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CN108904808A - A kind of pharmaceutical composition and its application for treating constipation - Google Patents

A kind of pharmaceutical composition and its application for treating constipation Download PDF

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Publication number
CN108904808A
CN108904808A CN201810928336.2A CN201810928336A CN108904808A CN 108904808 A CN108904808 A CN 108904808A CN 201810928336 A CN201810928336 A CN 201810928336A CN 108904808 A CN108904808 A CN 108904808A
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starch sodium
carboxyrnethyl starch
pharmaceutical composition
constipation
carboxyrnethyl
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陈涛
卫东
卢伍党
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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XI'AN LIBANG MEDICINE SCIENCE AND TECHNOLOGY Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/454—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
    • A61K31/558—Eicosanoids, e.g. leukotrienes or prostaglandins having heterocyclic rings containing oxygen as the only ring hetero atom, e.g. thromboxanes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7052—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
    • A61K31/716—Glucans
    • A61K31/718—Starch or degraded starch, e.g. amylose, amylopectin
    • 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
    • A61P1/10—Laxatives

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Abstract

The pharmaceutical composition formed disclosure sets forth the water soluble starch salt modified by carboxylic acid group and rush digestive tract power reinforcing medicine or rush secretion medicine is preventing and treating the use in conjunction in constipation, it is applicable to various functional consitipations, especially there is good curative effect to old Refractory Constipation, chronic constipation, habitual constipation, drug induced constipation etc., and adverse reaction is slight, can be suitably used for various crowds.The representative drugs of the water soluble starch salt of the carboxylic acid group modification are carboxyrnethyl starch sodium；The rush digestive tract power reinforcing medicine promotees secretion medicine selected from dopamine-receptor antagonist, 5-HT4 receptor stimulating agent, motilin agonists, chloride channel activators, guanylate cyclase agonist.Two kinds of ingredients can be prepared into any oral pharmaceutical dosage form, including oral solution, oral suspensions, granule, powder, tablet, capsule etc. by suitable weight ratio combination.

Description

A kind of pharmaceutical composition and its application for treating constipation
Technical field
The present invention relates to a kind of pharmaceutical composition and its medicinal usages, and in particular to a kind of water solubility of carboxylic acid group modification Starch salt and rush digestive tract power reinforcing medicine promote doctor of the secretion medicine for the pharmaceutical composition of active pharmaceutical ingredient and its for constipation therapy Medicinal way, the invention belongs to field of medicaments.
Background technique
Constipation refer to normal defecation form change, times of defecation reduction, difficult defecation etc., constipation is a kind of clinic Common complicated symptom, it is reported that illness rate of the constipation in crowd is up to 27%.Chronic constipation was within quite long period in past It is despised by people, in recent years may be due to people's unreasonable diet structure, the reasons such as sitting, manual labor are reduced, constipation Illness rate increases year by year, and because of cause of disease complexity, the course of disease is repeatedly touching, and patient often has manifold vexations, and seriously affects people's lives matter Amount, and have researches show that constipation and acute cardiovascular and cerebrovascular disease, dementia, Colorectal Cancer close relation, cause to get over Carry out more concerns.
Constipation pathogenesis is still not clear, and lacks effective therapeutic agent.Clinically chronic constipation treatment usually using compared with More is laxative, including bulk-forming laxative (common drug has psyllium, calcium polycarbophil, wheat bran etc.), permeability purgatives (packet Include polyethylene glycol, lactulose and magnesium sulfate etc.), irritant laxative (including Bisacody, phenolphthalein, Anthraquinone and castor oil Deng).Though purgatives can short-term relief constipation symptom, be unable to improve patient's long-term life quality, especially to it is chronic, habitual just Secret, constipation touching breaking-out repeatedly seriously perplexs patient, anxiety, depressive state easily occurs, seriously affect quality of life, physiology, It is psychological to generate apparent negative effect, while mental handicape can influence the regulation of brain intestines axis, further damage defecation mechanism, make Patient lacks confidence and patience, reduces curative compliance.Network-based investigation display in 2014, there is 57% patient couple Laxative is not exclusively satisfied, wherein 82% due to unsatisfactory curative effect, 16% due to adverse reaction.There are also more constipation patients to use Promote digestive tract power reinforcing medicine, gastrointestinal tract contraction, promotion and stimulation gastric emptying can be increased by increasing gastrointestinal propulsive effect movement to improve The symptoms such as functional dyspepsia FD.
Promoting digestive tract power reinforcing medicine can be divided on pharmacological mechanism and action target spot：(1) dopamine-receptor antagonist, such as first Oxygen Emetisan, domperidone, Itopride and clebopride etc. can significantly increase gastroduodenal movement, promote gastric emptying, add Fast small intestine and large intestine by the time, and play its full stomach and intestine small intestinal transit.Cause maincenter due to can pass through blood-brain barrier There is extrapyramidal system adverse reaction in neurological side effects, and it is dense to can inhibit acetylcholine esterase active, the blood of influence prolactin , often there are the adverse reactions such as related lactation, paramenia in degree.(2) 5-HT4 receptor stimulating agent represents drug Cisapride, not The serotonin of Sha Bili and prucalopride, alternative excitement gastrointestinal tract cholinergic intrerneuron and myoneural clump by Body, stimulation acetylcholine discharges, to enhance gastrointestinal motility, while can enhance colon beam and reflect the contraction of electrical excitation, promote Intestinal pushing effect, the decline of colon tension is to reach aperient effects.But influence due to proarrhythmia and to heart function and limit Its application is made, Cisapride is even more to stop using since fatal arrhythmia cordis occurs during clinical use.(3) stomach Therbligs receptor stimulating agent, excitement are located at the Motilin receptor of gastrointestinal smooth muscle, stimulate antrum and duodenal contractility, cause intestines compacted It is dynamic to change, lead to diarrhea, enterospasm, representing drug has erythromycin.
Promoting secretion medicine mainly includes chloride channel (CIC) activator and guanosine cyclic mono-phosphate (GC-C) agonist, CIC Activator acts on chloride channel, promotes liquid transporting in enteron aisle, secretion, Lubiprostone 1 be it is first be used to treat it is chronic just Secret CIC activator, can CIC2 on efficient activation enterocyte, promote intestinal fluid secretion, increase stool volume, accelerate small The mass transfer of intestines and colon, common adverse reaction are nausea, diarrhea.GC-C agonist belongs to small peptide, can be big by promoting The uncommon bacterium of intestines angstrom generates heat-stable toxin, increases intestinal fluid secretion and intestinal movement frequency indirectly, and can be relieved the abdomen of constipation patient The discomforts such as flatulence improve patients ' life quality, and representative drugs include Linaclotide, Pu Kana peptide etc..
Although carboxyrnethyl starch sodium there is no to find in research before for treating the medical usage of constipation, my company at present Carboxyrnethyl starch sodium belongs to one kind of modification of polysaccharides, not soluble easily in water by gastrointestinal tract absorption after taking orally, and can make enteral osmotic pressure It increases, large quantity of moisture can be absorbed and prevent intestinal absorption moisture, then enteral is able to retain large quantity of moisture, volume increase expansion intestines Road, to intestinal mucosa generate stimulation so as to cause enterocinesia enhancing, achieve the purpose that treat constipation, from the mechanism of action for belong to In bulk cathartic.But have a disadvantage in that different crowd is different to the response situation of drug, especially certain women are chronic just Secret patient reacts bad to it.Common adverse reaction has abdominal distension, diarrhea, nausea etc..
In view of the studies above it is found that old Refractory Constipation, chronic constipation, habitual constipation etc. are more obstinate, often one Class defaecation drug can not reach good therapeutic effect, and treatment difficulty is big, should take complex treatment measure.The present invention passes through joint It is prepared into different types of oral preparation using carboxyrnethyl starch sodium and rush digestive tract power reinforcing medicine or rush secretion medicine and is applied to constipation patient, Promote digestive tract power reinforcing medicine enhancing gastrointestinal motility ability, intestines is promoted to push ability；Promote secretion medicine and promote liquid secretion and transport in enteron aisle, Increase intestinal movement frequency；Carboxyrnethyl starch sodium increases enteral moisture, expansion enteron aisle volume, and heterogeneity is made by different approach For constipation patient, synergistic effect is generated, extraordinary curative effect is all achieved in all kinds of patients.And synergistic effect It generates, so that the dose of two kinds of ingredients can decline to a great extent, significant decrease has relatively been used alone in adverse reaction rate, and And it is slight.Meanwhile U.S. Food and Drug Administration (FDA) announcement active polysaccharide can significantly reduce the morbidity of human diseases Rate, carboxyrnethyl starch sodium are exactly that such a endogenous immune adjusts active polysaccharide, be used for a long time not but not cause patient according to Lai Xing enhances autoimmunity for patient instead, improves disease resistance and is very beneficial, and constipation is asked in the raising of immunity The improvement of topic is also to do a great deal of good.
Summary of the invention
The purpose of the present invention is to provide a kind of pharmaceutical compositions for treating constipation.
Pharmaceutical composition of the present invention is mainly made of following two active pharmaceutical ingredient：
(1) the water soluble starch salt of carboxylic acid group modification,
(2) promote digestive tract power reinforcing medicine or promote secretion medicine.
The weight ratio of the two is：0.1~10:0.000008~1, more preferably selection is 0.5~2:0.000008~1.
Wherein, the water soluble starch salt of carboxylic acid group modification, between the molecular weight area of the compound between 1~500,000, more Good selection be between 5~300,000,
The carboxylic acid group degree of substitution of the compound between 0.2~2, more preferably selection be between 0.4~2,
The carboxylic acid group of the compound is：(CH2) xCO2Y, wherein x is the metals such as sodium, potassium, iron, zinc, tin between 1-5, Y One of cation is a variety of.
It is furthermore preferred that the water soluble starch salt of carboxylic acid group modification is carboxyrnethyl starch sodium.
Wherein, promote digestive tract power reinforcing medicine and be selected from dopamine-receptor antagonist, 5-HT4 receptor stimulating agent, Motilin receptor excitement One of agent；Promote secretion medicine and is selected from one of chloride channel activators and guanylate cyclase agonist.
Wherein, dopamine-receptor antagonist is selected from：Metoclopramide, domperidone, Itopride or clebopride；5- HT4 receptor stimulating agent is selected from：Mosapride or prucalopride；Motilin agonists are selected from：Erythromycin, roxithromycin, gram Draw mycin or azithromycin；Chloride channel activators are：Lubiprostone 1；Guanylate cyclase agonist is selected from：Li Naluo Peptide or Pu Kana peptide.
Preferably, pharmaceutical composition of the invention is following combination：
(1) carboxyrnethyl starch sodium：Metoclopramide=0.5~2：0.005~0.03
(2) carboxyrnethyl starch sodium：Domperidone=0.5~2：0.01~0.08
(3) carboxyrnethyl starch sodium：Itopride=0.5~2：0.015~0.15
(4) carboxyrnethyl starch sodium：Clebopride=0.5~2：0.00068~0.00204
(5) carboxyrnethyl starch sodium：Mosapride=0.5~2：0.002~0.015
(6) carboxyrnethyl starch sodium：Prucalopride=0.5~2：0.0005~0.002
(7) carboxyrnethyl starch sodium：Erythromycin=0.5~2：0.25~1
(8) carboxyrnethyl starch sodium：Roxithromycin=0.5~2：0.05~0.3
(9) carboxyrnethyl starch sodium：Clarithromycin=0.5~2：0.125~0.5
(10) carboxyrnethyl starch sodium：Azithromycin=0.5~2：0.125~0.5
(11) carboxyrnethyl starch sodium：Lubiprostone 1=0.5~2：0.000008~0.000048
(12) carboxyrnethyl starch sodium：Linaclotide=0.5~2：0.00005~0.000145
(13) carboxyrnethyl starch sodium：Peptide=0.5~2 Pu Kana：0.0005~0.003.
It is further preferred that pharmaceutical composition of the invention is following combination：
(1) carboxyrnethyl starch sodium：Metoclopramide=0.5~2：0.005~0.015
(2) carboxyrnethyl starch sodium：Domperidone=0.5~2：0.01~0.06
(3) carboxyrnethyl starch sodium：Itopride=0.5~2：0.03~0.1
(4) carboxyrnethyl starch sodium：Clebopride=0.5~2：0.00068~0.00136
(5) carboxyrnethyl starch sodium：Mosapride=0.5~2：0.005~0.01
(6) carboxyrnethyl starch sodium：Prucalopride=0.5~2：0.0005~0.001
(7) carboxyrnethyl starch sodium：Erythromycin=0.5~2：0.25~0.75
(8) carboxyrnethyl starch sodium：Roxithromycin=0.5~2：0.05~0.15
(9) carboxyrnethyl starch sodium：Clarithromycin=0.5~2：0.125~0.375
(10) carboxyrnethyl starch sodium：Azithromycin=0.5~2：0.125~0.375
(11) carboxyrnethyl starch sodium：Lubiprostone 1=0.5~2：0.000008~0.000024
(12) carboxyrnethyl starch sodium：Linaclotide=0.5~2：0.00005~0.0001
(13) carboxyrnethyl starch sodium：Peptide=0.5~2 Pu Kana：0.001~0.002.
It is furthermore preferred that pharmaceutical composition of the invention is following combination：
(1) carboxyrnethyl starch sodium：Domperidone=0.5：0.02
(2) carboxyrnethyl starch sodium：Prucalopride=0.5：0.0005
(3) carboxyrnethyl starch sodium：Roxithromycin=0.5：0.1
(4) carboxyrnethyl starch sodium：Azithromycin=0.5：0.25
(5) carboxyrnethyl starch sodium：Lubiprostone 1=0.5：0.000012
(6) carboxyrnethyl starch sodium：Linaclotide=0.5：0.00001
(7) carboxyrnethyl starch sodium：Peptide=0.5 Pu Kana：0.0015.
Pharmaceutical composition of the invention can be prepared into any oral pharmaceutical dosage form.
Pharmaceutical composition of the present invention, with carboxylic acid group modify water soluble starch salt, and promote digestive tract power reinforcing medicine or Promoting secretion medicine is active pharmaceutical ingredient, and 0.1%~99.9% is accounted in pharmaceutical composition, remaining For the excipient pharmaceutically allowed.
Pharmaceutical composition of the present invention can be any peroral dosage form, these dosage forms include：Tablet, such as sugar coated tablet Agent, film coated tablet, enteric coated tablet；Capsule, such as hard capsule, soft capsule；Oral solution；Mouth containing agent；Granule；It dissipates Agent；Solution.
Preferably, preparation formulation of the invention is：Oral solution, oral suspensions, granule, tablet, capsule.
The excipient pharmaceutically allowed, including but not limited to sugar alcohol, such as mannitol, sorbierite, xylitol；Amino acid, Such as cysteine hydrochloride, methionine, glycine；Vitamin C；EDETATE SODIUM, Ethylenediaminetetraacetic Acid Calcium Salt；Inorganic salts, such as monoacidic base gold Carbonate, acetate, phosphate or its aqueous solution of category；Sodium chloride, potassium chloride；Sodium pyrosulfite, sodium hydrogensulfite, thio sulphur Sour sodium；Calcium carbonate, calcium bicarbonate；Stearate, such as calcium stearate, magnesium stearate；Inorganic acid, such as hydrochloric acid, acetic acid, sulphur Acid, phosphoric acid；Acylate, such as sodium lactate；Oligosaccharides, polysaccharide, cellulose and its derivates, such as maltose, glucose, fruit Sugar, dextran, sucrose, lactose, cyclodextrin (such as beta-cyclodextrin), microcrystalline cellulose, starch, hydroxypropyl cellulose, hydroxypropyl Methylcellulose, alginate；Gelatin；Polyvinylpyrrolidone；Glycerol；Agar；Surfactant, such as Tween 80, dodecane Base sodium sulphate；Polyethylene glycol；Phospholipid material；Kaolin；Talcum powder etc..
Preferably, type of the excipient in liquid preparation includes solvent, pH adjusting agent, sweetener, essence, metal-chelating One of agent is a variety of, and the type in solid pharmaceutical preparation includes filler, disintegrating agent, adhesive, lubricant, sweetener, acid One of taste agent, essence are a variety of.
It is another object of the present invention to provide the pharmaceutical composition, answering in preparation prevention and/or treatment constipation With.
The pharmaceutical composition is applicable to various functional consitipations, especially to old Refractory Constipation, it is acute and chronic just Secret, habitual constipation, drug induced constipation etc. have good curative effect, and adverse reaction is rare and slight, can be suitably used for various crowds, Lead to the crowd etc. of constipation including adult, children, pregnant woman, the elderly, drug induced constipation crowd, long-term bed.
The water soluble starch salt and promote digestive tract power reinforcing medicine or promote to divide that pharmaceutical composition of the invention contains carboxylic acid group modification Secrete two kinds of active pharmaceutical ingredients of medicine.The mechanism of action of two kinds of active pharmaceutical ingredients is different, unexpected to produce after two kinds of pharmaceutical compositions Raw extraordinary synergy, the pharmaceutical composition will daily arrange the therapeutic effect of constipation increasing patient more comprehensively Just it obviously due to the folk prescription of same dose in terms of measuring, enhancing Intestinal Mucosal Injury in Patients Undergoing propulsive force and reduce sphincter pressures, mentions Show that the pharmaceutical composition has obviously therapeutic effect to functional consitipation.Inventor is by reasonably selecting two in composition The usage ratio of kind active constituent, selects suitable pharmaceutical dosage form, so that greatly dropping while constipation therapy effect promoting Low toxic side effect.Moreover, drug ingedient is clear, property is stable, consistency problem is not present, controlled convenient for quality, it is very suitable Close industrialized production.
When for treating, the dosage of carboxyrnethyl starch sodium is 0.1~10g/d, preferably 0.5~2g/ in pharmaceutical composition d；Promote digestive tract power reinforcing medicine or promote secretion medicine because of the difference of its type, dosage can be the 10%~100% of its conventional amount used, specifically It is as follows：5~30mg/d of Metoclopramide, 10~80mg/d of domperidone, 15~150mg/d of Itopride, clebopride 0.5 ~2mg/d, Mosapride 2mg~15mg/d, 0.5~2mg/d of prucalopride, 0.2~1g/d of erythromycin, roxithromycin 30~ 300mg/d, 50~500mg/d of clarithromycin, 0.1~0.5g/d of azithromycin, 8~48 μ g/d of Lubiprostone 1, Linaclotide 15~150 μ g/d, 0.5~3mg/d of Pu Kana peptide.
The embodiment of the present invention shows that each compound group is increasing the average daily feces volume of mouse, enhancing mouse intestinal propulsive force, increasing It is used alone with two kinds of drugs there are significant difference in terms of adding enteron aisle ICC quantity and reducing sphincter pressures, prompts two There is significant synergistic effect at above-mentioned aspect in kind drug.
Specific embodiment
In order to verify the pharmaceutical composition for the therapeutic effect of constipation, the present invention provides following embodiments to be said It is bright, but not as limitation of the invention.
First part, pharmaceutical composition of the invention
The preparation of 1 oral administration solution of embodiment
Prescription：
Method：
90ml distilled water is taken, potassium sorbate 0.01g is added, heating stirring makes whole dissolutions, boils 10 minutes, let cool, obtain Solution is 1.；Carboxyrnethyl starch sodium bulk pharmaceutical chemicals (degree of substitution 1) 25.0g is added to solution is 1. middle, stirring makes whole dissolutions, obtains solution 2.； Mannitol 10.0g, citric acid 0.08g, sodium citrate 0.02g, Aspartame 0.15g and flavoring pineapple essence is added to solution is 2. middle 0.1g is sufficiently stirred, and makes it completely dissolved, and obtains solution 3.；The solution of (0.1mol/l) is made in sodium hydroxide, is slowly added into molten Liquid 3. in, adjust pH value of solution to 7~9, add distilled water to be settled to 100ml.
The preparation of 2 oral administration solution of embodiment
Prescription：
Method：
Raw material is logical to be sieved with 100 mesh sieve, and auxiliary material takes 80ml distilled water by 80 meshes, and potassium sorbate 0.01g is added, and heating is stirred Mixing makes whole dissolutions, boils 10 minutes, lets cool, obtains solution 1.；Carboxyrnethyl starch sodium bulk pharmaceutical chemicals (degree of substitution 1) is added to solution is 1. middle 20.0g, stirring make whole dissolutions, obtain solution 2.；Prucalopride 20.0mg is added to solution is 2. middle, stirring makes to be uniformly mixed, obtain Solution is 3.；Stevioside 0.1g and lemon extract 0.01g is added to solution is 3. middle, is sufficiently stirred, makes it completely dissolved, obtain solution ④；The solution of 1% (v/v) is made in hydrochloric acid, be slowly added into solution 4. in, adjust pH value of solution to 7~9, add distilled water to be settled to 100ml。
The preparation of 3 oral administration solution of embodiment
Prescription：
Method：
800ml distilled water is taken, potassium sorbate 0.1g is added, heating stirring makes whole dissolutions, boils 10 minutes, let cool, obtain Solution is 1.；Carboxyrnethyl starch sodium bulk pharmaceutical chemicals (degree of substitution 1) 100.0g is added to solution is 1. middle, stirring makes whole dissolutions, obtains solution 2.； Lubiprostone 1 2.4mg is added to solution is 2. middle, stirring makes to be uniformly mixed, and obtains solution 3.；Stevioside is added to solution is 3. middle 1.0g and lemon extract 0.1g, is sufficiently stirred, makes it completely dissolved, and obtains solution 4.；The solution of 1% (v/v) is made in hydrochloric acid, slowly Be added to solution 4. in, adjust pH value of solution to 7~9, add distilled water to be settled to 1000ml.
The preparation of 4 oral administration mixed suspension of embodiment
Prescription：
Method：
Raw material is logical to be sieved with 100 mesh sieve, and auxiliary material takes 80ml distilled water by 80 meshes, and potassium sorbate 0.01g is added, and heating is stirred Mixing makes whole dissolutions, boils 10 minutes, lets cool, obtains solution 1.；Carboxyrnethyl starch sodium (degree of substitution 0.4) is added to solution is 1. middle 25.0g, stirring make whole dissolutions, obtain solution 2.；Domperidone 1.0g is added to solution is 2. middle, makes to mix within high speed shear 3 minutes Uniformly, solution is obtained 3.；Stevioside 1.0g and lemon extract 0.1g is added to solution is 3. middle, is sufficiently stirred, makes it completely dissolved, Obtain solution 4.；The solution of 1% (v/v) is made in hydrochloric acid, be slowly added into solution 4. in, adjust pH value of solution to 7~9, add distilled water It is settled to 100ml.
The preparation of 5 granule of embodiment
Prescription：
Carboxyrnethyl starch sodium (degree of substitution 0.6) 80g
Icing Sugar 35g
PVPk30 (5% aqueous solution) about 20ml
Method：
Carboxyrnethyl starch sodium and Icing Sugar are weighed by recipe quantity, crossing sieve method is uniformly mixed, and povidone k30 is configured to concentration 5% Aqueous solution, PVP solution softwood processed in right amount is added, crosses the granulation of 12 meshes, wet granular is in 60 DEG C of dryings, 12 mesh sieves, pack To obtain the final product.
The preparation of 6 powder of embodiment
Prescription：
Method：
Supplementary material sieves with 100 mesh sieve, and weighs material by recipe quantity, and equivalent gradually-increased is uniformly mixed, and superfine silica gel powder mixing is added Uniformly, per packed 10g to get.
The preparation of 7 tablet of embodiment
Prescription：
Method：
Carboxyrnethyl starch sodium, lactose and roxithromycin are weighed by recipe quantity, crossing sieve method is uniformly mixed, povidone k30 is prepared At the aqueous solution of concentration 5%, PVP solution softwood processed in right amount is added, crosses the granulation of 24 meshes, wet granular is in 60 DEG C of dryings, 24 meshes Magnesium stearate is added in whole grain, is uniformly mixed, and adjustment tablet press machine loading amount makes average slice weight 183.5mg, be coated to get.
The preparation of 8 tablet of embodiment
Prescription：
Method：
Material is weighed by recipe quantity, equivalent gradually-increased is uniformly mixed with lactose, then is uniformly mixed with microcrystalline cellulose, is added Magnesium stearate is uniformly mixed, and adjustment tablet press machine loading amount makes average slice weight 0.120g, be coated to get.
The preparation of 9 capsule of embodiment
Prescription：
Method：
Material is weighed by recipe quantity, equivalent gradually-increased is uniformly mixed with L-Leu, then is mixed with calcium chloride dihydrate, Be uniformly mixed later with carboxyrnethyl starch sodium (degree of substitution 1), be added magnesium stearate, be uniformly mixed, encapsulated (loading amount 119mg) i.e. ?.
Second part：The pharmacodynamic study of pharmaceutical composition
1 carboxyrnethyl starch sodium of experimental example combines domperidone treatment Aged Mice Constipation Model research
(1) intestinal propellant movement function is tested
1. experimental group and administration：NIH Aged Mice 36, half male and half female, 37~45g of weight is randomly divided into 4 groups, point It Wei not control group, carboxyrnethyl starch sodium group, domperidone group and administering drug combinations group.Four groups of mouse are with compound diphenoxylate (1.5mg/kg) stomach-filling 1 time, establishes compound diphenoxylate Constipation Model.Control group is filled to distilled water, carboxyrnethyl starch sodium group mouse Stomach 0.2ml/10g carboxymethylstarch sodium solution 1 time, domperidone group intragastric administration on mice 0.2ml/10g Domperidone suspension 1 time, connection It closes 4 sample of administration group intragastric administration on mice 0.2ml/10g example of formulations 1 time.After giving given the test agent 7 days respectively, each group mouse fasting It can't help water 16 hours, for control group to distilled water, administration group gives compound diphenoxylate (10mg/kg), gives compound diphenoxylate 0.5 After hour, control group prepared Chinese ink stomach-filling, each administration group gives the prepared Chinese ink of each group drug.
2. defecation test and index observing：It is individually raised for examination mouse, since filling prepared Chinese ink, records every mouse for the first time Row melena time (min) and the total grain number of melaena and water content being discharged in 6 hours.
(2) small intestine charcoal end Promoting Experiment
1. choosing healthy geriatric mouse 36, half male and half female is randomly divided into 4 groups, and grouping is same as above.
2. each group mouse is deprived of food but not water 16 hours, and blank control group is to distilled water, respectively respectively to after given the test agent 7 days Administration group gives compound diphenoxylate (5mg/kg), and to after compound diphenoxylate 0.5 hour, control group prepared Chinese ink stomach-filling is respectively given Medicine group gives the prepared Chinese ink of each group drug, individually raises for examination mouse.
Cervical dislocation puts to death mouse immediately after 3.25 minutes, opens abdominal cavity and separates mesenterium, large intestine upper end to pylorus is " small intestine Total length " is " prepared Chinese ink propulsion length " from pylorus to prepared Chinese ink forward position.Ink progradation is calculated as follows：
Ink progradation (%)=prepared Chinese ink promotes length/total small intestinal length * 100%
Weigh with scale the weight in wet base of small intestine, and then by 80 DEG C of small intestine, drying to constant weight, calculates the moisture content of small intestine.
(3) result
1. the influence of the normal motor function of pair Aged Mice
After the completion of modeling, control group defecation time significantly extends, defecation frequency reduce, particle is small and hard, show modeling at Function；Defecation frequency and quantity can be obviously increased after administration, particle is big, and matter is soft, shortens defecation time for the first time.It the results are shown in Table 1.
2. small intestine charcoal end Promoting Experiment
After the completion of modeling, the charcoal end propulsion rate of control group is substantially reduced, small intestine water content also below normal level,；Respectively give The charcoal end propulsion rate of medicine group is apparently higher than model group.It the results are shown in Table 2.
(4) conclusion：The experimental results showed that each administration group can significantly increase Aged Mice intestine movement function, it is effectively improved Enteral water environment stimulates intestines peristalsis, and every defecation index is clearly better, and administering drug combinations group effect be substantially better than two individually to Medicine group.
1 carboxyrnethyl starch sodium of table and domperidone to Aged Mice Constipation Model intestine movement function influence (N=12)
Note：Compared with the control group,*P < 0.01；Compared with being administered alone group,**P < 0.05
Influence that 2 carboxyrnethyl starch sodium of table and domperidone promote Aged Mice Constipation Model small intestine charcoal end (N=10)
Note：Compared with blank control group,*P < 0.01；Compared with being administered alone group,**P < 0.05
The spleen injury Constipation Model that 2 carboxyrnethyl starch sodium of experimental example joint Lubiprostone 1 treatment overfeeding delicious food method is established is ground Study carefully
(1) experimental group and administration：Kunming small white mouse 36, weight (20 ± 2) g, half male and half female is randomly divided into 3 groups, point It Wei not blank control group, model group and administration group.Constipation Model caused by spleen injury is established using overfeeding delicious food method, specific side Method is that model group and administration group mouse give every 0.5ml of stomach-filling refined lard, 2 times a day, continuous 8 days.
(2) defecation test and index observing：Model group mouse according to 2% prepared Chinese ink of volume stomach-filling of 0.4ml/10g physiology Salt water, the 2% prepared Chinese ink suspension that 3 sample of example of formulations of administration group stomach-filling equal volume is made into, 1 times/day, for three days on end. Last dose observes the melaena that the time (min) of melaena is discharged in every mouse for the first time and mouse is discharged in 6 hours after 1 hour total Grain number.
(3) result：Compared to the blank group, melena efflux time significantly extends model group mouse for the first time, 6 hours melaena points (P < 0.05) is substantially reduced, shows modeling success.Compared with model group, administration group can be obviously shortened melena efflux time for the first time (P < 0.01) is counted with 6 hours discharge melaena are increased.It the results are shown in Table 3.
(4) conclusion：The result shows that carboxyrnethyl starch sodium has good treatment to spleen injury type constipation caused by overfeeding delicious food Effect can be obviously shortened defecation time for the first time and increase feces volume.
3 carboxyrnethyl starch sodium of table combine Lubiprostone 1 to overfeeding delicious food Constipation Model mouse defecation influence (N=12)
Note：Compared with blank control group,*P < 0.05；Compared with model group,**P < 0.01
3 carboxyrnethyl starch sodium of experimental example combines the Drug-dependent constipation that azithromycin treatment rheum officinale decocting liquid administration by gavage is established Model research
(1) experimental group and administration：Wistar male rat 24, weight (310 ± 20) g, 3 groups are randomly divided into, respectively For blank control group, model group and administration group.Model group and the equal non-fasting of administration group rat, continuous 5 days water restrictions cause big Mouse constipation；Then rheum officinale and phenolphthalein stomach-filling are used, initial dose 200mg/kg, daily 20mg/kg is incremented by, until animal more than half It when there is loose stools, maintains this dosage constant, so that rat is generated dependence to drug, then taper off and restrict water supply, the final dosage of rheum officinale is 3.2g/kg, the final dosage of phenolphthalein are 4.2g/kg, stop administration after raising 3 months with this dosage.
(2) defecation test and index observing：It is discontinued the 2nd day, the physiological saline of 2% prepared Chinese ink of model group rats stomach-filling, administration The 2% prepared Chinese ink suspension that group is prepared according to 10mg/kg drug-delivery preparation embodiment 6, one time a day, continuous 5 days.Every rat is independent It feeds, cage bottom spreads filter paper, the big mouse's head pellet of each group just efflux time and 12 hours defecation grain numbers is observed after administration, and measure excrement Water content.
(3) result：Compared with blank control group, model group defecation time significantly extends, and defecation frequency is reduced, and excrement is aqueous Amount reduces；Administration group can obviously increase defecation frequency and quantity, and defecation time, excrement water content significantly increase for the first time for shortening.Knot Fruit is shown in Table 4.
(4) conclusion：Experimental result shows that it is big that carboxyrnethyl starch sodium joint azithromycin can effectively improve Drug-dependent constipation Every defecation index of mouse, indicates its application value in the treatment of Drug-dependent constipation.
4 carboxyrnethyl starch sodium of table combine azithromycin to Drug-dependent constipation rat model defecation influence (N=8)
Note：Compared with blank control group,*P < 0.05；Compared with model group,**P < 0.01
4 carboxyrnethyl starch sodium of experimental example combines the treatment of Pu Kana peptide and prohibits the mice with constipation model research that water non-fasting method is established
(1) experimental group and administration：NIH mouse 60, half male and half female, weight (20 ± 2) g is randomly divided into 5 groups, respectively For blank control group, model group, administration carboxyrnethyl starch sodium group (1 sample of example of formulations), administration Pu Kana peptide group (implemented by preparation 8 sample of example) and administering drug combinations group (two medicines are same to be given).Model group and administration group mouse prohibit water non-fasting, for three days on end, cause to lose Water constipation Constipation Model.
(2) defecation test and index observing：The physiological saline of 2% prepared Chinese ink of model group intragastric administration on mice, administration group is according to grouping Every 10g weight gives 2% prepared Chinese ink that first starch sodium solution 0.2ml carboxylic or Pu Kana peptide piece 12mg (removal coating) are prepared respectively Suspension, one time a day, for three days on end.Every mouse is individually fed, and cage bottom spreads filter paper, observes every mouse after the last administration for the first time The time (min) of discharge melaena and the total grain number of melaena that mouse is discharged in 6 hours.
(3) result：Compared with blank control group, model group defecation time significantly extends, defecation frequency reduce, particle it is small and Firmly, show modeling success；Carboxyrnethyl starch sodium joint Pu Kana peptide administration group can obviously increase defecation frequency and quantity, and particle is big, Matter is soft, and defecation time, improvement are substantially better than two kinds of drug given alone groups for the first time for shortening.It the results are shown in Table 5.
(4) conclusion：The experimental results showed that the carboxyrnethyl starch sodium joint Pu Kana peptide treatment dry street type anti-constipation effect of dehydration is aobvious It writes, every defecation index of animal pattern is significantly improved, and the improvement of drug combination is substantially better than two kinds of drug lists The effect being solely administered.
5 carboxyrnethyl starch sodium of table combines Pu Kana peptide to the influence (x for prohibiting the Constipation Model mouse defecation that water non-fasting method is established ± s, n=12)
Note：Compared with blank control group,*P < 0.05；Compared with model group,**P < 0.01
5 carboxyrnethyl starch sodium of experimental example combines the clinical observation of Linaclotide treatment opioid drug constipation induced
Opioid drug constipation induced 32 is treated using carboxyrnethyl starch sodium Linaclotide capsule (preparation of example of formulations 9) Example, and 32 controlled observations are treated with hemp seed soft capsule, it is as a result as follows：
1. data and method
It chooses in medical 64 of 08 month~in February, 201 in 2017, severe pain need to take orally opioid analgesic drug Cancer patient is randomly divided into 2 groups.Treatment group 32, male 17, female 15；Age 40~81 years old, average (63.07 ± 14.38) year；Lung cancer 16, liver cancer 4, gastric cancer 5, oophoroma 3, breast cancer 3, cancer of pancreas 1；Antalgesic makes daily Morphine amount 92mg is averagely equivalent to dosage (intravenous injection and non-morphine opiates are converted into oral dose calculating).Control group 32 Example, male 16, female 16；Age 39~79 years old, average (62.56 ± 16.36) year；Lung cancer 14, liver cancer 5, gastric cancer 5, The cancer of the esophagus 2, breast cancer 4, cancer of pancreas 2；The daily dosage of antalgesic is averagely equivalent to morphine amount 92mg.Two group one As data comparing difference it is not statistically significant (P > 0.05), be comparable.
2. treatment method
The carboxyrnethyl starch sodium Linaclotide capsule (50mg, 1.0 μ g) for the treatment of group's pharmaceutical preparation embodiment 91,2 times/day.
Control group hemp seed soft capsule 2,2 times/day.
Two groups of equal 10d are 1 course for the treatment of, count curative effect after 1 course for the treatment of.
Observation index compares two groups of curative effects, two groups of pretherapy and post-treatment symptom integrals of observation, Cattell scoring variation.Symptom integral mark It is quasi-：The infrequent defecation time is more than that 1d or 3d or more person is 1 point；The infrequent defecation time is more than that 2d or 4d or more person is 2 points；Row Just it is 3 points that interval time, which is more than 3d or 5d or more person,.Just soft person is 1 point after matter is first done；The dry and cracked person that defecates is 2 points；Dry and hard excrement It is 3 points such as sheep dung shape or with blood.Defecation is 1 point slightly arduously, with slight sense of discomfort or pain sensation or awareness of defecation sense person not to the utmost；Defecation It is relatively elaborate, it is sometimes 2 points with defecation sense of discomfort or pain sensation or awareness of defecation sense person not to the utmost；Defecation is very laborious and gimmick is needed to help It helps, defecation sense of discomfort or pain sensation or awareness of defecation often occurs to feel not to the utmost being 3 points.Each 10~20min person of defecation time is 1 point； 21~30min person is 2 points；30min or more person is 3 points.
Criterion of therapeutical effect recovery from illness：Just the soft profit of matter, when solution, are unobstructed, and 1~2d defecation 1 time；It is effective：Symptom is obviously improved, and just matter is slightly Profit, defecation is more unobstructed, and 2~3d defecation 1 time；Effectively：Symptom improves, and defecation owes unobstructed, and the infrequent defecation time shortens, remaining symptom Take a favorable turn；In vain：Clinical symptoms are without improvement.
3. result
Two groups of curative effects compare, and two groups of total effective rate comparing differences are statistically significant (P < 0.01), and treatment group's curative effect is better than Control group.It is shown in Table 6.
6 two groups of curative effects of table compare
Note：Compared with the control group, * P < 0.01
Two groups of pretherapy and post-treatment symptom integrals and Cattell scoring are compared, drop before symptom integral relatively this group treatment after two groups of treatments Low (P < 0.05, P < 0.01) increases (P < 0.05) before Cattell scoring relatively this group treatment after treatment group's treatment.Treatment group's treatment Symptom integral is higher than after control group treatment (P < 0.01) lower than (P < 0.01) after control group treatment, Cattell scoring afterwards.It is shown in Table 10.
7 two groups of pretherapy and post-treatment symptom integrals of table and Cattell scoring are compared
Note：Compared with pretherapy and post-treatment with this group, * P < 0.05, * * P < 0.01；Compared with after control group treatment, △ P < 0.01 4. conclusion
Observation the results show that the total effective rate of carboxyrnethyl starch sodium Linaclotide capsule for treating opioid drug constipation induced with Control group comparing difference is statistically significant (P < 0.01), prompts carboxyrnethyl starch sodium Linaclotide capsule for treating opioid drug Constipation induced curative effect affirmative；Two groups of pretherapy and post-treatment symptom integrals are declined, and the statistically significant (P of comparison among groups difference < 0.01), show that carboxyrnethyl starch sodium Linaclotide capsule can be substantially reduced constipation patient clinical symptoms；Cattell after treatment group's treatment Scoring increases (P < 0.01) compared with control group, illustrates that carboxyrnethyl starch sodium Linaclotide capsule can improve patients ' life quality, is worth facing Bed promotes and applies.
The clinical observation of 6 carboxyrnethyl starch sodium prucalopride Solution In The Treatment pregnant woman constipation of experimental example
37 are treated using carboxyrnethyl starch sodium prucalopride Solution In The Treatment pregnant woman constipation 37, and with lactulose oral solution Controlled observation, it is as a result as follows：
1. data and method
Selection 08 month in February, 2018 in 2017 has pregnant woman 74 of constipation in the pregnant inspection diagnosis of outpatient service, is health without conjunction And disease pregnant woman, previously without constipation and other intestines problem histories, the age 20~37 years old, wherein early pregnancy (< 12 weeks) 6, in pregnant (12 ~27 weeks) 39, late pregnant (> 28 weeks) 29.All cases are divided into two groups, treatment group and control group each 37, compare two groups it is pregnant The data such as the age of woman, locating pregnancy period, are statistically analyzed, and no significant difference (P > 0.05) is comparable.
1. treatment method
Treatment group：The carboxyrnethyl starch sodium prucalopride Solutions Solution (100ml of pharmaceutical preparation embodiment 2：20g, 20mg) 10ml, 2 times/day.Control group：Lactulose oral solution (667mg/ml) 10ml, is that 1 course for the treatment of judges curative effect with 7d, sees by 3 times/day Onset time and adverse reaction are examined, is had a blood test before and after medication, routine urinalysis, hepatic and renal function.Other lead to is deactivated for two groups during treatment Just drug.
Time after efficacy determination medication to first time defecation is known as " first time defecation time ".It is effective：First time defecation Time < 18h, i.e. " defecation overnight "；Effectively：First time 18~72h of defecation time；Progress：First time 72~96h of defecation time； In vain：Still constipation person.
3. result
After treatment (P > 0.05) not statistically significant between two groups of patient clinical curative effects, the two is prompted to have greatly pregnant woman constipation Cause identical therapeutic effect；Two groups of adverse reaction is compared, and treatment group is substantially better than control group, and difference has conspicuousness (X2= 4.23, P < 0.05) it has a blood test before and after two groups of patient medications of, routine urinalysis, hepatic and renal function has no significant change, and is shown in Table 8,9.
8 treatment group of table and control group Clinical efficacy comparison
Note：Compared with the control group, P < 0.05
9 treatment group of table is compared with control group adverse reaction
Note：Compared with the control group, P < 0.05
4. conclusion
Observation the results show that the total effective rate of carboxyrnethyl starch sodium prucalopride Solution In The Treatment pregnant woman constipation compared with the control group No significant difference (P < 0.05) prompts carboxyrnethyl starch sodium prucalopride Solution In The Treatment pregnant woman constipation curative effect to be better than newborn fruit Sugared oral administration solution；Treatment group's adverse reaction rate is significantly reduced with control group, and the statistically significant (P of comparison among groups difference < 0.05), show carboxyrnethyl starch sodium prucalopride solution can be obviously improved pregnant woman constipation patient clinical symptom and action temperature and, no Good reaction odds very degree is lower, has better safety and tolerance, is worth clinical application.
7 carboxyrnethyl starch sodium azithromycin of experimental example dissipates the clinical observation for the treatment of 8 years old or less constipation in children
Treatment 52 clinical observation on the therapeutic effect of functional consitipation infant are dissipated using carboxyrnethyl starch sodium azithromycin, it is as a result as follows：
1. data and method
08 month in February, 2018 in 2017 is chosen in outpatient service functional form constipation infant 52 are research object, random point For control group and treatment group, every group 26.Control group male 12, female 14, the age 16 months~8 years old, average (4.2 ± 0.3) Year.Treatment group male 11, female 15, the age 18 months~8 years old, average (4.4 ± 0.3) year.It is statistically analyzed, difference is without aobvious Work property (P > 0.05), is comparable.
2. treatment method
Control group infant routine symptomatic treatment allows infant mostly using the food for being rich in dietary fiber to adjust based on diet, Such as veterinary antibiotics, coarse food grain, and abdomen is cooperated to loop clockwise massage, daily timing defecation, and it is aided with liquid stone if necessary The treatment means such as wax, enema.Treatment group adds the carboxymethylstarch with drug example of formulations 6 on the basis of control group is treated Sodium azithromycin dissipates (0.5g, 0.25g)/bag.Suggested use and dosage：Age < 4 years old, half bag/time, 1 times/day；Age > 4 years old, 1 Bag/time, 1 times/day.Treatment time is 1 week, compares two groups of infant clinical therapeutic efficacies.
Efficacy determination recovery from illness：It takes medicine after 1~2d, stool shape restores normal, and the symptoms such as Nausea and vomiting completely disappear, food It is intended to significantly improve, has no the adverse reactions such as abdominal pain, abdominal distension, and be discontinued within 1 week without repeatedly.Effectively：Stool can be discharged still still So more difficult, dry, Nausea and vomiting symptom disappears substantially, has no the adverse reactions such as abdominal pain and abdominal distension, and symptom recurs after drug withdrawal. In vain：Stool cannot solve, and ill symptoms, which have no, to be significantly improved, and has further degradating trend.
3. result
Two groups of Clinical efficacy comparisons, are shown in Table 10.
10 treatment group of table and control group Clinical efficacy comparison
Note：Compared with the control group, P < 0.05
Two groups of adverse reactions a situation arises comparison, be shown in Table 11.
11 treatment group of table is compared with control group adverse reaction
Note：Compared with the control group, P < 0.05
4. conclusion
After treatment (P < 0.05) statistically significant between two groups of patient clinical curative effects, treatment group is significant in efficacy better than control Group, two groups of adverse reaction are compared, and difference has conspicuousness (P < 0.05), and treatment group is significantly lower than control group, illustrate carboxymethylstarch Sodium azithromycin dissipates curative for effect for Functional Constipation in Children, and adverse reaction rate is low, is worth clinical application.
8 carboxyrnethyl starch sodium of experimental example combines the clinical observation that Pu Kana peptide treats old Refractory Constipation
Old Refractory Constipation 36 is treated using carboxyrnethyl starch sodium joint Pu Kana peptide, it is as a result as follows：
1. data and method
Select 08 month in February, 2018 in 2017 at outpatient service old age Refractory Constipation patient 36, male 16, female 20 Example, the age (69.5 ± 4.8) year；All patients, which meet, following is included in standard：(1) constipation symptom is lasting, seriously affects life Quality；(2) bad to common remedy measures reaction, cathartic is relied on and is abused；(3) the used various cathartics of patient and bowel lavage etc. Treatment, but systematic treating is not carried out；(4) patient has carried out medical history inquiry, physical examination, necessary blood biochemistry detection and enteron aisle inspection It looks into, constipation caused by organic disease is discharged.
2. treatment method
Give the carboxymethylstarch sodium solution (100ml of pharmaceutical preparation embodiment 1：25g) 2ml, 1 times/day, pharmaceutical preparation is implemented The Pu Kana peptide piece (1.5mg) of example 8,1 times/day.The course for the treatment of is 3 weeks, observes and records patient's abdominal distension, loss of appetite, insomnia, weekly It lives alone defecation frequency and gastrointestinal tract Emptying Rate, checks index of correlation after treatment end, observe the symptoms and improve situation.During treatment Two groups deactivate other defaecation drugs.
3. efficacy determination
(1) it is known as " onset time " to the time of first time defecation after taking medicine；(2) times of defecation and stool shape：By suffering from The every day entry of person.1,2,3 types be it is abnormal, 4,5,6 types be it is normal, 7 types are excessive；(3) abdominal distension, loss of appetite, difficult defecation Whether improve with symptoms such as insomnias；(4) gastrointestinal tract Emptying Rate detects：Disposably swallowed when the 1st day morning 8 of subject 20 it is impermeable X-ray marker takes the photograph plain abdominal radiograph respectively at 48h, 72h, observes retention quantity and position of the marker in colon, and calculate Gastrointestinal tract Emptying Rate.
4. result
Curative effect evaluation before and after subject：(1) onset time：Occur after 55.6% (20/36) subject medication 1d There is defecation in 7d in defecation, remaining subject 44.4% (16/36).(2) variation of defecation frequency：Autonomous defecation frequency from (1.2 ± 0.3) times/week before treating increase to (3.7 ± 0.5) times/week (the P < 0.05) after treatment, increase in defecation frequency While with the improvement of difficult defecation (table).(3) pretherapy and post-treatment gastrointestinal tract Emptying Rate：By treatment in 3 weeks, 48h, 72h Gastrointestinal tract Emptying Rate increases to (77.1 ± 8.3) %, (86.6 ± 4.2) % by (54.4 ± 7.9) %, (72.6 ± 3.5) %.
Adverse reaction situation：There are 4 (11.1%) adverse reaction occur after combination therapy, wherein 1 is abdominal distension, 3 are Times of defecation increases, and all alleviates within 48h after the tablet has been ingested.
The old Refractory Constipation patient of table 12 autonomous defecation situation (n=36) weekly before and after treatment
Note：Compared with before treatment,*P < 0.05
4. conclusion
Carboxymethylstarch sodium solution combine Pu Kana peptide piece treat old Refractory Constipation clinical observation on the therapeutic effect the results show that Combination therapy patient subjective feeling occurs after medication before autonomous defecation frequency and gastrointestinal tract Emptying Rate are significantly better than that treatment weekly Abdominal distension and times of defecation to increase equal adverse reactions smaller, can restore automatically without being discontinued.In conclusion carboxymethylstarch Sodium solution combines Pu Kana peptide piece and treats old Refractory Constipation safely, effectively, is worth clinical application.

Claims (10)

1. a kind of pharmaceutical composition for treating constipation, which is characterized in that be mainly made of following two active pharmaceutical ingredient：
(1) the water soluble starch salt of carboxylic acid group modification,
(2) promote digestive tract power reinforcing medicine or promote secretion medicine,
The weight ratio of the two is：0.1~10:0.000008~1, more preferably it is selected as 0.5~2:0.000008~1.
2. pharmaceutical composition according to claim 1, which is characterized in that 1~500,000 between the molecular weight area of the compound Between, more preferably selection is between 5~300,000, and the carboxylic acid group degree of substitution of the compound more preferably selects between 0.2~2 Selecting is between 0.4~2, and the carboxylic acid group of the compound is：(CH2) xCO2Y, wherein x is between 1-5, Y be sodium, potassium, iron, One of metal cations such as zinc, tin are a variety of.
3. pharmaceutical composition according to claim 1, which is characterized in that the water soluble starch salt of carboxylic acid group modification, most Excellent is selected as carboxyrnethyl starch sodium.
4. pharmaceutical composition according to claim 1, which is characterized in that promote digestive tract power reinforcing medicine and be selected from dopamine receptor antagonism One of agent, 5-HT4 receptor stimulating agent, motilin agonists；Promote secretion medicine and is selected from chloride channel activators and bird One of thuja acid cyclase agonist.
5. pharmaceutical composition according to claim 4, which is characterized in that dopamine-receptor antagonist is selected from：Methoxychlor is general Amine, domperidone, Itopride or clebopride；5-HT4 receptor stimulating agent is selected from：Mosapride or prucalopride；Motilin Receptor stimulating agent is selected from：Erythromycin, roxithromycin, clarithromycin or azithromycin；Chloride channel activators are：Before the ratio of Shandong Column ketone；Guanylate cyclase agonist is selected from：Linaclotide or Pu Kana peptide.
6. pharmaceutical composition according to claim 1, which is characterized in that the pharmaceutical composition is following combination：
(1) carboxyrnethyl starch sodium：Metoclopramide=0.5~2：0.005~0.03
(2) carboxyrnethyl starch sodium：Domperidone=0.5~2：0.01~0.08
(3) carboxyrnethyl starch sodium：Itopride=0.5~2：0.015~0.15
(4) carboxyrnethyl starch sodium：Clebopride=0.5~2：0.00068~0.00204
(5) carboxyrnethyl starch sodium：Mosapride=0.5~2：0.002~0.015
(6) carboxyrnethyl starch sodium：Prucalopride=0.5~2：0.0005~0.002
(7) carboxyrnethyl starch sodium：Erythromycin=0.5~2：0.25~1
(8) carboxyrnethyl starch sodium：Roxithromycin=0.5~2：0.05~0.3
(9) carboxyrnethyl starch sodium：Clarithromycin=0.5~2：0.125~0.5
(10) carboxyrnethyl starch sodium：Azithromycin=0.5~2：0.125~0.5
(11) carboxyrnethyl starch sodium：Lubiprostone 1=0.5~2：0.000008~0.000048
(12) carboxyrnethyl starch sodium：Linaclotide=0.5~2：0.00005~0.000145
(13) carboxyrnethyl starch sodium：Peptide=0.5~2 Pu Kana：0.0005~0.003.
7. pharmaceutical composition according to claim 1, which is characterized in that the pharmaceutical composition is following combination：
(1) carboxyrnethyl starch sodium：Metoclopramide=0.5~2：0.005~0.015
(2) carboxyrnethyl starch sodium：Domperidone=0.5~2：0.01~0.06
(3) carboxyrnethyl starch sodium：Itopride=0.5~2：0.03~0.1
(4) carboxyrnethyl starch sodium：Clebopride=0.5~2：0.00068~0.00136
(5) carboxyrnethyl starch sodium：Mosapride=0.5~2：0.005~0.01
(6) carboxyrnethyl starch sodium：Prucalopride=0.5~2：0.0005~0.001
(7) carboxyrnethyl starch sodium：Erythromycin=0.5~2：0.25~0.75
(8) carboxyrnethyl starch sodium：Roxithromycin=0.5~2：0.05~0.15
(9) carboxyrnethyl starch sodium：Clarithromycin=0.5~2：0.125~0.375
(10) carboxyrnethyl starch sodium：Azithromycin=0.5~2：0.125~0.375
(11) carboxyrnethyl starch sodium：Lubiprostone 1=0.5~2：0.000008~0.000024
(12) carboxyrnethyl starch sodium：Linaclotide=0.5~2：0.00005~0.0001
(13) carboxyrnethyl starch sodium：Peptide=0.5~2 Pu Kana：0.001~0.002.
8. pharmaceutical composition according to claim 1, which is characterized in that the pharmaceutical composition is following combination：
(1) carboxyrnethyl starch sodium：Domperidone=0.5：0.02
(2) carboxyrnethyl starch sodium：Prucalopride=0.5：0.0005
(3) carboxyrnethyl starch sodium：Roxithromycin=0.5：0.1
(4) carboxyrnethyl starch sodium：Azithromycin=0.5：0.25
(5) carboxyrnethyl starch sodium：Lubiprostone 1=0.5：0.000012
(6) carboxyrnethyl starch sodium：Linaclotide=0.5：0.00001
(7) carboxyrnethyl starch sodium：Peptide=0.5 Pu Kana：0.0015.
9. pharmaceutical composition according to claim 1, which is characterized in that any oral pharmaceutical dosage form can be prepared into.
10. application of the pharmaceutical composition described in claim 1 in preparation prevention and/or treatment constipation.
CN201810928336.2A 2018-08-15 2018-08-15 A kind of pharmaceutical composition and its application for treating constipation Pending CN108904808A (en)

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Application publication date: 20181130