointestinal tract a series of symptoms.
IBS patient has visceral paresthesia more, show as the long-term hypersensitive state of gastrointestinal tract, gastrointestinal reaction obviously increases, in the pathophysiological change of IBS, the abnormal problem of stomach and intestine dynamics is the most prominent, and researches show that gastrointestinal hormone and gastrointestinal tract dynamia are abnormal closely related, the regulation of bi-directional path between brain intestines axis is closely related again for its regulation, when extraneous various stimulus act on brain-gut axis, gastrointestinal hormone will appear diacrisis, brain-intestines interactive balance state is destroyed, lead to body microcirculation disorder, to induce a series of internal organ Gao Min, gastrointestinal reaction obviously increases, abdominal pain, diarrhea, abdominal distension, a series of clinical symptoms such as constipation.Scholar studies discovery gastrointestinal disease with Intestinal Microcirculation, and IBS rat model visceral sensitivity increases, and Mesentery microcirculation obstacle is algesiogenic main cause.Numerous studies confirm that the bioactive substances such as IBS rat model calcitonin generelated peptide, Endothelin, vasoactive intestinal peptide, interleukins adjust imbalance, and then the damage of endothelial cell is caused to cause microcirculation disorder.So the generation of IBS, development, variation it is all closely related with microcirculating state.
European hippocastanum Aesculus hippocastanum Linn. is Hippocastanaceae, buckeye, alias Europe horse-chestnut, European horse-chestnut.Aesculus shares more than plant 30, and China has 16 kinds.This platymiscium horse chestnut A.chinensis Bun.0ge, Zhejiang Buckeye A.chinensis Bun.0ge var.chekian.0gensis (Hu et Fan.0g) Fan.0g and Aesculus A.wilsonii Rehd. dry mature seed in China be traditional qi-regulating Chinese medicine, there are regulating the flow of QI to ease the stomach, protecting the stomach and relieve the pain and other effects, for diseases such as swollen bored, the stomach wrist pain of chest and abdomen.Hippocastanum seed and bark are traditional folk medicines in Europe, and for treating hemorrhoid, uterine hemorrhage, phlebangioma, cholestatis and hepatopathy illness, the otoginsenoside therefrom extracted is a kind of good anti-inflammation detumescence drug.Common dosage forms have tablet and powder-injection to hippocastanum seed extract (alcohol extract) in clinical application, mainly have aescin for injection and spirit piece advanced in years, main active is otoginsenoside (escin).Hippocastanum seed extract has the function of anti-oxidant, antioedematous, anti-inflammatory and to blood vessel.Otoginsenoside is clinically widely used in treating chronic venous insufficiency, various oedema, hemorrhoid, asthma and the illnesss such as antitumor, has antioxidation, impervious, detumescence effect, and antitumor action improves microcirculation.
Otoginsenoside is a kind of impermeability dehydrating agent, has significant stable vascular endothelial cell, improving micro_circulation effect.Otoginsenoside is protected the collagenous fibres of vein tube wall, is gradually restored the elasticity and contractile function of affected veins tube wall, improve its tension and intensity by the effect of protease in inhibition blood；Otoginsenoside also directly acts on vascular endothelial cell receptor simultaneously, and vein is caused to shrink, and increases venous backflow speed, reduces vein pressure, improves microcirculation.
In the therapeutic agent of existing irritable bowel syndrome, Linaclotide (Linaclotide) is the first guanylate cyclase-C agonist in the whole world, it is a kind of polypeptide containing 14 amino acid, guanosine cyclic mono-phosphate receptor that is combinable and activating enterocyte official jargon surface causes intracellular and extracellular loop guanylic acid to increase.Linaclotide is respectively at August in 2012 30 days and acquisition U.S. FDA on November 26th, 2012 and European Union EMEA approval listing.The most common adverse reaction reported in IBS patient is diarrhea, abdominal pain, flatulence and abdominal distension.
Hippocastanum extract is combined by the present invention with Linaclotide, can preferably treat irritable bowel syndrome.
Summary of the invention
The purpose of the present invention is to provide hippocastanum extracts and Linaclotide composition.Pass through application of the hippocastanum extract in preparation treatment irritable bowel syndrome drug, the therapeutic effect of irritable bowel syndrome can be improved, the dosage of guanylate cyclase-C receptor stimulating agent is reduced, mitigates the treatment toxic side effect of guanylate cyclase-C receptor stimulating agent, improves the compliance of patient medication.For this purpose, the present invention provides following technical scheme.
It includes hippocastanum extract, Linaclotide and pharmaceutically acceptable auxiliary material that the present invention, which provides a kind of hippocastanum extract and Linaclotide composition, the composition,.
The dosage form of the composition is the sustained release pellet of oral administration.
The sustained release pellet is made of the supplementary material of following weight percent: hippocastanum extract 10.0~75.0%, Linaclotide 20~88%, moulding material 0.8~3.0%, slow-release material 1.0~6.0%, plasticizer 0.2~0.8%, antiplastering aid 0.2~0.8%.
Preferably, the sustained release pellet is made of the supplementary material of following weight percent: hippocastanum extract 20.0~70.0%, Linaclotide 25~75%, moulding material 1.0~2.5%, slow-release material 1.5~5.0%, plasticizer 0.4~0.7%, antiplastering aid 0.3~0.6%.
Preferably, the mass ratio of hippocastanum extract and Linaclotide is 1:1~1:12.
The sustained release pellet of oral administration provided by the invention, preparation method are as follows:
1) various raw materials are prepared by the ratio of the sustained release pellet, is first uniformly mixed the hippocastanum extract of preparation, Linaclotide with moulding material, be then conventionally prepared into using dry granulating machine and carry medicine fine pellet core；
2) slow-release material, plasticizer, antiplastering aid of preparation are then prepared by mixing into slow release layer coating solution；
3) the load medicine pellet being prepared into is placed in fluidized bed, and the slow release layer coating solution being prepared into is sprayed into fluidized bed, medicine fine pellet core will be carried and be conventionally coated, sustained release pellet is prepared.
According to the sustained release pellet of above-mentioned oral administration, the slow-release material be selected from ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin, hydroxypropyl cellulose, hydroxyethyl cellulose acetyl cellulose, Cellulose Acetate Phthalate, shellac, cellulose acetate phthalate, vinyl acetate phthalate ester, hydroxypropyl methyl cellulose phthalate, refined gram preferably, any one of hydroxypropyl methylcellulose succinate, polylactic acid and palm wax or more than one.
Preferably, the slow-release material is selected from polyacrylic resin or ethyl cellulose.
According to the sustained release pellet of above-mentioned oral administration, the moulding material be selected from any one of microcrystalline cellulose, algal polysaccharides, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copolyvidone, hydrogenated vegetable oil and Compritol 888 ATO or more than one.
Preferably, the moulding material is selected from microcrystalline cellulose or copolyvidone.
According to the sustained release pellet of above-mentioned oral administration, the plasticizer be selected from any one of triethyl citrate, acetyl tributyl citrate triethylenetetraminehexaacetic acid ester, tributyl 2-acetylcitrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, tristerin, tributyl citrate, diethyl succinate, oleic acid, fractionated coconut oil and propylene glycol or more than one；
Preferably, the plasticizer is selected from polyethylene glycol or triethyl citrate.
According to the sustained release pellet of above-mentioned oral administration, the antiplastering aid be selected from any one of talcum powder, colloidal silicon dioxide, lactose, mannitol, povidone, hydroxypropyl methylcellulose and glycerin monostearate or more than one.
Preferably, the antiplastering aid is selected from talcum powder or hydroxypropyl methylcellulose.
Application of the composition in treatment irritable bowel syndrome.
It is according to above-mentioned hippocastanum extract and Linaclotide sustained release pellet, preparation method
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract, Linaclotide and moulding material by recipe quantity, crushed 80~120 meshes；Open Cryo Refrigerator; temperature is controlled at 5~15 DEG C, is put in hopper material into after 10min, is selected vertical speed for 12~20r/min; 40~60r/min of horizontal velocity; last item 14~20r/min of speed, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed slow-release material is added in 95% ethanol solution is dissolved to clarification first, obtain slow-release material ethanol solution, then weighed plasticizer, antiplastering aid are dissolved in slow-release material ethanol solution, are stirred to clarify, obtain sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40~45 DEG C, 60~70m3*h-1 of dry air flow, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2~3ml/min in a manner of the spray of bottom, atomizing pressure is 1.8~2.5bar, it steps up and is pumped into rate and is finished to 13~20ml/min to coating solution, stream temperature is improved to 45~50 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, pellet between 16~24 mesh is chosen, is sustained release pellet after passed examination.
Substantially nonirritant using the hippocastanum extract and guanylate cyclase-C receptor stimulating agent composition of technical solution of the present invention preparation, toxic side effect is few, is convenient for patient's long-term treatment, and improve the compliance of medication.
Take the hippocastanum extract and Linaclotide sustained release pellet of technical solution of the present invention preparation, it is daily primary to can guarantee 24 hours internal active drug concentration, and can be reduced the gastrointestinal reactions such as nausea,vomiting,diarrhea caused by gastrointestinal irritation brought by ordinary preparation.
The vitro release of Fig. 1 embodiment of the present invention 1 gained hippocastanum extract and Linaclotide sustained release pellet.
Embodiment of the present invention is described in detail below in conjunction with embodiment, it will be appreciated by those skilled in the art that the following example is merely to illustrate the present invention, and should not be taken as limiting the scope of the invention.
Embodiment 1
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 50.0g, Linaclotide 600.0g and microcrystalline cellulose 5.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 5 DEG C, is put in hopper material into after 10min, is selected vertical speed for 12r/min; horizontal velocity 40r/min; last item speed 20r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed polyacrylic resin 50.0g is added in 95% ethanol solution is dissolved to clarification first, obtain polyacrylic resin ethanol solution, then weighed polyethylene glycol 5.0g, talcum powder 2.0g are dissolved in polyacrylic resin ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 60m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 1.8bar is stepped up and is pumped into rate and is finished to 13ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 2
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 50.0g, Linaclotide 50.0g, crushed 120 meshes；Open Cryo Refrigerator; temperature is controlled at 10 DEG C, is put in hopper material into after 10min, is selected vertical speed for 15r/min; horizontal velocity 40r/min; last item speed 15r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed ethyl cellulose 8.0g is added in 95% ethanol solution is dissolved to clarification first, obtain ethyl cellulose ethanol solution, then weighed triethyl citrate 2.0g, hydroxypropyl methylcellulose 1.0g are dissolved in ethyl cellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 65m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 3ml/min in a manner of the spray of bottom, and atomizing pressure 1.9bar is stepped up and is pumped into rate and is finished to 15ml/min to coating solution, stream temperature is improved to 46 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 3
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 200.0g, Linaclotide 400.0g and copolyvidone 2.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 5 DEG C, is put in hopper material into after 10min, is selected vertical speed for 20r/min; horizontal velocity 40r/min; last item speed 20r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed hydroxypropyl methylcellulose 50.0g is added in 95% ethanol solution is dissolved to clarification first, obtain hydroxypropyl methylcellulose ethanol solution, then weighed diethyl succinate 5.0g, talcum powder 4.0g are dissolved in hydroxypropyl methylcellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 60m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 1.8bar is stepped up and is pumped into rate and is finished to 13ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 4
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 150.0g, Linaclotide 525.0g and hydrogenated vegetable oil 5.0g, crushed 80~120 meshes；Open Cryo Refrigerator; temperature is controlled at 5~15 DEG C, is put in hopper material into after 10min, is selected vertical speed for 20r/min; horizontal velocity 50r/min; last item speed 20r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed hydroxypropyl cellulose 60.0g is added in 95% ethanol solution is dissolved to clarification first, obtain hydroxypropyl cellulose ethanol solution, then weighed glyceryl triacetate 5.0g, colloidal silicon dioxide 5.0g are dissolved in hydroxypropyl cellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 60m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 2.5bar is stepped up and is pumped into rate and is finished to 20ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 5
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 200.0g, Linaclotide 500.0g and hydroxypropyl methylcellulose 5.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 10 DEG C, is put in hopper material into after 10min, is selected vertical speed for 15r/min; horizontal velocity 40r/min; last item speed 15r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed Cellulose Acetate Phthalate is added in 95% ethanol solution is dissolved to clarification first, obtain Cellulose Acetate Phthalate ethanol solution, then weighed acetyl tributyl citrate triethylenetetraminehexaacetic acid ester, mannitol are dissolved in Cellulose Acetate Phthalate ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 60m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 1.8bar is stepped up and is pumped into rate and is finished to 13ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 6
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 180.0g, Linaclotide 720.0g and hydroxypropyl cellulose 8.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 5 DEG C, is put in hopper material into after 10min, is selected vertical speed for 12r/min; horizontal velocity 40r/min; last item speed 14r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed ethyl cellulose 60.0g is added in 95% ethanol solution is dissolved to clarification first, obtain ethyl cellulose ethanol solution, then weighed tributyl 2-acetylcitrate 5.0g is dissolved in ethyl cellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40 DEG C, dry air flow 60m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 2.5bar is stepped up and is pumped into rate and is finished to 15ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 7
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 120.0g, Linaclotide 840.0g, crushing sieves with 100 mesh sieve；Open Cryo Refrigerator; temperature is controlled at 10 DEG C, is put in hopper material into after 10min, is selected vertical speed for 15r/min; horizontal velocity 40r/min; last item speed 14r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed cellulose acetate phthalate 100.0g is added in 95% ethanol solution is dissolved to clarification first, obtain cellulose acetate phthalate ethanol solution, then weighed dibutyl phthalate 5.0g, talcum powder 2.0g are dissolved in cellulose acetate phthalate ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 45 DEG C, dry air flow 70m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 3ml/min in a manner of the spray of bottom, and atomizing pressure 2.0bar is stepped up and is pumped into rate and is finished to 16ml/min to coating solution, stream temperature is improved to 50 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 8
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 80.0g, Linaclotide 480.0g and ethyl cellulose 5.0g, crushed 120 meshes；Open Cryo Refrigerator; temperature is controlled at 15 DEG C, is put in hopper material into after 10min, is selected vertical speed for 20r/min; horizontal velocity 40r/min; last item speed 20r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed hydroxypropyl methylcellulose 50.0g is added in 95% ethanol solution is dissolved to clarification first, obtain hydroxypropyl methylcellulose ethanol solution, then weighed tributyl citrate 5.0g, hydroxypropyl methylcellulose 2.0g are dissolved in hydroxypropyl methylcellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 45 DEG C, dry air flow 70m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 3ml/min in a manner of the spray of bottom, and atomizing pressure 1.8bar is stepped up and is pumped into rate and is finished to 13ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 9
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 50.0g, Linaclotide 600.0g and povidone 5.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 15 DEG C, is put in hopper material into after 10min, is selected vertical speed for 12r/min; horizontal velocity 40r/min; last item speed 14r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed polyacrylic resin 50.0g is added in 95% ethanol solution is dissolved to clarification first, obtain polyacrylic resin ethanol solution, then weighed oleic acid 5.0g, lactose 2.0g are dissolved in polyacrylic resin ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 45 DEG C, dry air flow 70m3*h-1, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2ml/min in a manner of the spray of bottom, and atomizing pressure 1.8bar is stepped up and is pumped into rate and is finished to 13ml/min to coating solution, stream temperature is improved to 45 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, choose pellet between 16~24 mesh, is sustained release pellet after passed examination.
Embodiment 10
(1), it carries the preparation of medicine fine pellet core: weighing hippocastanum extract 80.0g, Linaclotide 400.0g and microcrystalline cellulose 1.0g, crushed 80 meshes；Open Cryo Refrigerator; temperature is controlled at 5 DEG C, is put in hopper material into after 10min, is selected vertical speed for 12r/min; horizontal velocity 40r/min; last item speed 14r/min, dry granulating machine by supplementary material extrusion forming and under the action of arranging knife formed uniform particle diameter load medicine pellet, sieving; take the pellet between 18~30 mesh; it is squeezed again less than 30 mesh, until whole components are extruded as the pellet between 18~30 mesh to get load medicine fine pellet core；
(2), the preparation of sustained release pellet: weighed hydroxyethyl cellulose acetyl cellulose is added in 95% ethanol solution is dissolved to clarification first, obtain hydroxyethyl cellulose acetyl cellulose ethanol solution, then weighed propylene glycol, hydroxypropyl methylcellulose are dissolved in hydroxyethyl cellulose acetyl cellulose ethanol solution, it stirs to clarify, obtains sustained release coating liquid；It takes and carries medicine fine pellet core, stream temperature is adjusted to 40~45 DEG C, 60~70m3*h-1 of dry air flow, take gained sustained release coating liquid, spray chamber atomization coating is pumped into the flow velocity of peristaltic pump 2~3ml/min in a manner of the spray of bottom, atomizing pressure is 1.8~2.5bar, it steps up and is pumped into rate and is finished to 13~20ml/min to coating solution, stream temperature is improved to 45~50 DEG C, continue fluidized drying in a fluidized bed to take out after 30 minutes, pellet between 16~24 mesh is chosen, is sustained release pellet after passed examination.
11 drug release determination of embodiment
Using sustained release pellet obtained in embodiment 1 as test sample, release experimental method is as follows:
1 products obtained therefrom of Example, according to drug release determination method (the first method of annex XD), using the device of dissolution method (the second method of annex XC), using water 900ml as solvent, revolving speed is 50 turns per minute, is operated according to methods, through 1,2,4,6,8 and 12 hour, solution is taken to filter in right amount, synthermal same volume medium is supplemented simultaneously, discards at least 10ml primary filtrate, it is appropriate that precision measures subsequent filtrate, it is diluted with water the solution being made in every 1ml containing 0.67mg, as test solution.Using YMC ProTM C18 column (size: 3.0x 150mm, 3.5um, Waters Corp., Milford, MA) or equivalent column, and maintain 40 DEG C.Mobile phase A (MPA) containing 0.1% trifluoroacetic water by forming, and Mobile phase B (MPB) is by 95% acetonitrile: 5% forms containing 0.1% trifluoroacetic water.By external standard method with calculated by peak area burst size.
Experimental result is shown in attached drawing 1, under identical testing conditions, experimental result is same as Example 1 for the products obtained therefrom of embodiment 2~9, meets the requirements.
Influence of the embodiment 12 to IBS rat model
Newborn Wistar rats 54, cleaning grade, normal group (n=6) and model group (n=48) are randomly divided by weight, 6 are left and taken after molding at random and is only used as model control group, remaining is respectively as therapeutic agent group of the present invention (embodiment 1,3,5,7,8,9, n=6) and Linaclotide drugs compared group (n=6).
IBS rat model is prepared using mother and sons' separation and acetic acid enema.To 2~21 age in days young rats, it is separated into 2h with female rat daily, and give acetic acid in rectum to stimulate, i.e., the central venous catheter (diameter 1mm) after paraffin oil lubrication is inserted into anus 2cm, injects 0.5% acetic acid 0.5ml.In 2 weeks from experiment the 22nd day, without any experimental implementation, to the 5th weekend, visceral sensitivity assessment is carried out to normal group and model group rats by the method for the introductions such as Al-chaer, normal rats person is substantially less than with model group rats abdomen rebound reflex (AWR) capacity threshold as the success of IBS model, 48 equal Cheng Mo of rat.Treatment was since the 6th week, and therapeutic agent group gives embodiment 1,3,5,7,8,9 group of 2 μ g/kg of drug respectively, and drugs compared group gives Linaclotide 2 μ g/kg.
Visceral sensitivity evaluation index
Visceral sensitivity assessment was carried out by AWR to each group rat in the 2nd day after treatment end, rat is put into special transparent plastic cage, can only move forward and backward, cannot turn round, 2F double lumen catheter after paraffin oil lubrication is inserted into through rat anus, air bag end is apart from anus 1cm.With adhesive plaster conduit and rat tail root tangle up, fixation balloon.After rat adapts to environment, into air bag, gradually enteron aisle 20s is expanded in water filling.Observation AWR causes the capacity threshold (filling the water ml number) that each group rat abdomen lifts (abdomen shrinks and lifts) and back is arched upward (back of a bow simultaneously lifts pelvis) respectively.
To obtain accurate assessment result, each threshold measurement is all repeated 3 times, data take mean value, the results are shown in Table 1.
1 each group rat abdomen of table lifts value, back is arched upward, and value compares
P < 0.01 * compared with normal group, P < 0.01 * * compared with model group
Compared with normal group, model group abdomen lifts value and the back value that arches upward and reduces, and has extremely significant sex differernce (P < 0.01)；Compared with model group, 1,3,5,7,8,9 group of Linaclotide group, embodiment abdomen lift value and back is arched upward, and value is increased, and has extremely significant sex differernce (P < 0.01).Embodiment group effect is better than contrast groups.
Mesentery microcirculation detection
The 2nd day after treatment end, give 20% urethane intramuscular injection (0.7ml/100.0g) of rat anesthesia, abdomen is opened along abdomen median line, involve lower ileum, by mesenterium tiling, it is fixed on the constant temperature perfusion box of micro-circle microscope objective table, physiological saline maintains 37 DEG C of isoperibols, and microscope is connect with image analysis system.Mesenteric microvessels are raked about, the caliber and blood flow state of (x40) every same capilary of animal mesenterium is observed continuously under 30min scope, record 10min, 20min, 30min image change.The characteristics of blood flow state combines this experiment according to field ox sxemiquantitative flow velocity fractionation testing method is divided into 4 grades: 0 grades, and blood flow is fast, in smooth rope strip, nothing or has microparticle sense；I grade, blood flow is very fast, there is apparent granular sensation；II grade, blood flow is slow, at silt shape, flows slow or swing；III grade, blood flow cessation is motionless or blood flow is invisible.Measured value is for statistical analysis when taking observation 10min, 20min, 30min.To obtain accurate assessment result, each measured value is all repeated 3 times, data take mean value.
Influence to mesenteric microvessels caliber, the results are shown in Table 2.
The variation of 2 each group rat microvascular diameter of table
P < 0.05 * compared with normal group, P < 0.01 * * P < 0.05, * * * compared with model group
Compared with normal group, model group microvascular diameter is obviously shunk, and difference is statistically significant (P < 0.05), and compared with model group, contrast groups, 1,3,5,7,8,9 group of difference of embodiment is statistically significant (P < 0.05 or P < 0.01).Embodiment group effect is better than contrast groups.
Influence to mesenteric microvessels blood flow state, is shown in Table 3.
The variation of 3 each group Rat Mesenteric Microcirculation blood flow state of table
Note) P < 0.01 * compared with normal group
Compared with normal group, model group slow blood flow or stopping, II~III grade of person be more, difference has conspicuousness statistical significance (P < 0.01), compared with model group, contrast groups, 1,3,5,7,8,9 group of blood flow of embodiment is obviously accelerated, and full recovery is to 0~I grade.Embodiment group effect is better than contrast groups.
Claims (15)
- A kind of hippocastanum extract and Linaclotide composition, which is characterized in that the composition includes hippocastanum extract, Linaclotide and pharmaceutically acceptable auxiliary material.
- Hippocastanum extract and Linaclotide composition according to claim 1, wherein the dosage form of composition is the sustained release pellet of oral administration.
- The sustained release pellet of oral administration according to claim 2, it is characterized in that, the sustained release pellet is made of the supplementary material of following weight percent: hippocastanum extract 10.0~75.0%, Linaclotide 20~88%, moulding material 0.8~3.0%, slow-release material 1.0~6.0%, plasticizer 0.2~0.8%, antiplastering aid 0.2~0.8%.
- The sustained release pellet of oral administration according to claim 3, it is characterized in that, the sustained release pellet is made of the supplementary material of following weight percent: hippocastanum seed extract 20.0~70.0%, Linaclotide 25~75%, moulding material 1.0~2.5%, slow-release material 1.5~5.0%, plasticizer 0.4~0.7%, antiplastering aid 0.3~0.6%.
- The sustained release pellet of oral administration according to any one of claims 1 to 4, which is characterized in that the mass ratio of hippocastanum extract and Linaclotide is 1:1~1:12.
- According to the sustained release pellet of the oral administration any in claim 2~4, which is characterized in that preparation method are as follows:1) various raw materials are prepared according to the ratio of sustained release pellet described in claim 3 or 4; the hippocastanum extract of preparation, Linaclotide are uniformly mixed with moulding material first, is then conventionally prepared into using dry granulating machine and carries medicine fine pellet core；2) slow-release material, plasticizer, antiplastering aid of preparation are then prepared by mixing into slow release layer coating solution；3) the load medicine pellet being prepared into is placed in fluidized bed, and the slow release layer coating solution being prepared into is sprayed into fluidized bed, medicine fine pellet core will be carried and be conventionally coated, sustained release pellet is prepared.
- According to the sustained release pellet of any oral administration of claim 3 or 4, it is characterized in that, slow-release material be selected from ethyl cellulose, hydroxypropyl methylcellulose, polyacrylic resin, hydroxypropyl cellulose, hydroxyethyl cellulose acetyl cellulose, Cellulose Acetate Phthalate, shellac, cellulose acetate phthalate, vinyl acetate phthalate ester, hydroxypropyl methyl cellulose phthalate, refined gram preferably, any one of hydroxypropyl methylcellulose succinate, polylactic acid and palm wax or more than one.
- Slow-release material according to claim 7 preferably is selected from polyacrylic resin or ethyl cellulose.
- According to the sustained release pellet of any oral administration of claim 3 or 4, it is characterized in that, moulding material be selected from any one of microcrystalline cellulose, algal polysaccharides, ethyl cellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, povidone, copolyvidone, hydrogenated vegetable oil and Compritol 888 ATO or more than one.
- Moulding material according to claim 9 preferably is selected from microcrystalline cellulose or copolyvidone.
- According to the sustained release pellet of any oral administration of claim 3 or 4, it is characterized in that, plasticizer be selected from any one of triethyl citrate, acetyl tributyl citrate triethylenetetraminehexaacetic acid ester, tributyl 2-acetylcitrate, dibutyl sebacate, glyceryl triacetate, polyethylene glycol, diethyl phthalate, dibutyl phthalate, tristerin, tributyl citrate, diethyl succinate, oleic acid, fractionated coconut oil and propylene glycol or more than one；
- Plasticizer according to claim 11 preferably is selected from polyethylene glycol or triethyl citrate.
- According to the sustained release pellet of any oral administration of claim 3 or 4, which is characterized in that antiplastering aid be selected from any one of talcum powder, colloidal silicon dioxide, lactose, mannitol, povidone, hydroxypropyl methylcellulose and glycerin monostearate or more than one.
- Antiplastering aid according to claim 13 preferably is selected from talcum powder or hydroxypropyl methylcellulose.
- Application of the composition described in claim 1 in treatment irritable bowel syndrome.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/CN2018/072588 WO2019136744A1 (en) | 2018-01-15 | 2018-01-15 | Composition of hippocastanum extract and linaclotide |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN110337302A true CN110337302A (en) | 2019-10-15 |
| CN110337302B CN110337302B (en) | 2023-07-21 |
Family
ID=67218434
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201880011039.XA Active CN110337302B (en) | 2018-01-15 | 2018-01-15 | Horse chestnut extract and linaclotide composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN110337302B (en) |
| WO (1) | WO2019136744A1 (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101023952A (en) * | 2006-02-20 | 2007-08-29 | 张丽娟 | Use of aesin in releasing abdominal distention and astriction |
| US20110288011A1 (en) * | 2008-12-05 | 2011-11-24 | Jean-Paul Castaigne | Peptide therapeutic conjugates and uses thereof |
| 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 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU2014218599C1 (en) * | 2013-02-25 | 2018-09-06 | Bausch Health Ireland Limited | Guanylate cyclase receptor agonists for use in colonic cleansing |
| 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 |
-
2018
- 2018-01-15 CN CN201880011039.XA patent/CN110337302B/en active Active
- 2018-01-15 WO PCT/CN2018/072588 patent/WO2019136744A1/en active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101023952A (en) * | 2006-02-20 | 2007-08-29 | 张丽娟 | Use of aesin in releasing abdominal distention and astriction |
| US20110288011A1 (en) * | 2008-12-05 | 2011-11-24 | Jean-Paul Castaigne | Peptide therapeutic conjugates and uses thereof |
| 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 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN110337302B (en) | 2023-07-21 |
| WO2019136744A1 (en) | 2019-07-18 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN102085252B (en) | Pharmaceutical composition for treating ulcerative colitis and colon-targeted micro-pill preparation thereof | |
| CN105997985A (en) | Application of marihuana extract in preparation of gout treating medicine | |
| US20160151435A1 (en) | Pharmaceutical composition adjuvant to chemotherapy drugs and applications thereof | |
| CN102526164A (en) | Traditional Chinese medicine composition for preventing insulin resistance and related metabolic syndrome thereof | |
| WO2017129056A1 (en) | Medicament for use in treating cardiovascular and cerebrovascular diseases | |
| CN108888670A (en) | A kind of segmented intestine targeted capsule that treating ulcerative colitis and its preparation process | |
| Yan et al. | Reactive oxygen species-responsive nanocarrier ameliorates murine colitis by intervening colonic innate and adaptive immune responses | |
| CN108853008A (en) | A kind of preparation method and applications of injectable natural products gel | |
| CN1689575A (en) | Application of ocotillol in the preparing process of medicine for treating or preventing cardiovascular and cerebrovascular disease | |
| CN105327069A (en) | Formulation, preparation method and application of liver soothing traditional Chinese herbal medicine composition | |
| CN102895278A (en) | Application of arctinin and arctigenin in resisting parkinsonism | |
| CN110337302A (en) | A kind of hippocastanum extract and Linaclotide composition | |
| CN110292596A (en) | Black raspberry anthocyanin is preparing the application in anti-liver injury medicament or health food | |
| CN101095716A (en) | Use of cortex eucommiae total polyoses in the preparing of the medicine for preventing and treating systematic lupus erythematosus | |
| CN106074464A (en) | Cannabidiol application in preparation treatment gout medicine | |
| CN102784157B (en) | The purposes of Gracillin and the pharmaceutical composition containing Gracillin | |
| CN101327235A (en) | Use of pseudo-ginseng saponins for treating septicemia | |
| CN110038002A (en) | Salviandic acid A prevents and treats the purposes of muscular atrophy, myopathy and muscle skeleton complication | |
| CN100360120C (en) | Application of fenugreek total alkali extract in preparing medicine for ulcerative colitis and preparation method of colon targeted preparation | |
| CN109419787A (en) | A kind of purposes of Diterpene class compound | |
| CN106554349A (en) | Wild anistree new isopentene group replaces C6‑C3Class compound and preparation method thereof, application and its pharmaceutical composition | |
| CN105919991B (en) | Application of the euparin in preparation medicament for treatment of depression | |
| CN106074714B (en) | It is a kind of to treat irritable bowel syndrome pharmaceutical composition | |
| CN104096089A (en) | Traditional Chinese medicine composition for treating ischemia apoplexy, and capsules and preparation method thereof | |
| CN103505488A (en) | Traditional Chinese medicine composition of pseudo-ginseng and sea-buckthorn and preparation method of composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |