[go: up one dir, main page]

WO2021078110A1 - 预防或治疗肠易激综合征的药物组合 - Google Patents

预防或治疗肠易激综合征的药物组合 Download PDF

Info

Publication number
WO2021078110A1
WO2021078110A1 PCT/CN2020/122082 CN2020122082W WO2021078110A1 WO 2021078110 A1 WO2021078110 A1 WO 2021078110A1 CN 2020122082 W CN2020122082 W CN 2020122082W WO 2021078110 A1 WO2021078110 A1 WO 2021078110A1
Authority
WO
WIPO (PCT)
Prior art keywords
lysozyme
pharmaceutical composition
preparation
oral
dosmaate
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.)
Ceased
Application number
PCT/CN2020/122082
Other languages
English (en)
French (fr)
Inventor
孙明杰
孙天宇
蒋娟艳
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd
Nanjing Kangfushun Pharmaceutical Co Ltd
Xiangbei Welman Pharmaceutical Co Ltd
Guangzhou Century Clinical Research Co Ltd
Original Assignee
GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd
Nanjing Kangfushun Pharmaceutical Co Ltd
Xiangbei Welman Pharmaceutical Co Ltd
Guangzhou Century Clinical Research Co Ltd
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by GUANGZHOU WELMAN NEW DRUG R&D CO Ltd, Guangzhou Xin Chuangyi Biopharmaceutical Co Ltd, Nanjing Kangfushun Pharmaceutical Co Ltd, Xiangbei Welman Pharmaceutical Co Ltd, Guangzhou Century Clinical Research Co Ltd filed Critical GUANGZHOU WELMAN NEW DRUG R&D CO Ltd
Priority to US17/771,105 priority Critical patent/US20220362353A1/en
Priority to JP2022524584A priority patent/JP7342259B2/ja
Priority to CN202080075281.0A priority patent/CN114786711B/zh
Priority to EP20878112.0A priority patent/EP4035672A4/en
Publication of WO2021078110A1 publication Critical patent/WO2021078110A1/zh
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/47—Hydrolases (3) acting on glycosyl compounds (3.2), e.g. cellulases, lactases
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y302/00—Hydrolases acting on glycosyl compounds, i.e. glycosylases (3.2)
    • C12Y302/01—Glycosidases, i.e. enzymes hydrolysing O- and S-glycosyl compounds (3.2.1)
    • C12Y302/01017—Lysozyme (3.2.1.17)

Definitions

  • the invention relates to the field of medicine, in particular to a drug combination for preventing or treating irritable bowel syndrome.
  • Irritable bowel syndrome (Irritable bowel syndrome, IBS) is a common functional bowel disease with a high prevalence rate. Meta analysis shows that the prevalence of irritable bowel syndrome in the Chinese population is 1.0% to 16.0%, and the overall prevalence rate is 6.5%. Among them, the prevalence rate that meets the Manning criteria is 11.5%, and the prevalence rate that meets the Rome III criteria is 8.9. %.
  • Irritable bowel syndrome is a chronic disease characterized by abdominal pain or abdominal discomfort associated with changes in bowel movements or bowel habits. Abdominal pain, bloating, distension and defecation disorders are common symptoms of irritable bowel syndrome, and they can recur, causing great pain to patients and reducing the quality of life.
  • irritable bowel syndrome can be divided into: diarrhea-type irritable bowel syndrome (IBS-D), constipation-type irritable bowel syndrome (IBS-C), and mixed bowel syndrome Irritable syndrome (IBS-M) and indeterminate irritable bowel syndrome (Un-subtyped IBS). Patients usually switch between these subtypes.
  • IBS-D diarrhea-type irritable bowel syndrome
  • IBS-C constipation-type irritable bowel syndrome
  • IBS-M mixed bowel syndrome Irritable syndrome
  • Un-subtyped IBS Un-subtyped IBS
  • Irritable bowel syndrome lacks a detectable organic cause, and its cause is still unknown.
  • Laboratory examination, X-ray examination and biopsy showed no anatomical abnormalities. Emotional factors, diet, drugs or hormones may induce or aggravate digestive tract symptoms.
  • Visceral hypersensitivity is the core pathogenesis of irritable bowel syndrome, and it plays an important role in the occurrence of irritable bowel syndrome symptoms and disease development. Most studies have confirmed that patients with irritable bowel syndrome have high visceral sensitivity in the rectum and colon, that is, the intestine is more sensitive to stimuli. Visceral hypersensitivity is the core pathophysiological mechanism of abdominal discomfort such as abdominal pain and bloating in irritable bowel syndrome. Patients with irritable bowel syndrome are sensitive to colorectal dilatation (pressure) stimulation, and the pain threshold of patients with diarrhea or constipation irritable bowel syndrome is lower than that of the control group.
  • pressure colorectal dilatation
  • Antispasmodics can relieve the symptoms of patients with diarrhea-type irritable bowel syndrome in a short period of time, and have a certain effect on abdominal pain.
  • Such drugs include selective intestinal smooth muscle relaxants (such as pinaverium bromide, otifenium bromide, cetaverium bromide, mebeverine, alveticine) and anticholinergic drugs (such as scopolamine) and so on.
  • selective intestinal smooth muscle relaxants such as pinaverium bromide, otifenium bromide, cetaverium bromide, mebeverine, alveticine
  • anticholinergic drugs such as scopolamine
  • the 5-HT3 receptor antagonist Alosetron was initially approved by the FDA in the United States for the treatment of female patients with diarrheal irritable bowel syndrome. The drug caused complications of ischemic colitis and constipation, and later narrowed its indications. Scope, only for patients with severe symptoms. Tegaserod, a partial 5-HT4 receptor agonist, is approved for short-term treatment of women with constipated irritable bowel syndrome. However, due to the risk of adverse cardiovascular events, sales of this drug in the United States have been suspended. Rifaximin is approved for the treatment of diarrhea-type irritable bowel syndrome in the United States, but the label of the label has a black box warning about Clostridium difficile-related diarrhea.
  • the purpose of the present invention is to provide the application of a drug combination of dosmaate and lysozyme in the preparation of a medicine for preventing or treating irritable bowel syndrome, and to provide a method for preventing irritable bowel syndrome and treating irritable bowel syndrome. And a method for preventing or treating irritable bowel syndrome.
  • the present invention proposes the application of a drug combination in the preparation of a drug for the prevention or treatment of irritable bowel syndrome, the drug combination comprising dosmaate and lysozyme.
  • the drug combination comprising dosmaate and lysozyme.
  • the irritable bowel syndrome includes the characteristics of visceral hypersensitivity.
  • the mass ratio of dosmaate to lysozyme in the drug combination has a greater impact on the combined treatment of irritable bowel syndrome.
  • the mass ratio of dosmaate to lysozyme in the combination is (0.05-100):1, excluding 0.05:1.
  • the mass ratio of dosmaate to lysozyme in the combination is (0.1-10):1.
  • the mass ratio of dosmamate to lysozyme is 0.05:1, there is no synergy.
  • the mass ratio is (0.1 ⁇ 10):1, there is significant synergy.
  • the ratio exceeds this interval, the synergy is weakened.
  • the titer of the lysozyme is greater than 20000 U/mg.
  • Dosmaate and lysozyme in the drug combination can be administered as separate preparations (combined medication), or they can be administered in the same preparation (pharmaceutical composition). In some examples, dosmamate and lysozyme are administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition is an oral formulation.
  • the oral preparation is any one of oral regular-release preparations, oral sustained-release preparations, and oral controlled-release preparations.
  • the oral preparation is selected from any one of tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, and oral emulsions.
  • the pharmaceutical composition also contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from fillers, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, suspending agents , At least one of thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, absorption enhancers and coating materials.
  • doximamate and lysozyme are administered as separate formulations.
  • the stand-alone formulation also contains pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are selected from fillers, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, suspending agents, enhancers At least one of thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, absorption enhancers, and coating materials.
  • the inventors found that compared with other preparations of lysozyme, the lysozyme adopts enteric-coated preparations, especially in the large intestine, especially in the colon. Synergistic effect, produce better curative effect in the treatment of irritable bowel syndrome.
  • the enteric-coated preparations are in the form of enteric-coated preparations such as regular-release preparations, sustained-release preparations, and controlled-release preparations with enteric function, and can be enteric-coated tablets, capsules, pills, granules, etc.
  • the form of soluble preparation can also be any combination of them.
  • the enteric-coated formulation is an enteric-coated tablet.
  • the enteric-coated formulation is a colon-coated tablet.
  • the dosmamate is in the form of an oral formulation.
  • the dosmamate is in the form of a regular-release preparation, a sustained-release preparation, or a controlled-release preparation, etc., which can be tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, etc. Formulations such as pharmaceuticals and oral emulsions can also be any combination of them.
  • the dosmamate is a tablet.
  • the present invention proposes a pharmaceutical composition for preventing or treating irritable bowel syndrome, the pharmaceutical composition comprising dosmaate and lysozyme.
  • the pharmaceutical composition comprising dosmaate and lysozyme.
  • the inventor found that the combined use of dosmaate and lysozyme can prevent and treat irritable bowel syndrome, and the two have obvious synergistic effects.
  • the mass ratio of dosmaate to lysozyme in the pharmaceutical composition has a greater impact on the synergistic treatment of irritable bowel syndrome by the two.
  • the mass ratio of dosmaate to lysozyme in the pharmaceutical composition is (0.05-100):1, and does not include 0.05:1.
  • the mass ratio of dosmaate to lysozyme in the pharmaceutical composition is The mass ratio is (0.1 ⁇ 10):1.
  • the titer of the lysozyme is greater than 20000 U/mg.
  • the pharmaceutical composition is an oral formulation.
  • the oral preparation is any one of oral regular-release preparations, oral sustained-release preparations, and oral controlled-release preparations.
  • the oral preparation is selected from any one of tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, and oral emulsions.
  • the pharmaceutical composition also contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from fillers, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, suspending agents , At least one of thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, absorption enhancers and coating materials.
  • the pharmaceutical composition can be prepared by the following method:
  • Dosmaate is mixed with lysozyme, and pharmaceutically acceptable auxiliary materials are added to prepare a pharmaceutical composition.
  • doximamate and lysozyme and pharmaceutically acceptable auxiliary materials are respectively made into doximamate preparation subunit and lysozyme preparation subunit, and the two preparation subunits are mixed to obtain a pharmaceutical composition.
  • the subunit of the doxima ester preparation is enteric or gastric-solvent
  • the subunit of the lysozyme preparation is the enteric-solvent.
  • the present invention provides a method for preventing or treating irritable bowel syndrome, which comprises administering an effective amount of dosmaate and lysozyme to patients with irritable bowel syndrome.
  • the mass ratio of dosmaate to lysozyme has a greater impact on the combined treatment of irritable bowel syndrome.
  • the mass ratio of dosmaate to lysozyme is (0.05-100):1, and does not include 0.05:1.
  • the mass ratio of dosmaate to lysozyme is (0.1-10):1.
  • the titer of the lysozyme is greater than 20000 U/mg.
  • the daily dosage of dosmaate is 0.05-20 g; preferably, the daily dosage of dosmamate is 0.1-10 g.
  • the dosmamate or lysozyme can be administered 1 to 3 times per day, respectively.
  • dosmaate or lysozyme can be administered in the form of separate preparations (combined medication), or in the form of being present in the same preparation (pharmaceutical composition).
  • dosmamate and lysozyme are administered in the form of a pharmaceutical composition.
  • the pharmaceutical composition is an oral formulation.
  • the oral preparation is any one of oral regular-release preparations, oral sustained-release preparations, and oral controlled-release preparations.
  • the oral preparation is selected from any one of tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, and oral emulsions.
  • the pharmaceutical composition also contains pharmaceutically acceptable excipients.
  • the pharmaceutically acceptable excipients are selected from fillers, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, suspending agents , At least one of thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, absorption enhancers and coating materials.
  • doximamate and lysozyme are administered as separate formulations.
  • the stand-alone formulation also contains pharmaceutically acceptable excipients.
  • pharmaceutically acceptable excipients are selected from fillers, binders, disintegrating agents, lubricants, solubilizers, flavoring agents, coloring agents, taste masking agents, pH adjusting agents, suspending agents, enhancers At least one of thickeners, preservatives, stabilizers, antioxidants, wetting agents, surfactants, suspending agents, absorption enhancers, and coating materials.
  • the inventors found that compared with other preparations of lysozyme, the lysozyme adopts enteric-coated preparations, especially in the large intestine, especially in the colon. Synergistic effect, produce better curative effect in the treatment of irritable bowel syndrome.
  • the enteric-coated preparations are in the form of enteric-coated preparations such as regular-release preparations, sustained-release preparations, and controlled-release preparations with enteric function, and can be enteric-coated tablets, capsules, pills, granules, etc.
  • the form of soluble preparation can also be any combination of them.
  • the enteric-coated formulation is an enteric-coated tablet.
  • the enteric-coated formulation is a colon-coated tablet.
  • the dosmamate is in the form of an oral formulation.
  • the dosmamate is in the form of a regular-release preparation, a sustained-release preparation, or a controlled-release preparation, etc., which can be tablets, capsules, granules, powders, pills, syrups, oral solutions, oral suspensions, etc.
  • Formulations such as pharmaceuticals and oral emulsions can also be any combination of them.
  • the dosmamate is a tablet.
  • the combination of dosmaate and lysozyme provided by the present invention can significantly improve irritable bowel syndrome, and the two have a synergistic effect in improving irritable bowel syndrome. It is found through experiments that the combination of dosmaate and lysozyme of the present invention can significantly reduce the abdominal wall withdrawal reflex (AWR) score and the electromyogram (EMG) AUC value of the irritable bowel syndrome model animal, and significantly improve the visceral hypersensitivity state. In addition, since visceral hypersensitivity features exist in various types of irritable bowel syndrome, the combination of the present invention can be applied to various types of irritable bowel syndrome. In addition, the continuous administration for one month showed no obvious toxicity in all the experimental animals, indicating that the side effects were small. Therefore, the present invention provides a new, widely applicable drug combination for the treatment of irritable bowel syndrome with good curative effect and small side effects.
  • AWR abdominal wall withdrawal reflex
  • EMG electromyogram
  • Irritable bowel syndrome is a functional bowel disease, manifested as abdominal pain or abdominal discomfort related to changes in bowel or bowel habits; abdominal pain, bloating, and abdomen Distension and defecation disorders are common features.
  • Visceral hypersensitivity refers to the increased sensitivity of the intestines to stimuli, including the phenomenon that the threshold for causing visceral pain or uncomfortable stimuli is reduced, the internal organs are uncomfortable to physiological stimuli, or have a strong response to noxious stimuli. Not only the rectum and colon can exhibit visceral hypersensitivity, but other areas of the digestive tract such as jejunum and esophagus can also exhibit visceral hypersensitivity. Animals or patients with irritable bowel syndrome have visceral hypersensitivity, which is the core pathophysiological mechanism of abdominal discomfort such as abdominal pain and bloating in irritable bowel syndrome. Visceral hypersensitivity can amplify gastrointestinal motility events and produce symptoms.
  • the visceral hypersensitivity of an animal or patient with irritable bowel syndrome includes, but is not limited to, sensitivity to colorectal dilatation (pressure) stimulation, high sensitivity to temperature stimulation, and high responsiveness to physiological stimuli (such as meals).
  • Dosmalfate is a gastric mucosal protective agent, approved for the treatment of gastric and duodenal ulcers. Its chemical name is Diomin seven double (bisulfate) aluminum complex, and its molecular formula is Al 7 (OH) 14 (C 28 H 25 O 36 S 7 ) [Al(OH) 3 ] 7 . Animal experiments and human studies have shown that dosmaate can effectively treat peptic ulcers with mild adverse reactions and low incidence.
  • Lysozyme is a lysozyme derived from animals, plants, microorganisms, or a recombinant product of natural lysozyme. For example, it can be egg lysozyme, human lysozyme, recombinant human lysozyme, phage lysozyme, etc.
  • the lysozyme in the present invention also includes its pharmaceutically acceptable salts, such as hydrochloride, chloride, sulfate, or amino acid salt.
  • Egg lysozyme is the main commercial source of lysozyme, and its activity is close to human lysozyme.
  • the lysozyme used in many marketed drugs is egg lysozyme. Human lysozyme is widely distributed and abundant in the human body. Lysozyme is very safe.
  • Enteric-coated preparations are those that do not release or hardly release the drug in the stomach, but enter the intestine, and can release most or all of the drug in some parts of the intestine.
  • the human intestine includes the small intestine and the large intestine.
  • the small intestine is divided into duodenum, jejunum, and ileum, and the large intestine is divided into cecum, colon, and rectum.
  • Different parts of the digestive tract have different pH values. For example, the pH value in the stomach is about 1 to 3, the pH value in the small intestine is about 4-7, and the pH value in the large intestine is about 7-8.
  • pH-dependent degradable materials As preparation auxiliary materials, it is possible to prepare a preparation that releases drugs in a specific part of the digestive tract, such as a small intestine enteric preparation or a large intestine enteric preparation. Specifically, it may include duodenal enteric preparations, jejunal enteric preparations, ileal enteric preparations, cecal enteric preparations, colonic enteric preparations, or rectal enteric preparations.
  • the following describes an exemplary preparation method of a single formulation of dosmaate, a single formulation of lysozyme, and a pharmaceutical composition of dosmaate and lysozyme.
  • the lysozyme raw material can be obtained commercially, and the potency is greater than 20000 U/mg; the dosmamate raw material can be prepared according to the prior art method.
  • Dosmaate tablets take dosmaate as raw material and use common tablet auxiliary materials to obtain tablets.
  • Lysozyme granules Take lysozyme as raw material, add the same amount of starch, mix evenly, add binder (water) to granulate, and dry it.
  • Lysozyme colonic enteric granules take lysozyme as raw material, add the same amount of starch, mix well, add binder (water) to granulate, dry to obtain lysozyme granule.
  • the prepared lysozyme granules are coated with a commercially available colonic enteric coating according to a conventional method to obtain lysozyme colonic enteric granules.
  • Dosmaate lysozyme compound capsule Take lysozyme as raw material, add the same amount of starch, mix evenly, add binder (water) for granulation, and dry to obtain lysozyme granules.
  • the prepared lysozyme granules are coated with a commercially available colonic enteric coating according to a conventional method to obtain lysozyme colonic enteric granules.
  • Doximamate is used as a raw material, and common granule auxiliary materials are added to granulate to obtain doximamate granules.
  • the lysozyme colonic enteric granules and dosmaate granules are filled into ordinary empty capsules in an appropriate ratio, namely, dosmaate lysozyme compound capsules.
  • test animals and reagents used are all commercially available.
  • the related test methods used in the experiment and the specific operation methods of related instruments are well known to those skilled in the art.
  • the dosmaate and lysozyme colonic enteric-coated granules used were provided by Xiangbei Wellman Pharmaceutical Co., Ltd.
  • newborn Sprague-Dawley rats (Sprague-Dawley rats) were given daily colorectal dilatation as a stimulating factor during the period of 8 days to 21 days of age to induce the irritable bowel syndrome model, which has intestinal tractability.
  • Visceral hypersensitivity of irritable syndrome is not accompanied by colon inflammation or mucosal damage; no colorectal dilatation stimulation will be given from 21 days to 8 weeks of age; test drugs or daily gavage will be given between 8 weeks of age and 3 months of age Placebo; the rats are tested on the abdominal wall reflex test and electromyography test at 8 weeks of age (before the start of the 1-month dosing period) and about 3 months of age (after the end of the 1-month dosing period) Rectal dilatation stimulates behavioral and neural responses.
  • the SD rats were randomly divided into a normal control group, a model group, a dosmaate group, a lysozyme group, a combination group (the ratio of the dosage of dosmamate to lysozyme 0.05:1), and a combination two groups ( The dose ratio of dosmaate to lysozyme is 0.1:1), the combination of three groups (the dose of dosmaate to lysozyme is 10:1) and the combination of four groups (the dose of dosmaate and lysozyme is 10:1). The dose ratio is 20:1), and 12 animals are allocated to each group.
  • rats in the other groups were given daily colorectal dilatation (CRD) stimulation to induce irritable bowel syndrome from 8 days to 21 days of age.
  • CCD colorectal dilatation
  • the specific operation method is: make surgical glove fingers A flexible balloon (with a PTFE catheter; the balloon should be inflated overnight before the experiment to make it more compliant). After applying petroleum jelly, it is inserted through the anus of the rat to the colon and fixed at the tail 2cm from the anus. .
  • the balloon is connected to the valve through a catheter, and the valve is additionally connected to a sphygmomanometer.
  • the rat was placed in a small plastic cage to restrict its turn and adapt for 30 minutes. Slowly inflate the balloon to 60mm Hg with a sphygmomanometer, deflate after 20 seconds of stimulation; repeat the stimulation 2 times within 1 hour (each interval is 30 minutes).
  • the treatment method of the rats in the normal control group was similar to that of the other groups, but the balloon was not inserted into the colon, but the perineal area was gently touched every day during the period of 8 days to 21 days of age.
  • the rats in the other groups were given the test drug (moistened in 0.5% sodium carboxymethyl cellulose solution) by intragastric gavage daily during the period of 8 weeks to 3 months, and the dosage was 8ml.
  • Lysozyme group lysozyme colonic enteric-coated particles 100mg/kg (calculated as lysozyme).
  • Dosmaate group dosmaate 100mg/kg.
  • Combination group lysozyme colonic enteric-coated granules 100mg/kg (calculated as lysozyme), dosmaate 5mg/kg.
  • Combination group two lysozyme colonic enteric-coated particles 100mg/kg (calculated as lysozyme), dosmaate 10mg/kg.
  • lysozyme colon enteric-coated particles 100mg/kg (calculated as lysozyme), dosmaate 1000mg/kg.
  • lysozyme colonic enteric-coated particles 100mg/kg (calculated as lysozyme), dosmaate 2000mg/kg.
  • the model group was given the same amount of 0.5% sodium carboxymethyl cellulose solution every day.
  • the normal control group was not given any drugs.
  • the colorectal dilatation (CRD) model has become a standard tool for evaluating the sensitivity of animal internal organs. Abdominal wall withdrawal reflex and electromyography test are the most commonly used methods to evaluate animal response to colorectal dilatation stimulation.
  • the abdominal wall withdrawal reflex test is used to test the behavioral response of rats to colorectal dilatation stimulation. It was performed when the rats of the respective groups reached 8 weeks of age (before the start of the 1-month dosing period) and 3 months of age (after the end of the 1-month dosing period). Fasting overnight before the abdominal wall withdrawal reflex test to reduce the contents of the digestive tract.
  • a flexible balloon made of the fingers of the surgical glove (with a thin-walled PTFE catheter; the balloon should be inflated overnight before the experiment to make it more compliant), and then it was inserted into the anus of the rat after applying petroleum jelly It reaches the colon at 7 cm and is fixed at the tail 2 cm from the anus.
  • the balloon is connected to the valve through a catheter, and the valve is additionally connected to a sphygmomanometer.
  • the rat was placed in a small plastic cage to restrict its turn and adapt for 30 minutes. Use a sphygmomanometer to inflate the balloon to pressures of 20, 40, and 60 mm Hg for testing.
  • the pressure is maintained for 20 seconds, and the abdominal wall withdrawal reflex score of the rat during the 20-second period of the pressure maintenance is recorded by a blind observer.
  • the test is repeated 3 times under each pressure condition, and the average value of the 3 tests is taken as a result. Let the rats rest for 10 minutes between each test, and also rest for 10 minutes between different pressures.
  • AWR abdominal wall withdrawal reflex
  • the rat's visceral hypersensitive response (nerve response) to colorectal dilatation was quantified. After the rats in each group reached 3 months of age (after the end of the 1-month dosing period), the abdominal wall withdrawal reflex test was performed.
  • the rats were intraperitoneally injected with an appropriate amount of pentobarbital solution (50 mg/ml) and fully anesthetized. Cut the hair of the lower abdomen and back neck, implant the needle electrode (tungsten microelectrode) into the left side of the rat's abdomen, fix it in the muscle layer of the external oblique muscle, and pass the electrode wire under the skin of the left body of the rat Pass through a small incision at the back of the neck and pass through the small incision. The wounds on the abdomen and neck of the rat were sutured and put back into the cage. On the 3rd day after the operation, fasting overnight to reduce the contents of the digestive tract.
  • pentobarbital solution 50 mg/ml
  • the EMG test was started. Use the same method as the abdominal wall withdrawal reflex test to stimulate the colorectal dilatation, and use the physiological signal acquisition and processing system to record the discharge activity of the rat external oblique muscle under the stimulation of each colorectal dilatation pressure (20, 40, and 60 mm Hg). Maintain the pressure for 20 seconds each time, test each pressure 3 times, and take the average of the 3 tests as the result. Let the rats rest for 10 minutes between each test, and also rest for 10 minutes between different pressures.
  • the EMG test result is expressed by the area under the curve (AUC) during the 30 seconds after the start of colorectal dilatation, and each data is normalized relative to the average baseline amplitude (100%).
  • Table 1 The score results of the abdominal wall withdrawal reflex test of each group of animals at the age of 8 weeks
  • Table 2 Score results of abdominal wall withdrawal reflex test of each group of animals at the age of 3 months
  • ** indicates a significant difference compared with the normal control group under the corresponding pressure (P ⁇ 0.01)
  • ## indicates a significant difference compared with the model group under the corresponding pressure (P ⁇ 0.01)
  • && indicates a significant difference with the corresponding pressure
  • & means that there is a difference compared with the lysozyme group under the corresponding pressure (P ⁇ 0.05).
  • ** indicates a significant difference compared with the normal control group under the corresponding pressure (P ⁇ 0.01)
  • ## indicates a significant difference compared with the model group under the corresponding pressure (P ⁇ 0.01)
  • && indicates a significant difference with the corresponding pressure
  • & means that there is a difference compared with the lysozyme group under the corresponding pressure (P ⁇ 0.05).
  • Colorectal distension is a reproducible evaluation method of visceral sensitivity widely used in preclinical and clinical research.
  • Colorectal dilatation is a harmful stimulus to the intestines.
  • Subjects or animals with high sensitivity to colorectal dilatation can cause visceral pain responses.
  • This mechanical dilatation model can better simulate the intestines.
  • Patients with irritable syndrome have abdominal pain, abdominal discomfort and other symptoms, and this form of visceral stimulation is easy to control and reproducible.
  • Colorectal dilatation is often used to evaluate visceral sensitivity in rodents (such as rats and mice). The colorectal dilatation model has become a standard tool for evaluating visceral sensitivity in rodents.
  • the abdominal wall withdrawal reflex and EMG test results of the combined group have a tendency to decrease compared with the model group, but there is no statistical difference; it indicates that the ratio of dosmaate to lysozyme in the combination affects the intestines
  • the combination of the two must reach a certain ratio in order to better exert the synergistic effect.
  • the rats were sacrificed on the day the EMG test was completed, and the brain, heart, liver, spleen, lung, kidney, and digestive tract (including colon) were subjected to histopathological examination.
  • the combination group has small side effects and high safety after administration.
  • no typical inflammation, mucosal damage or other abnormalities were found in colonic histopathological examination, so the association between inflammation and mucosal damage and high visceral sensitivity of the experimental animals is excluded.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Physiology (AREA)
  • Nutrition Science (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

本发明公开了一种预防或治疗肠易激综合征的药物组合，所述药物组合包含多司马酯和溶菌酶。

Description

预防或治疗肠易激综合征的药物组合 技术领域
本发明涉及医药领域，具体涉及预防或治疗肠易激综合征的药物组合。
背景技术
肠易激综合征(Irritable bowel syndrome，IBS)是一种常见的功能性肠道疾病，患病率高。Meta分析显示中国人群肠易激综合征患病率为1.0％～16.0％，总体患病率为6.5％，其中符合Manning标准的患病率为11.5％，符合罗马Ⅲ标准的患病率为8.9％。
肠易激综合征为一种慢性疾病，表现为与排便或排便习惯改变相关的腹痛或腹部不适。腹痛、腹胀(bloating)、腹部膨隆(distension)和排便障碍是肠易激综合征的常见症状，且会反复发作，给患者带来很大痛苦，降低生活质量。
根据罗马III标准，并基于患者的大便性状，肠易激综合征可分为：腹泻型肠易激综合征(IBS-D)、便秘型肠易激综合征(IBS-C)、混合型肠易激综合征(IBS-M)和不定型肠易激综合征(Un-subtyped IBS)。患者通常在这些亚型中转换。
肠易激综合征缺乏可检测的器质性病因，其病因仍然未知。实验室检查、X线检查及活检未见解剖学异常。情感因素、饮食、药物或者激素可能诱发或者加重消化道症状。
内脏高敏感(Visceral hypersensitivity)是肠易激综合征的核心发病机制，在肠易激综合征症状发生和疾病发展中有重要作用。绝大多数研究证实，肠易激综合征患者存在直肠和结肠的内脏高敏感，即肠道对刺激的感受性增强。内脏高敏感是肠易激综合征的腹痛、腹胀等腹部不适症状发生的核心病理生理机制。肠易激综合征患者对结直肠扩张(压力)刺激敏感，无论腹泻型还是便秘型肠易激综合征患者的疼痛阈值均比对照组降低。
目前的肠易激综合征治疗药物包括解痉药、泻药、止泻药、抗抑郁药(TCAs、SSRIs)、抗生素、5-HT3受体拮抗剂、5-HT4受体部分激动剂、鸟苷酸环化酶-C激动剂和μ-阿片受体激动剂等，但是现有的肠易激综合征治疗药物存在明显的副作用。解痉药可以短期缓解腹泻型肠易激综合征患者的症状，对腹痛有一定疗效。这类药物包括选择性肠道平滑肌松弛药(如匹维溴铵、奥替溴铵、西托溴铵、美贝维林、阿尔维林)和抗胆碱药(如东莨菪碱)等。平滑肌松弛类解痉药的常见副作用包括呼吸困难、头痛、晕眩、皮肤瘙痒和红疹等。抗胆碱类解痉药可导致心跳加快、视力模糊、便秘等，患有胃食管反流病、急性心肌梗死、高血压、甲亢和容易患上闭角青光眼的病人须慎用，前列腺增生患者须避免使用。5-HT3受体拮抗剂阿洛 司琼在美国最初被FDA批准用于治疗腹泻型肠易激综合征女性患者，因该药引起缺血性结肠炎和便秘并发症，后来又缩小了适应症范围，仅用于症状严重的患者。5-HT4受体部分激动剂替加色罗被批准用于女性便秘型肠易激综合征患者缓解症状的短期治疗。但由于存在心血管不良事件的风险，这种药物在美国的销售已经暂停。利福昔明在美国被批准用于腹泻型肠易激综合征的治疗，但说明书标签有关于难辨梭菌相关腹泻的黑框警告。
临床上对于疗效好、不良反应少或副作用小的肠易激综合征治疗药物仍存在迫切的需求。
发明内容
本发明的目的在于提供多司马酯和溶菌酶的药物组合在制备用于预防或治疗肠易激综合征的药物中的应用，提供一种用于预防肠易激综合征、治疗肠易激综合征的药物组合物，以及一种预防或治疗肠易激综合征的方法。
为此，在本发明的第一方面，本发明提出了药物组合在制备用于预防或治疗肠易激综合征的药物中的应用，所述药物组合包含多司马酯和溶菌酶。发明人发现，将多司马酯与溶菌酶组合使用，可预防和治疗肠易激综合征，二者具有明显的协同增效作用。
在一些实例中，所述肠易激综合征包含内脏高敏感的特征。
发明人还发现，药物组合中多司马酯与溶菌酶的质量比对于二者协同治疗肠易激综合征有较大影响。在一些实例中，所述组合中多司马酯与溶菌酶的质量比为(0.05～100):1，且不包括0.05:1。在一些实例中，所述组合中多司马酯与溶菌酶的质量比为(0.1～10):1。多司马酯与溶菌酶的质量比为0.05:1时无协同作用，质量比在(0.1～10):1时有显著的协同作用，比例超过这一区间时协同作用减弱。
在一些实例中，所述溶菌酶的效价大于20000U/mg。
药物组合中的多司马酯和溶菌酶可分别以独立制剂的形式给药(联合用药)，也可以以存在于同一制剂中的形式(药物组合物)给药。在一些实例中，多司马酯和溶菌酶以药物组合物的形式给药。
在一些实例中，所述药物组合物为口服制剂。在一些实例中，所述口服制剂为口服常释制剂、口服缓释制剂、口服控释制剂中的任意一种。在一些实例中，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂中的任意一种。
在一些实例中，所述药物组合物中还含有药学上可接受的辅料。在一些实例中，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料中的至少一种。
在一些实例中，多司马酯和溶菌酶分别以独立制剂的形式给药。
在一些实例中，所述独立制剂还含有药学上可接受的辅料。在一些实例中，药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料中的至少一种。
发明人经过进一步研究发现，与溶菌酶的其他制剂相比，所述溶菌酶采用肠溶制剂，特别是在大肠，尤其是在结肠释放药物的制剂时，能更好地发挥与多司马酯的协同作用，在治疗肠易激综合征时产生更好的疗效。
根据具体需要，所述肠溶制剂为具有肠溶功能的常释制剂、缓释制剂、控释制剂等肠溶制剂形式，可以是具有肠溶功能的片剂、胶囊、丸剂、颗粒剂等肠溶制剂形式，也可以是它们的任意组合。在一些实例中，所述肠溶制剂为肠溶片剂。在一些实例中，所述肠溶制剂是结肠肠溶的片剂。
在一些实例中，所述多司马酯为口服制剂形式。根据具体需要，所述多司马酯为常释制剂、缓释制剂或控释制剂等制剂形式，可以是片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等制剂形式，也可以是它们的任意组合。在一些实例中，所述多司马酯为片剂。
在本发明的第二方面，本发明提出了一种用于预防或治疗肠易激综合征的药物组合物，所述药物组合物包含多司马酯和溶菌酶。发明人发现，将多司马酯与溶菌酶组合使用，可预防和治疗肠易激综合征，二者具有明显的协同增效作用。
发明人发现，药物组合物中所述多司马酯与溶菌酶的质量比对于二者协同治疗肠易激综合征有较大影响。在一些实例中，药物组合物中多司马酯与溶菌酶的质量比为(0.05～100):1，且不包括0.05:1，在一些实例中，，药物组合物中多司马酯与溶菌酶的质量比为(0.1～10):1。
在一些实例中，所述溶菌酶的效价大于20000U/mg。
在一些实例中，所述药物组合物为口服制剂。在一些实例中，所述口服制剂为口服常释制剂、口服缓释制剂、口服控释制剂中的任意一种。在一些实例中，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂中的任意一种。
在一些实例中，所述药物组合物中还含有药学上可接受的辅料。在一些实例中，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料中的至少一种。
所述药物组合物可通过以下方法制备得到：
将多司马酯与溶菌酶混合，再添加药学上可接受的辅料制得药物组合物。
或者分别将多司马酯和溶菌酶与药学上可接受的辅料制成多司马酯制剂亚单元和溶菌酶制剂亚单元，将两种制剂亚单元混合得到药物组合物。优选地，多司马酯制剂亚单元为肠溶剂型或胃溶剂型，溶菌酶制剂亚单元为肠溶剂型。
在本发明的第三方面，本发明提出了一种预防或治疗肠易激综合征的方法，包括向肠易激综合征患者给药有效量的多司马酯和溶菌酶。
发明人发现，多司马酯与溶菌酶的质量比对于二者协同治疗肠易激综合征有较大影响。在一些实例中，多司马酯与溶菌酶的质量比为(0.05～100):1，且不包括0.05:1。在一些实例中，多司马酯与溶菌酶的质量比为(0.1～10):1。
在一些实例中，所述溶菌酶的效价大于20000U/mg。
在一些实例中，所述多司马酯的每日给药量为0.05～20g；优选地，所述多司马酯的每日给药量为0.1～10g。
在一些实例中，所述多司马酯或者溶菌酶可分别给药1～3次/天。
在一些实例中，多司马酯或溶菌酶可分别以独立制剂的形式给药(联合用药)，也可以以存在于同一制剂中的形式(药物组合物)给药。
在一些实例中，多司马酯和溶菌酶以药物组合物的形式给药。
在一些实例中，所述药物组合物为口服制剂。在一些实例中，所述口服制剂为口服常释制剂、口服缓释制剂、口服控释制剂中的任意一种。在一些实例中，所述口服制剂选自片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂中的任意一种。
在一些实例中，所述药物组合物中还含有药学上可接受的辅料。在一些实例中，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料的至少一种。
在一些实例中，多司马酯和溶菌酶分别以独立制剂的形式给药。
在一些实例中，所述独立制剂还含有药学上可接受的辅料。在一些实例中，药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料中的至少一种。
发明人经过进一步研究发现，与溶菌酶的其他制剂相比，所述溶菌酶采用肠溶制剂，特别是在大肠，尤其是在结肠释放药物的制剂时，能更好地发挥与多司马酯的协同作用，在治疗肠易激综合征时产生更好的疗效。
根据具体需要，所述肠溶制剂为具有肠溶功能的常释制剂、缓释制剂、控释制剂等肠溶 制剂形式，可以是具有肠溶功能的片剂、胶囊、丸剂、颗粒剂等肠溶制剂形式，也可以是它们的任意组合。在一些实例中，所述肠溶制剂为肠溶片剂。在一些实例中，所述肠溶制剂是结肠肠溶的片剂。
在一些实例中，所述多司马酯为口服制剂形式。根据具体需要，所述多司马酯为常释制剂、缓释制剂或控释制剂等制剂形式，可以是片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂等制剂形式，也可以是它们的任意组合。
在一些实例中，所述多司马酯为片剂。
本发明的有益效果是：
本发明提供的多司马酯和溶菌酶的组合可显著改善肠易激综合征，二者在改善肠易激综合征方面具有协同增效作用。通过试验发现，本发明的多司马酯和溶菌酶组合可明显降低肠易激综合征模型动物的腹壁撤退反射(AWR)评分和肌电图(EMG)AUC值，明显改善内脏高敏感状态。此外由于内脏高敏感特征存在于各型肠易激综合征中，因此本发明的组合可适用于各型肠易激综合征。另外，持续给药一个月在所有试验动物身上均未显示出明显的毒性，说明副作用小。因此本发明提供了一种新的、适用广泛的、疗效好且副作用小的治疗肠易激综合征的药物组合。
具体实施方式
下面进一步列举实施例以详细说明本发明。同样应理解，以下实施例只用于对本发明进行进一步说明，不能理解为对本发明保护范围的限制，本领域技术人员根据本发明阐述的原理做出的一些非本质的改进和调整均属于本发明的保护范围。下述示例具体的工艺参数等也仅是合适范围中的一个示例，即本领域技术人员可以通过本文的说明做合适范围内的选择，而并非要限定于下文示例的具体数据。
定义：
肠易激综合征(Irritable bowel syndrome，IBS)：肠易激综合征是一种功能性肠道疾病，表现为与排便或排便习惯改变相关的腹痛或腹部不适；腹痛、腹胀(bloating)、腹部膨隆(distension)和排便障碍是常见的特征。
内脏高敏感(Visceral hypersensitivity)：内脏高敏感是指肠道对刺激的感受性增强，包括引起内脏疼痛或不适刺激的阈值降低、内脏对生理性刺激产生不适感或者对伤害性刺激反应强烈的现象。不仅直肠和结肠可表现出内脏高敏感，消化道其他区域如空肠、食管也可表现出内脏高敏感。肠易激综合征动物或患者存在内脏高敏感，内脏高敏感是肠易激综合征的腹痛、腹胀等腹部不适症状发生的核心病理生理机制。内脏高敏感可以放大胃肠动力事件而产生症状。肠易激综合征动物或患者的内脏高敏感包括但不限于对结直肠扩张(压力)刺激敏感、 对温度的刺激呈高敏感、对生理刺激(例如进餐)的高反应性。
多司马酯(Dosmalfate)：多司马酯是一种胃粘膜保护剂，被批准用于治疗胃、十二指肠溃疡。其化学名称为地奥明七双(硫酸氢盐)铝复合物，分子式为Al 7(OH) 14(C 28H 25O 36S 7)[Al(OH) 3] 7。动物实验和人体研究均表明，多司马酯可有效治疗消化道溃疡，其不良反应轻微且发生率低。
溶菌酶(Lysozyme)：溶菌酶，是来源于动物、植物、微生物的溶菌酶，或者是天然溶菌酶的重组物。例如可以是鸡蛋溶菌酶、人溶菌酶、重组人溶菌酶、噬菌体溶菌酶等。本发明中的溶菌酶还包括其药用盐，例如盐酸盐、氯化物、硫酸盐或氨基酸盐等。鸡蛋溶菌酶为溶菌酶的主要商业来源，其活性与人溶菌酶接近，许多上市药物使用的溶菌酶即为鸡蛋溶菌酶。人溶菌酶在人体内广泛分布、大量存在。溶菌酶的安全性很高。
肠溶制剂：肠溶制剂是指在胃中不释放或是几乎不释放药物，而进入肠中，在肠道的某些部位能大部分或全部释放药物的制剂。人体的肠道包括小肠和大肠，其中小肠又分为十二指肠、空肠、回肠，大肠又分为盲肠、结肠、直肠。消化道的不同部位具有不同的pH值，例如胃中pH值约1～3，小肠中pH值约4-7，大肠中pH值约7-8。通过选用pH依赖性降解材料作为制剂辅料，可以制备得到在消化道特定部位定向释放药物的制剂，例如小肠肠溶制剂或大肠肠溶制剂。具体可以包括十二指肠肠溶制剂、空肠肠溶制剂、回肠肠溶制剂、盲肠肠溶制剂、结肠肠溶制剂或者直肠肠溶制剂等。
下面描述了多司马酯的单独制剂、溶菌酶的单独制剂，以及多司马酯和溶菌酶的药物组合物的示例性制备方法。
溶菌酶原料可以市售获得，效价大于20000U/mg；多司马酯原料可以根据现有技术方法制备得到。
多司马酯片：以多司马酯为原料，使用普通片剂辅料压片即得。
溶菌酶颗粒剂：以溶菌酶为原料，加入等量的淀粉，混合均匀，加入粘合剂(水)制粒，干燥即得。
溶菌酶结肠肠溶颗粒剂：以溶菌酶为原料，加入等量的淀粉，混合均匀，加入粘合剂(水)制粒，干燥，得到溶菌酶颗粒。将制备的溶菌酶颗粒按照常规方法包市售结肠肠溶衣，得到溶菌酶结肠肠溶颗粒剂。
多司马酯溶菌酶复方胶囊：以溶菌酶为原料，加入等量的淀粉，混合均匀，加入粘合剂(水)制粒，干燥，得到溶菌酶颗粒。将制备的溶菌酶颗粒按照常规方法包市售结肠肠溶衣，得到溶菌酶结肠肠溶颗粒。以多司马酯为原料，加入普通颗粒剂辅料，制粒得到多司马酯颗粒。将溶菌酶结肠肠溶颗粒和多司马酯颗粒以适当的配比装入普通空胶囊中，即得多司马酯 溶菌酶复方胶囊。
下述实施例通过动物试验对本发明进行具体的说明。
所用的试验动物、试剂等均通过市售获得。试验中采用的相关测试方法以及相关仪器的具体操作方式等均是本领域技术人员所熟知的。所用的多司马酯，以及溶菌酶结肠肠溶颗粒剂均为湘北威尔曼制药有限公司提供。
实施例
多司马酯与溶菌酶的组合对肠易激综合征模型动物的治疗作用
本实施例通过对新生SD大鼠(Sprague-Dawley rats)在8日龄至21日龄期间每日施以结直肠扩张作为刺激因素，诱导产生肠易激综合征模型，该模型动物存在肠易激综合征的内脏高敏感，且不伴随有结肠炎症或黏膜损伤；21日龄至8周龄期间不再予以结直肠扩张刺激；8周龄至3月龄期间每日灌胃给予试验药物或安慰剂；在8周龄(1个月的给药期间开始之前)和3月龄左右(1个月的给药期间结束之后)时通过腹壁撤退反射试验和肌电图试验测试大鼠对结直肠扩张刺激的行为和神经反应。
1、动物及分组处理
正常体重的8日龄新生雄性SD大鼠，暴露于12:12小时的亮-暗周期循环。每12只新生大鼠与1只成年雌鼠同笼鼠乳喂养，直至25日龄。然后将新生大鼠每4只同笼喂养，可自由进食和饮水。
将所述SD大鼠随机分为正常对照组、模型组、多司马酯组、溶菌酶组、组合一组(多司马酯与溶菌酶的给药量之比0.05:1)、组合二组(多司马酯与溶菌酶的给药量之比0.1:1)、组合三组(多司马酯与溶菌酶的给药量之比10:1)和组合四组(多司马酯与溶菌酶的给药量之比20:1)，每组分配12只动物。
2、造模
除正常对照组外，其余各组大鼠在8日龄至21日龄期间每日施以结直肠扩张(CRD)刺激来诱导肠易激综合征，具体操作方法为：将手术手套手指做成的一个柔性球囊(带聚四氟乙烯导管；球囊在实验前应充气过夜，使其具有较好的顺应性)涂抹凡士林后经大鼠肛门插入到达结肠，在距肛门2cm的尾部处固定。球囊通过导管与阀门相连，阀门另外还连接有血压计。将大鼠置于小塑料笼中限制其转身，适应30分钟。用血压计将球囊缓慢充气到60mm Hg，刺激20秒后放气；1小时内再重复刺激2次(每次间隔30分钟)。
正常对照组大鼠处理方法与其它组相似，但未将球囊插入结肠，而是在大鼠8日龄至21日龄期间每天轻轻地触摸其会阴区。
造模完成时，仅正常对照组有1只大鼠死亡，其余动物均完成了后续实验过程。
3、药物配制和给药
除正常对照组和模型组外，其余各组大鼠在8周龄至3月龄期间每日灌胃给予试验药物(润湿于0.5％羧甲基纤维素钠溶液中)，给药量为8ml。
溶菌酶组：溶菌酶结肠肠溶颗粒100mg/kg(以溶菌酶计)。
多司马酯组：多司马酯100mg/kg。
组合一组：溶菌酶结肠肠溶颗粒100mg/kg(以溶菌酶计)，多司马酯5mg/kg。
组合二组：溶菌酶结肠肠溶颗粒100mg/kg(以溶菌酶计)，多司马酯10mg/kg。
组合三组：溶菌酶结肠肠溶颗粒100mg/kg(以溶菌酶计)，多司马酯1000mg/kg。
组合四组：溶菌酶结肠肠溶颗粒100mg/kg(以溶菌酶计)，多司马酯2000mg/kg。
模型组每日给予等量的0.5％羧甲基纤维素钠溶液。正常对照组不给任何药物。
4、测试
结直肠扩张(CRD)模型已成为评估动物内脏敏感性的标准工具。腹壁撤退反射和肌电图测试是评价结直肠扩张刺激后动物反应的最常用方法。
4.1腹壁撤退反射(abdominal withdrawal reflex,AWR)试验
腹壁撤退反射试验用于测试大鼠对结直肠扩张刺激的行为反应。在相应各组大鼠达到8周龄(1个月的给药期间开始之前)和3月龄(1个月的给药期间结束之后)时进行。腹壁撤退反射测试前禁食过夜，以减少消化道内容物。
试验时，将手术手套手指做成的一个柔性球囊(带聚四氟乙烯薄壁导管；球囊在实验前应充气过夜，使其具有较好的顺应性)涂抹凡士林后经大鼠肛门插入7cm到达结肠，在距肛门2cm的尾部处固定。球囊通过导管与阀门相连，阀门另外还连接有血压计。将大鼠置于小塑料笼中限制其转身，适应30分钟。用血压计分别将球囊充气到20、40和60mm Hg压力下进行测试。每次测试时，将压力维持20秒，由盲法观察者记录在压力维持的20秒期间内大鼠的腹壁撤退反射评分，每个压力条件下重复测试3次，取3次测试的平均值作为结果。每次测试之间让大鼠休息10分钟，不同压力之间也休息10分钟。
腹壁撤退反射(AWR)评分规则如下：0＝无行为反应；1＝头部短暂运动，然后静止不动；2＝腹肌收缩；3＝腹部抬离笼的平台；4＝骨盆结构拱起。
4.2肌电图(electromyography,EMG)试验
通过测量腹外斜肌的肌电图活性，定量大鼠对结直肠扩张的内脏高敏感反应(神经反应)。在各组大鼠达到3月龄(1个月的给药期间结束之后)，完成腹壁撤退反射试验后进行。
在各组大鼠达到3月龄，完成腹壁撤退反射试验的次日，给大鼠腹腔注射适量戊巴比妥溶液(50mg/ml)，充分麻醉。剪去下腹部和后颈部的毛发，将针电极(钨微电极)植入到大鼠的 腹部左侧，固定在腹外斜肌肌肉层内，将电极丝线经大鼠左侧身体的皮下穿过至后颈处的一个小切口，从该小切口处穿出。缝合大鼠腹部和颈部的伤口，放回笼中。手术后第3日，禁食过夜，以减少消化道内容物。手术后第4日，开始肌电图测试。用与腹壁撤退反射试验相同的方法进行结直肠扩张刺激，同时用生理信号采集处理系统记录在各个结直肠扩张压力(20、40和60mm Hg)刺激下大鼠腹外斜肌的放电活动，每次将压力维持20秒，每个压力测试3次，取3次测试的平均值作为结果。每次测试之间让大鼠休息10分钟，不同压力之间也休息10分钟。
肌电图测试结果用结直肠扩张起始后的30秒期间的曲线下面积(AUC)表示，每个数据相对平均基线振幅(average baseline amplitude，定为100％)进行归一化处理。
5、试验结果和评价
腹壁撤退反射与肌电图测试
腹壁撤退反射的评分越高，表明大鼠对结直肠扩张刺激的行为反应越强烈，进一步说明内脏敏感性越高，因此表明肠易激综合征越严重。
肌电图的AUC值(相对平均基线振幅归一化)越大，说明大鼠对结直肠扩张刺激的神经反应越强烈，进一步说明内脏敏感性越高，因此表明肠易激综合征越严重。表1～3列出了该试验的统计结果。
表1：8周龄时各组动物的腹壁撤退反射试验评分结果
Figure PCTCN2020122082-appb-000001
**表示与相应压力下正常对照组相比有显著差异(P<0.01)。
表2：3月龄时各组动物的腹壁撤退反射试验评分结果
Figure PCTCN2020122082-appb-000002
Figure PCTCN2020122082-appb-000003
**表示与相应压力下的正常对照组相比有显著差异(P<0.01)，##表示与相应压力下的模型组相比有显著差异(P<0.01)，&&表示与相应压力下的溶菌酶组相比有显著差异(P<0.01)，&表示与相应压力下的溶菌酶组相比有差异(P<0.05)。
表3：3月龄时各组动物的肌电图测试结果
Figure PCTCN2020122082-appb-000004
**表示与相应压力下的正常对照组相比有显著差异(P<0.01)，##表示与相应压力下的模型组相比有显著差异(P<0.01)，&&表示与相应压力下的溶菌酶组相比有显著差异(P<0.01)，&表示与相应压力下的溶菌酶组相比有差异(P<0.05)。
本试验对新生大鼠连续施加结直肠扩张刺激，诱导产生肠易激综合征模型，造成动物内脏高敏感。结直肠扩张(colorectal distension,CRD)是临床前和临床研究中广泛应用的、可重复的内脏敏感性评估方法。结直肠扩张作为一种对肠道的有害性刺激，通过对内脏高敏感的受试者或受试动物施加结直肠扩张刺激可引起内脏疼痛反应，这种机械性扩张模型可以较好 地模拟肠易激综合征患者的腹痛、腹部不适等症状，而且这种内脏刺激形式易于控制，重复性好。结直肠扩张评价内脏敏感性常在啮齿动物(如大鼠、小鼠)中进行，结直肠扩张模型已成为评估啮齿动物内脏敏感性的标准工具。
从腹壁撤退反射和肌电图测试结果可以看出，肠易激综合征动物模型造模成功，所述动物模型存在内脏高敏感，可类比人类各型肠易激综合征。与正常对照组相比，在各个试验压力下模型组动物对结直肠扩张刺激的行为反应和神经反应均明显加强。由表1-3数据可知，与正常对照组相比，模型组腹壁撤退反射评分明显增加(P<0.01)、肌电图测试的曲线下面积AUC值也明显增大(P<0.01)。说明模型组动物至少在8周龄至3月龄期间维持了肠易激综合征的内脏高敏感状态。
从试验结果可以得出以下结论：
1.给药后，溶菌酶组的腹壁撤退反射和肌电图测试结果数值与模型组相比无统计学差异(P>0.05)，表明溶菌酶单独使用治疗肠易激综合征基本没有疗效。多司马酯组情况类似。
2.给药后，组合一组的腹壁撤退反射和肌电图测试结果数值相比模型组有降低的趋势，但并无统计学差异；表明组合中多司马酯与溶菌酶的比例影响对肠易激综合征的治疗效果，二者组合须达到一定的比例才能更好地发挥协同增效作用。
3.给药后，组合二组、组合三组及组合四组的腹壁撤退反射和肌电图测试结果数值比模型组及溶菌酶组明显降低(P<0.01)；表明多司马酯溶菌酶组合起到了两种组分单独所不具有的功效，发挥了协同增效作用，可用于治疗肠易激综合征。
本试验中肌电图测试完成当天，处死大鼠，对脑、心、肝、脾、肺、肾和消化道(包括结肠)等进行组织病理学检查。与正常对照组及模型组相比，组合一组、组合二组、组合三组及组合四组大鼠均未见明显病理变化。说明本发明的组合在给药后毒副作用小，安全性高。另外，在本发明中，结肠组织病理学检查未见典型的炎症、黏膜损伤或其它异常，因此排除了炎症及黏膜损伤与试验动物内脏高敏感之间的关联。
以上用一般性说明、具体实施方式等对本发明作了详尽的描述。在本发明的基础上，本领域技术人员可以对之作合理的修改或改进，在不偏离本发明精神的基础上所做的这些修改或改进，均属于本发明的内容。

Claims (10)

  1. 药物组合在制备用于预防或治疗肠易激综合征的药物中的应用，所述药物组合包含多司马酯和溶菌酶。
  2. 根据权利要求1所述的应用，其特征在于：药物组合中多司马酯与溶菌酶的质量比为(0.05～100):1，且不包括0.05:1。
  3. 根据权利要求1所述的应用，其特征在于：药物组合中多司马酯与溶菌酶的质量比为(0.1～10):1。
  4. 一种药物组合物，所述药物组合物用于预防或治疗肠易激综合征，所述药物组合物中含有多司马酯和溶菌酶。
  5. 根据权利要求4所述的药物组合物，其特征在于：药物组合物中多司马酯与溶菌酶的质量比为(0.05～100):1，且不包括0.05:1。
  6. 根据权利要求5所述的药物组合物，其特征在于：药物组合物中多司马酯与溶菌酶的质量比为(0.1～10):1。
  7. 根据权利要求4～6任一项所述的药物组合物，其特征在于：所述药物组合物为口服制剂，优选地，所述口服制剂为口服常释制剂、口服缓释制剂、口服控释制剂中的任意一种，更优选地，所述口服制剂为片剂、胶囊剂、颗粒剂、散剂、丸剂、糖浆剂、口服溶液剂、口服混悬剂和口服乳剂中的任意一种。
  8. 根据权利要求4～6任一项所述的药物组合物，其特征在于：所述药物组合物中还含有药学上可接受的辅料，优选地，所述药学上可接受的辅料选自填充剂、粘合剂、崩解剂、润滑剂、增溶剂、矫味剂、着色剂、掩味剂、pH调节剂、助悬剂、增稠剂、防腐剂、稳定剂、抗氧剂、润湿剂、表面活性剂、悬浮剂、吸收增强剂和包衣材料中的至少一种。
  9. 权利要求4～8任一项所述的药物组合物的制备方法，包括如下步骤：将多司马酯与溶菌酶混合。
  10. 权利要求8所述的药物组合物的制备方法，包括如下步骤：分别将多司马酯和溶菌酶与药学上可接受的辅料制成多司马酯制剂亚单元和溶菌酶制剂亚单元，将两种制剂亚单元混合得到药物组合物；优选地，多司马酯制剂亚单元为肠溶剂型或胃溶剂型，溶菌酶制剂亚单元为肠溶剂型。
PCT/CN2020/122082 2019-10-25 2020-10-20 预防或治疗肠易激综合征的药物组合 Ceased WO2021078110A1 (zh)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US17/771,105 US20220362353A1 (en) 2019-10-25 2020-10-20 Drug combination for preventing or treating irritable bowel syndrome
JP2022524584A JP7342259B2 (ja) 2019-10-25 2020-10-20 過敏性腸症候群の予防又は治療のための医薬的組み合わせ
CN202080075281.0A CN114786711B (zh) 2019-10-25 2020-10-20 预防或治疗肠易激综合征的药物组合
EP20878112.0A EP4035672A4 (en) 2019-10-25 2020-10-20 COMBINATION OF MEDICATIONS FOR THE PREVENTION OR TREATMENT OF IRRITABLE BOTTLE SYNDROME

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201911025557.XA CN112704730A (zh) 2019-10-25 2019-10-25 预防或治疗肠易激综合征的药物组合
CN201911025557.X 2019-10-25

Publications (1)

Publication Number Publication Date
WO2021078110A1 true WO2021078110A1 (zh) 2021-04-29

Family

ID=75540869

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2020/122082 Ceased WO2021078110A1 (zh) 2019-10-25 2020-10-20 预防或治疗肠易激综合征的药物组合

Country Status (5)

Country Link
US (1) US20220362353A1 (zh)
EP (1) EP4035672A4 (zh)
JP (1) JP7342259B2 (zh)
CN (2) CN112704730A (zh)
WO (1) WO2021078110A1 (zh)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN116157132B (zh) * 2020-10-30 2025-07-15 湘北威尔曼制药股份有限公司 一种降低血糖的组合、应用和方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1692909A (zh) * 2004-05-08 2005-11-09 孙明杰 多司马酯分散片及其制备办法
CN1778304A (zh) * 2004-11-23 2006-05-31 广州威尔曼新药开发中心有限公司 多司马酯胶囊及其制备方法
JP2009263307A (ja) * 2008-04-28 2009-11-12 Taiyo Kagaku Co Ltd 炎症性腸疾患の予防・治療剤
CN110267676A (zh) * 2017-01-04 2019-09-20 诺维信公司 用于治疗肠易激综合征或炎性肠病的微生物溶菌酶

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030236236A1 (en) * 1999-06-30 2003-12-25 Feng-Jing Chen Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs
CN102379970B (zh) * 2011-10-31 2013-02-27 江苏省中医药研究院 一种治疗肠易激综合征的中药组合物
CN103585289B (zh) * 2012-08-15 2016-09-28 四川济生堂药业有限公司 一种预防或治疗肠易激综合征的药物组合物
CN103989855B (zh) * 2014-06-05 2017-08-25 浙江省立同德医院 一种治疗腹泻型肠易激综合征的中药复方组合物及其制备方法和制剂
US10350230B2 (en) * 2015-02-26 2019-07-16 Zuoguang Zhang Use of albiflorin or pharmaceutically acceptable salt for prevention and/or treatment of irritable bowel syndrome

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1692909A (zh) * 2004-05-08 2005-11-09 孙明杰 多司马酯分散片及其制备办法
CN1778304A (zh) * 2004-11-23 2006-05-31 广州威尔曼新药开发中心有限公司 多司马酯胶囊及其制备方法
JP2009263307A (ja) * 2008-04-28 2009-11-12 Taiyo Kagaku Co Ltd 炎症性腸疾患の予防・治療剤
CN110267676A (zh) * 2017-01-04 2019-09-20 诺维信公司 用于治疗肠易激综合征或炎性肠病的微生物溶菌酶

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
ISABEL VILLEGAS , CARMEN LA CASA , AURELIO ORJALES , CATALINA ALARCON DE LA LASTRA: "Effects of dosmalfate, a new cytoprotective agent, on acute and chronic trinitrobenzene sulphonic acid-induced colitis in rats", EUROPEAN JOURNAL OF PHARMACOLOGY, vol. 460, no. 2-3, 24 January 2003 (2003-01-24), pages 209 - 218, XP002288779, ISSN: 0014-2999, DOI: 10.1016/S0014-2999(02)02949-7 *
ISABEL VILLEGAS, CATALINA ALARCON DE LA LASTRA, AURELIO ORJALES, CARMEN LA CASA: "A new flavonoid derivative, dosmalfate, attenuates the development of dextran sulphate sodium-induced colitis in mice", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 3, no. 13-14, 28 September 2003 (2003-09-28), pages 1731 - 1741, XP055751913, DOI: 10.1016/j.intimp.2003.07.002 *
LIU JIANXIANG; LIU XINGUA: "Irritable Bowel Syndrome with Ulcerative Colitis", MODERN DIGESTION & INTERVENTION, vol. 13, no. 3, 31 March 2008 (2008-03-31), pages 204 - 206, XP009527561, ISSN: 1672-2159 *
See also references of EP4035672A4 *

Also Published As

Publication number Publication date
US20220362353A1 (en) 2022-11-17
CN114786711B (zh) 2024-07-23
JP2022554231A (ja) 2022-12-28
JP7342259B2 (ja) 2023-09-11
CN112704730A (zh) 2021-04-27
EP4035672A4 (en) 2022-11-30
EP4035672A1 (en) 2022-08-03
CN114786711A (zh) 2022-07-22

Similar Documents

Publication Publication Date Title
EP0988028B1 (en) Use of a composition comprising capsaicin or resiniferatoxin for the treatment of Irritable Bowel Syndrome
KR20150013671A (ko) 피라졸 유도체 및 그 의약용도
RS50104B (sr) Nova oralna formulacija za 5-th4 agoniste ili antagoniste
ES2989706T3 (es) Composiciones de rifamicina SV oral
WO2024160030A1 (zh) 一种组合物及其在制备治疗神经性疼痛药物中的应用
US20230086867A1 (en) Polymorphic forms of metopimazine
CN107106587A (zh) 芍药内酯苷或其药学上可接受的盐预防和/或治疗肠易激综合征的用途
KR102486126B1 (ko) 알펠리십을 포함하는 제약 조성물
WO2021078110A1 (zh) 预防或治疗肠易激综合征的药物组合
EP3409271B1 (en) Local anesthetics to facilitate food intake and food retention
CN100381136C (zh) 一种治疗便秘的药物组合物及其制剂和制备方法
MXPA06006685A (es) Uso de gaboxadol para tratar el insomnio.
JP2024508514A (ja) 選択的ｃｂ２受容体アゴニストによる処置の方法
CN114073692B (zh) 含左卡尼汀或其衍生物的组合物及其应用
CN111671911B (zh) 一种治疗盆底失驰缓型便秘的药物组合物及其制备方法
EA049553B1 (ru) Новые полиморфные формы метопимазина
WO2025162430A1 (zh) 一种药物联用及其在预防或治疗神经退行性疾病中的用途
CN114788827A (zh) 螺环哌嗪季铵盐衍生物在制备治疗肠易激综合症药物中的用途
UA146763U (uk) Фармацевтична композиція
US2598530A (en) Enteric coated pyranisamine
TW202448422A (zh) 末梢神經障礙之治療或預防用的醫藥
EP4347022A1 (en) Pediatric formulations of ferric citrate
CN118846011A (zh) 一种组合物及其在制备通便、调节代谢和/或缓解疼痛的产品中的应用
CN117297106A (zh) 5-氨基乙酰丙酸在制备防治中老年人便秘的产品中的应用
UA146882U (uk) Комбінована фармацевтична композиція

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 20878112

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 2022524584

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

ENP Entry into the national phase

Ref document number: 2020878112

Country of ref document: EP

Effective date: 20220427

WWW Wipo information: withdrawn in national office

Ref document number: 2020878112

Country of ref document: EP