[go: up one dir, main page]

WO2024169170A1 - 一种双嘧达莫干混悬剂及其制备方法和应用 - Google Patents

一种双嘧达莫干混悬剂及其制备方法和应用 Download PDF

Info

Publication number
WO2024169170A1
WO2024169170A1 PCT/CN2023/118527 CN2023118527W WO2024169170A1 WO 2024169170 A1 WO2024169170 A1 WO 2024169170A1 CN 2023118527 W CN2023118527 W CN 2023118527W WO 2024169170 A1 WO2024169170 A1 WO 2024169170A1
Authority
WO
WIPO (PCT)
Prior art keywords
dipyridamole
dry suspension
suspension according
disease
diseases
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/CN2023/118527
Other languages
English (en)
French (fr)
Inventor
彭博
韩杨
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.)
Pediatric Immunity And Healthcare Guangzhou Biotechnology Co Ltd
Original Assignee
Pediatric Immunity And Healthcare Guangzhou Biotechnology 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 Pediatric Immunity And Healthcare Guangzhou Biotechnology Co Ltd filed Critical Pediatric Immunity And Healthcare Guangzhou Biotechnology Co Ltd
Publication of WO2024169170A1 publication Critical patent/WO2024169170A1/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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • 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
    • A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
    • 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
    • A61P1/12—Antidiarrhoeals
    • 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
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • 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
    • A61P1/18—Drugs for disorders of the alimentary tract or the digestive system for pancreatic disorders, e.g. pancreatic enzymes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/02—Nasal agents, e.g. decongestants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/04—Drugs for disorders of the respiratory system for throat disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/10—Anti-acne agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/14—Drugs for dermatological disorders for baldness or alopecia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/06—Antiglaucoma agents or miotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/02—Ophthalmic agents
    • A61P27/12—Ophthalmic agents for cataracts
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P27/00—Drugs for disorders of the senses
    • A61P27/16—Otologicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/14—Vasoprotectives; Antihaemorrhoidals; Drugs for varicose therapy; Capillary stabilisers
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present application belongs to the field of medicine, and specifically relates to a dipyridamole dry suspension and a preparation method and application thereof.
  • dipyridamole 2,2',2",2"',-[(4,8-dipiperidinylpyrimido[5,4-d]pyrimidine-2,6-diyl)bis(nitro)-tetraethanol
  • English name Dipyridamole molecular formula: C24H40N8O4
  • molecular weight 504.63
  • chemical structure formula is as follows:
  • Dipyridamole is a yellow crystalline powder; odorless and bitter. It is easily soluble in chloroform, soluble in ethanol, slightly soluble in acetone; almost insoluble in water, easily soluble in dilute acid, and pH-dependent.
  • pKa1 6.30 ⁇ 0.05
  • pKa2 0.8 ⁇ 0.1
  • distribution coefficient 8250 ⁇ 300 (octanol/buffer pH7)
  • BCS classification is Class II.
  • Dipyridamole was developed by Boehringer Ingelheim and was approved by the FDA for oral dipyridamole tablets in 1961.
  • the trade name is: (Pan Dingsheng). Dipyridamole has the effects of inhibiting phosphodiesterase, inhibiting platelet aggregation, and enhancing prostacyclin. It is mainly used clinically for anti-thrombosis and prevention and treatment of thrombotic diseases.
  • dipyridamole can inhibit adenosine reuptake and dilate coronary arteries.
  • Boehringer Ingelheim developed a dipyridamole injection that was approved by the FDA and used clinically in drug trials for the diagnosis of myocardial ischemia.
  • Dipyridamole is widely used clinically as an antithrombotic drug, often in combination with aspirin.
  • the FDA approved the marketing of aspirin dipyridamole sustained-release capsules developed by Boehringer Ingelheim to reduce the risk of stroke in patients with transient cerebral ischemia or complete ischemic stroke due to thrombosis.
  • Dipyridamole has been on the market worldwide for many years. Although there is no description of its use in children in the instructions, its safety in the real world is relatively good. Therefore, there are currently hundreds of cases of off-label use in clinical practice, and it has been widely used in children.
  • the current clinical dosage forms are only tablets and capsules, which are difficult to swallow, have inflexible dosages, and have poor acceptability due to the risks of choking, aspiration, and chewing.
  • the guardians of the children can only try to use the existing dosage forms according to the doctor's instructions, such as crushing dipyridamole tablets and mixing them with water or disassembling dipyridamole capsules and adding water to feed them.
  • the administration process cumbersome, but the bitter taste is very strong, which often leads to medication failure; the dosage is not easy to accurately control, which affects the efficacy or causes safety risks, and the compliance is very poor.
  • the present application provides a dipyridamole dry suspension and a preparation method and application thereof, which has excellent dispersion effect and taste masking effect, and can achieve low osmotic pressure administration; thereby greatly improving patient compliance and improving the efficacy of administration.
  • a dipyridamole dry suspension which is made of the following components in weight percentage: 0.1%-20% of a main drug, 0.1%-40% of a suspending agent, and 50%-99% of a filler.
  • the suspending agent includes one or more selected from xanthan gum, carbomer, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, povidone, sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, gum arabic, tragacanth gum, carrageenan, sodium alginate, and sodium carboxymethyl starch.
  • the suspending agent includes at least one of the following: hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, and carbomer.
  • the suspending agent is hydroxyethyl cellulose; preferably 0.1%-10% hydroxyethyl cellulose.
  • the suspending agent is xanthan gum; preferably 0.1%-5% xanthan gum.
  • the suspending agent is microcrystalline cellulose-sodium carboxymethyl cellulose; preferably 1%-30% microcrystalline cellulose-sodium carboxymethyl cellulose.
  • the suspending agent is carbomer; preferably 0.1%-5% carbomer.
  • the suspending agent is a combination of hydroxyethyl cellulose and xanthan gum, wherein the hydroxyethyl cellulose is 0.1%-10%, and the xanthan gum is 0.1%-5%.
  • the suspending agent is a combination of microcrystalline cellulose-sodium carboxymethyl cellulose and carbomer; wherein the microcrystalline cellulose-sodium carboxymethyl cellulose is 1%-30%, and the carbomer is 0.1%-5%.
  • the weight percentage of the main drug is 0.5%-10%.
  • the main drug is dipyridamole and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug thereof.
  • the pharmaceutically acceptable salt includes but is not limited to dipyridamole sodium salt or an inorganic acid salt.
  • the pharmaceutically acceptable salt includes but is not limited to dipyridamole sodium chloride and dipyridamole hydrochloride.
  • the weight percentage of the filler in the dry suspension is 60%-98%; more preferably 68%-95%.
  • the filler is selected from one or more of sucrose, glucose, lactose, maltodextrin, mannitol, sorbitol, starch, pregelatinized starch, and microcrystalline cellulose.
  • the filler is selected from one or more of glucose, maltodextrin, mannitol and sorbitol.
  • the filler is selected from one or both of glucose and maltodextrin.
  • the dry suspension further comprises one or more of a wetting agent, a glidant, an antibacterial agent, a buffer, a pigment, and a flavoring agent.
  • the dry suspension further comprises one or more of a wetting agent, a glidant, and a flavoring agent.
  • the dry suspension further comprises a wetting agent.
  • the dry suspension further comprises 0%-5% of a wetting agent.
  • the weight percentage of the wetting agent in the dry suspension is 0.1%-5%, more preferably 0.1%-3%, and even more preferably 0.1%-1%.
  • the wetting agent is selected from one or both of poloxamer and sodium lauryl sulfate.
  • the wetting agent is sodium lauryl sulfate.
  • the dry suspension further comprises a glidant.
  • the dry suspension further comprises 0%-5% of a glidant.
  • the weight percentage of the glidant in the dry suspension is 0.1%-5%, more preferably 0.5%-4%, and even more preferably 1.0%-3%.
  • the glidant is selected from one or more of silicon dioxide, magnesium stearate, talc, and sodium stearyl fumarate.
  • the glidant is selected from silicon dioxide.
  • the dry suspension further comprises a flavoring agent.
  • the dry suspension further comprises 0.1%-10% of a flavoring agent.
  • the weight percentage of the flavoring agent in the dry suspension is 0.1%-8%, more preferably 0.15%-5%.
  • the flavoring agent is selected from one or more of sweeteners and/or flavors.
  • the sweetener is selected from one or more of glucosyl steviol glycoside, sucralose, steviol glycoside, acesulfame potassium, sucrose, aspartame, sorbitol, maltitol, xylitol, saccharin sodium, cyclamate, sorbitol or mannitol.
  • the flavor is selected from one or more of fruit flavors, milk flavors, and cream flavors.
  • the flavoring agent is selected from one or more of glucosyl steviol glycoside, sucralose, steviol glycoside, fruit flavor, milk flavor, and cream flavor.
  • the flavoring agent is selected from one or more of glucosyl steviol glycoside, sucralose, and steviol glycoside.
  • the dry suspension may further contain one or more of an antibacterial agent, a buffer, and a pigment.
  • whether the antibacterial agent, buffer, or pigment is added, and the type and content of the added antibacterial agent, buffer, or pigment can be routinely screened and determined by a person skilled in the art.
  • the second aspect of the present application provides a method for preparing the dipyridamole suspension described in the first aspect of the present application, comprising: weighing the prescribed amount of raw materials and auxiliary materials according to the first aspect of the present application, and mixing them to obtain a dry suspension.
  • the third aspect of the present application provides a method for preparing a suspension, comprising taking the dry suspension described in the first aspect of the present application, dissolving the two in a ratio of 25 mg of dipyridamole to 1-50 mL of solvent, and mixing and stirring.
  • a method for preparing a suspension comprising taking the dry suspension described in the first aspect of the present application, mixing the dry suspension with a solvent in a ratio of 1 g of the dry suspension being dissolved in 1-50 mL of the solvent, and stirring.
  • the fourth aspect of the present application provides a suspension obtained by the preparation method of the third aspect of the present application.
  • the fifth aspect of the present application provides use of the dipyridamole dry suspension described in the first aspect of the present application and the dipyridamole suspension described in the fourth aspect of the present application in preparing a drug.
  • the drug is used to prevent and/or treat one or more of digestive system diseases, kidney diseases, respiratory diseases, heart diseases, brain diseases and cardiovascular and cerebrovascular diseases, blood diseases, skin diseases, and ENT diseases.
  • the medicament is used to prevent and/or treat one or more of the following digestive system diseases: viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons), biliary atresia, gastroenteritis (such as acute gastroenteritis), duodenal enteritis, gastrointestinal bleeding, infectious enteritis (viral or bacterial enteritis), cholangitis, common bile duct cyst, inguinal hernia, infantile hepatitis syndrome, gallstones, liver insufficiency, umbilical hernia, intussusception, intestinal obstruction, hepatoblastoma, hepatitis, cirrhosis, liver fibrosis, small intestine or colon ulcer, peritonitis, congen
  • the medicament is used to prevent and/or treat one or more of the following kidney diseases: renal syndrome, purpuric nephritis, lupus nephritis, IgA nephropathy, glomerulonephritis, renal hypertension, renal failure, renal injury.
  • kidney diseases renal syndrome, purpuric nephritis, lupus nephritis, IgA nephropathy, glomerulonephritis, renal hypertension, renal failure, renal injury.
  • the drug is used to prevent and/or treat one or more of the following respiratory diseases: respiratory tract infection (e.g., acute upper respiratory tract infection), respiratory distress syndrome, COVID-19, bronchitis, bronchopneumonia, community-acquired pneumonia, pleural effusion, respiratory failure, influenza, asthma, pulmonary fibrosis, pulmonary hypertension, and lung cancer.
  • respiratory tract infection e.g., acute upper respiratory tract infection
  • respiratory distress syndrome e.g., chronic upper respiratory tract infection
  • COVID-19 bronchitis
  • bronchopneumonia bronchopneumonia
  • community-acquired pneumonia e.g., pleural effusion
  • respiratory failure e.g., influenza, asthma, pulmonary fibrosis, pulmonary hypertension, and lung cancer.
  • the drug is used to prevent and/or treat one or more of the following heart diseases, brain diseases and cardiovascular and cerebrovascular diseases: congenital heart disease, coronary heart disease, angina pectoris, myocardial infarction, hypertension, vascular stones, thrombotic microangiopathy, nutcracker syndrome, portal vein cavernous change, myocardial damage, Kawasaki disease, portal hypertension, atrial/ventricular septal defect, congenital great artery malformation, angioneurotic edema, vasculitis, coronary artery aneurysm, congenital ventricular malformation, arrhythmia, thrombosis, stroke, meningitis, encephalitis, encephalomyelitis, hydrocephalus, epidemic encephalitis B, and dementia.
  • congenital heart disease congenital heart disease
  • coronary heart disease angina pectoris
  • myocardial infarction hypertension
  • vascular stones thrombotic microangiopathy
  • nutcracker syndrome portal vein cavernous change
  • the medicament is used to prevent and/or treat one or more of the following blood diseases: hyponatremia, iron deficiency anemia, hypogammaglobulinemia, thalassemia, hemolytic anemia, favism, thrombocytosis, sepsis, hypoproteinemia, leukemia, dyslipidemia.
  • blood diseases hyponatremia, iron deficiency anemia, hypogammaglobulinemia, thalassemia, hemolytic anemia, favism, thrombocytosis, sepsis, hypoproteinemia, leukemia, dyslipidemia.
  • the medicament is used to prevent and/or treat one or more of the following skin diseases: acne, rosacea, urticaria, fungal infection, herpes, solar dermatitis, atopic dermatitis, chickenpox, allergic purpura, vitiligo, psoriasis, nevus, melanoma, alopecia, seborrheic dermatitis, mite allergy, folliculitis, pemphigus, epidermal blisters, erythema and cutaneous eosinophilia.
  • skin diseases acne, rosacea, urticaria, fungal infection, herpes, solar dermatitis, atopic dermatitis, chickenpox, allergic purpura, vitiligo, psoriasis, nevus, melanoma, alopecia, seborrheic dermatitis, mite allergy, folliculitis, pemphigus, epidermal blisters, erythem
  • the drug is used to prevent and/or treat one or more of the following ENT diseases: glaucoma, cataract, conjunctivitis, sty, keratitis, rhinitis, sinusitis, caries, oral ulcers, tonsillitis, laryngitis, pharyngitis, tinnitus, and otitis media.
  • ENT diseases glaucoma, cataract, conjunctivitis, sty, keratitis, rhinitis, sinusitis, caries, oral ulcers, tonsillitis, laryngitis, pharyngitis, tinnitus, and otitis media.
  • the medicament is used to prevent and/or treat one or more of the following diseases: hydrocele, prostatitis, dwarfism, arthritis, inflammatory wrist disease, tendinitis, cytomegalovirus disease, adenovirus infection, hemodialysis status, stem cell transplant status, protein-energy malnutrition, growth retardation, glycogen storage disease, hypothyroidism, cellulitis, epilepsy, mineral metabolism disorders, fever, convulsions, shock, systemic inflammatory response syndrome, mastitis, vulvar pruritus, vaginitis, urethritis, hemorrhoids, mumps, breast cancer, ovarian cancer, hyperandrogenemia, ovarian polycystic changes, ovulation abnormalities and early embryonic maldevelopment, promotion of oocyte maturation, diabetic gangrene, diabetic neuropathy, leg ulcers, scleroderma, nerve disease, dizziness, sleep disorders, pain, erectile dysfunction, transplant and Host diseases, multiple s
  • the medicament is also used for preventing and/or treating allergic diseases and/or inflammatory diseases.
  • the sixth aspect of the present application provides a pharmaceutical composition, comprising the dry suspension described in the first aspect of the present application or the suspension described in the fourth aspect, and a second active ingredient.
  • the second active ingredient includes at least another ingredient for treating viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons), and biliary atresia.
  • viral enteritis including but not limited to rotavirus enteritis
  • inflammatory bowel disease including ulcerative colitis, Crohn's disease and indeterminate colitis
  • abdominal pain and diarrhea including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons
  • biliary atresia including but not limited to biliary atresia.
  • the pharmaceutical composition further comprises a pharmaceutically acceptable excipient.
  • the seventh aspect of the present application provides the use of the pharmaceutical composition of the sixth aspect of the present application in the preparation of drugs for preventing and/or treating viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons), and biliary atresia.
  • viral enteritis including but not limited to rotavirus enteritis
  • inflammatory bowel disease including ulcerative colitis, Crohn's disease and indeterminate colitis
  • abdominal pain and diarrhea including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons
  • biliary atresia including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons.
  • the dry suspension described in the first aspect of the present application, the suspension described in the fourth aspect, or the pharmaceutical composition described in the sixth aspect can be used in combination with surgery to treat biliary atresia.
  • a method for preventing and/or treating a disease comprising administering a preventive and/or therapeutically effective amount of dipyridamole and its pharmaceutically acceptable salts, hydrates, solvates, polymorphs, tautomers or prodrugs, the above-mentioned dipyridamole dry suspension or dipyridamole suspension to a patient in need, wherein the disease includes one or more of the diseases described in the fifth aspect of the present application.
  • the present application provides the above-mentioned dipyridamole dry suspension or dipyridamole suspension, pharmaceutical composition, or medicine containing them for preventing and/or treating one or more of digestive system diseases, kidney diseases, respiratory diseases, heart diseases, brain diseases and cardiovascular and cerebrovascular diseases, blood diseases, skin diseases, and ENT diseases.
  • a dipyridamole flavoring composition comprising or consisting of 0.1-20 parts by weight of a main drug and 0.1-10 parts by weight of a flavoring agent, wherein the main drug is selected from dipyridamole or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug thereof, and the flavoring agent includes one or more selected from glucosyl steviol glycoside, sucralose, and steviol glycoside.
  • the flavoring composition is composed of 2-5 parts by weight of a main drug and 1-8 parts by weight of a flavoring agent, wherein the main drug is selected from dipyridamole or a pharmaceutically acceptable salt thereof, and the flavoring agent is glucosyl stevioside.
  • the flavoring agent further includes one or more of fruit flavor, milk flavor, and cream flavor.
  • the weight proportions of the fruit flavor, milk flavor, and cream flavor are 0.1-10 parts, preferably 1-8 parts.
  • the flavoring composition does not contain any of fruit flavor, milk flavor, and cream flavor.
  • dipyridamole flavor-correcting composition in the preparation of an oral preparation.
  • dipyridamole flavor-correcting composition in the preparation of a dry suspension, a suspension, a granule, an orally disintegrating tablet, a dispersible tablet and/or a chewable tablet.
  • the dry suspension of the present application combines the characteristics of solid and liquid preparations, has a large gastrointestinal distribution area, is quickly absorbed, and is prepared before taking, so generally no antibacterial agent needs to be added. It is safe for children and has good safety.
  • ordinary tablets round or irregular shaped solid preparations made of raw materials or suitable excipients
  • capsules solid preparations made by filling hollow capsules with raw materials or suitable excipients or sealed in soft capsules
  • dispersible tablets tablettes that can disintegrate rapidly and disperse evenly in water, the raw materials in the dispersible tablets are insoluble, and the dispersible tablets can be dispersed in water and then taken orally
  • powders raw materials or suitable excipients are powdered and taken orally
  • Oral dosage forms such as suspensions (suspension liquid preparations made by dispersible solid raw materials dispersed in liquid media) overcome the following disadvantages: tablets or capsules are not easy to swallow; dispersible tablets are not flexible in dosage, not as uniform as suspensions after dispersion
  • the dry suspension described in the present application achieves that the same mass of dry suspension can be dissolved in a larger range of volumes of solvents by optimizing the screening of various excipients (especially the optimization screening of suspending agents).
  • 1 g of dry suspension is usually only applicable to dissolution in a relatively narrow range of solvent volumes, such as 1-5 mL of solvent.
  • 1g of the dry suspension of the present application can be dissolved not only in 1-5mL of solvent, but also in solvents as high as 10mL, 20mL, 25mL, and 50mL, and can still obtain excellent dispersion effect, and can be dissolved in solvents such as water within tens of seconds, which is convenient for carrying, preparing and taking; in addition, in order to ensure the dosage concentration, 1g of the dry suspension of the present application also often contains more main drugs and correspondingly more suspending agents. High content of suspending agents often leads to poor dispersion effect and agglomeration. Therefore, the dry suspension of the present application has higher requirements for the effect of the suspending agent.
  • the dry suspension described in the present application successfully masks the bitter taste of the raw material drug by optimizing and screening the flavor corrective, achieving a satisfactory taste, greatly improving the compliance of patients, especially infants, children and elderly patients, thereby improving the therapeutic effect of the drug.
  • the flavor corrective composition of the present application can also be applied to oral dosage forms that require taste masking, such as granules, orally disintegrating tablets, dispersible tablets and/or chewable tablets.
  • the present application creatively develops a new dosage form of dry suspension for dipyridamole, which fills the gap in the drug market, especially the drug market for infants and children.
  • the dry suspension described in the present application can prevent and treat diseases that can be prevented and treated by dipyridamole, such as biliary atresia and viral enteritis. This also reflects that the dry suspension described in the present application can be widely used in various indications for which dipyridamole is effective, and has broad application prospects.
  • Figure 1 is the dissolution curve of the dry suspension described in Example 1 in a pH 4.0 medium.
  • FIG. 2 is a graph showing the jaundice rate results of each group in the biliary atresia pharmacodynamics study experiment of Effect Example 5.
  • FIG. 3 is a graph showing the NSP3 results of each group in the pharmacodynamic study of biliary atresia in Effect Example 5.
  • FIG. 3 is a graph showing the NSP3 results of each group in the pharmacodynamic study of biliary atresia in Effect Example 5.
  • FIG. 4 is a HE staining image of liver paraffin sections of each group in the biliary atresia pharmacodynamics study experiment of Effect Example 5.
  • FIG. 5 is a graph showing the pathological staining Ishak scores of each group in the pharmacodynamic study of biliary atresia in Effect Example 5.
  • FIG. 6 is a photographic result of diarrhea in each group in the pharmacodynamic study experiment of dipyridamole dry suspension preparation in Effect Example 5 for viral enteritis.
  • FIG. 7 is a HE staining observation diagram of duodenal pathological sections of each group in the pharmacodynamic study experiment of dipyridamole dry suspension preparation of Effect Example 5 for viral enteritis.
  • the meanings of "one or more” and “at least one” are the same, meaning that any one or any combination of multiples can be selected; the “multiple” refers to all natural numbers greater than or equal to 2 and less than the optional range.
  • the percentage is a weight ratio, and the weight percentage refers to the weight percentage of each component relative to the total weight of the dry suspension.
  • all numbers used herein to represent the amount of ingredients, measured values or test conditions should be understood as being modified by the term “about” in all cases. When connected to a percentage, the term “about” can mean, for example, ⁇ 1%, preferably ⁇ 0.5%, and more preferably ⁇ 0.1%.
  • the singular terms herein cover the plural referents, and vice versa.
  • the word “or” herein is intended to include “and”.
  • the term “optional” or “optionally” herein means that the object it modifies may but does not necessarily exist, for example, "the dry suspension includes optional pharmaceutical excipients” means that the dry suspension includes or does not include pharmaceutical excipients.
  • preventively and/or therapeutically effective amount refers to the amount of active ingredient or drug sufficient to prevent or delay the occurrence or development of a disease or condition, or provide a clinical therapeutic benefit to the subject (including but not limited to improving, alleviating or alleviating the disease or condition, delaying or stopping the progression of the disease or condition).
  • the pharmaceutically acceptable pharmaceutical excipients described herein can be selected from, for example, but not limited to, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • solvents for example, but not limited to, solvents, propellants, solubilizers, cosolvents, emulsifiers, colorants, disintegrants, fillers, lubricants, wetting agents, osmotic pressure regulators, stabilizers, glidants, flavoring agents, preservatives, suspending agents, antioxidants, penetration enhancers, pH regulators, surfactants, diluents, etc.
  • solvents for example, but not limited to, solvents, propellant
  • a dipyridamole dry suspension which is made of the following components in weight percentage: 0.1%-20% of a main drug, 0.1%-40% of a suspending agent, and 50%-99% of a filler.
  • the suspending agent includes one or more selected from xanthan gum, carbomer, hydroxypropyl methylcellulose, methylcellulose, hydroxyethyl cellulose, povidone, sodium carboxymethyl cellulose, microcrystalline cellulose-sodium carboxymethyl cellulose, gum arabic, tragacanth gum, carrageenan, sodium alginate, and sodium carboxymethyl starch.
  • the suspending agent includes at least one of the following: hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, and carbomer.
  • the suspending agent is hydroxyethyl cellulose, preferably 0.1%-10% hydroxyethyl cellulose by weight.
  • the weight percentage of hydroxyethyl cellulose is 2%-10%, more preferably 4%-10%.
  • the suspending agent is xanthan gum, preferably 0.1%-5% xanthan gum by weight.
  • the weight percentage of xanthan gum is 1%-5%, more preferably 2%-5%.
  • the suspending agent is microcrystalline cellulose-sodium carboxymethyl cellulose, preferably 1%-30% microcrystalline cellulose-sodium carboxymethyl cellulose by weight.
  • the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 10%-30%, more preferably 20%-30%.
  • the suspending agent is carbomer, preferably 0.1%-5% carbomer by weight.
  • the weight percentage of carbomer is 1%-5%, more preferably 2%-5%.
  • the suspending agent is a combination of hydroxyethyl cellulose and xanthan gum, wherein the weight percentage of hydroxyethyl cellulose is 0.1%-10%, and the weight percentage of xanthan gum is 0.1%-5%.
  • the weight percentage of hydroxyethyl cellulose is 2%-10%, and the weight percentage of xanthan gum is 0.2%-2%.
  • the weight percentage of hydroxyethyl cellulose is 4%-10%, and the weight percentage of xanthan gum is 0.4%-1.0%.
  • the suspending agent is a combination of 6.5% hydroxyethyl cellulose and 0.5%-0.8% xanthan gum by weight.
  • the suspending agent is hydroxyethyl cellulose and xanthan gum; and at least one of microcrystalline cellulose-sodium carboxymethyl cellulose and carbomer.
  • the suspending agent is a combination of hydroxyethyl cellulose, xanthan gum, and carbomer.
  • the suspending agent is a combination of hydroxyethyl cellulose, xanthan gum, and microcrystalline cellulose-sodium carboxymethyl cellulose.
  • the suspending agent is a combination of hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, and carbomer.
  • the suspending agent is a combination of carbomer and xanthan gum, wherein the weight percentage of carbomer is 0.1%-5%, and the weight percentage of xanthan gum is 0.1%-5%.
  • the weight percentage of carbomer is 1%-8%, and the weight percentage of xanthan gum is 0.2%-2%.
  • the weight percentage of carbomer is 3%-5%, and the weight percentage of xanthan gum is 0.4%-1.0%.
  • the suspending agent is a combination of microcrystalline cellulose-sodium carboxymethyl cellulose and carbomer, wherein the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 1%-30%, and the weight percentage of carbomer is 0.1%-5%.
  • the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 5%-20%, and the weight percentage of carbomer is 0.5%-3%.
  • the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 8%-15%, and the weight percentage of carbomer is 1%-2%.
  • the suspending agent is 10% microcrystalline cellulose-sodium carboxymethyl cellulose and 1.5% carbomer by weight.
  • the suspending agent is a combination of carbomer, xanthan gum, and microcrystalline cellulose-sodium carboxymethyl cellulose, wherein the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 1%-30%, the weight percentage of carbomer is 0.1%-5%, and the weight percentage of xanthan gum is 0.1%-5%.
  • the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 5%-20%
  • the weight percentage of carbomer is 0.5%-3%
  • the weight percentage of xanthan gum is 0.2%-2.0%.
  • the weight percentage of microcrystalline cellulose-sodium carboxymethyl cellulose is 8%-15%
  • the weight percentage of carbomer is 1%-2%
  • the weight percentage of xanthan gum is 0.4%-1.0%.
  • the weight percentage of the main drug in the dry suspension is 0.5%-10%, such as 10%; preferably 1-5%; more preferably 5%, 2.5%.
  • the main drug is dipyridamole and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug thereof.
  • the pharmaceutically acceptable salt includes but is not limited to dipyridamole sodium salt or an inorganic acid salt.
  • the pharmaceutically acceptable salt includes but is not limited to dipyridamole sodium chloride and dipyridamole hydrochloride.
  • the weight percentage of the filler in the dry suspension is 60%-98%; more preferably 68%-95%.
  • the filler is selected from one or more of sucrose, glucose, lactose, maltodextrin, mannitol, sorbitol, starch, pregelatinized starch, and microcrystalline cellulose.
  • the filler is selected from one or more of glucose, maltodextrin, mannitol, and sorbitol.
  • the filler is selected from one or both of glucose and maltodextrin.
  • the filler includes glucose.
  • the weight percentage of glucose in the dry suspension is 50%-99%, more preferably 60%-98%, and even more preferably 68%-95%.
  • the filler comprises maltodextrin.
  • the weight percentage of maltodextrin in the dry suspension is 50%-99%, more preferably 60-98%, and even more preferably 68%-95%.
  • the filler comprises a combination of glucose and maltodextrin.
  • the weight percentage of glucose and maltodextrin in the dry suspension is 50%-99%; more preferably 60%-98%; and more preferably 68%-95%.
  • the glucose and maltodextrin can be mixed in any proportion.
  • the weight ratio of glucose to maltodextrin is (1-3):(3-1); preferably (1-2):(2-1); and more preferably 1:1.
  • the dry suspension comprises optional pharmaceutical excipients.
  • the dry suspension comprises one or more of a wetting agent, a glidant, and a flavoring agent.
  • the dry suspension further comprises a wetting agent.
  • the dry suspension further comprises 0%-5% by weight of a wetting agent.
  • the weight percentage of the wetting agent in the dry suspension is 0.1%-5%, preferably 0.1%-3%, and more preferably 0.1%-1%.
  • the wetting agent includes one or more selected from poloxamer and sodium lauryl sulfate.
  • the wetting agent is sodium lauryl sulfate.
  • the wetting agent is 0%-5% sodium dodecyl sulfate, or 0.1%-5% sodium dodecyl sulfate, or 0.1%-3% sodium dodecyl sulfate, 0.1%-1% sodium dodecyl sulfate, or 0.2% sodium dodecyl sulfate.
  • the dry suspension further comprises a glidant.
  • the dry suspension further comprises 0%-5% by weight of a glidant.
  • the weight percentage of the glidant in the dry suspension is 0.1%-5%, preferably 0.5%-4%, and more preferably 1.0%-3%.
  • the glidant is selected from one or more of silicon dioxide, magnesium stearate, talc, and sodium stearyl fumarate.
  • the glidant is silicon dioxide.
  • the glidant is 0%-5% by weight silicon dioxide, or 0.1%-5% by weight silicon dioxide, or 0.5%-4% by weight silicon dioxide, or 1.0%-3% by weight silicon dioxide, or 2% by weight silicon dioxide.
  • the dry suspension further comprises a flavoring agent.
  • the dry suspension further comprises 0.1%-10% by weight of a flavoring agent.
  • the weight percentage of the flavoring agent in the dry suspension is 0.1%-8%, more preferably 0.15%-5%.
  • the flavoring agent is selected from one or more of sweeteners and/or flavors.
  • the sweetener is selected from one or more of glucosyl steviol glycoside, sucralose, steviol glycoside, acesulfame potassium, sucrose, aspartame, sorbitol, maltitol, xylitol, saccharin sodium, cyclamate, sorbitol or mannitol.
  • the flavor is selected from one or more of fruit flavors, milk flavors, and cream flavors.
  • the flavoring agent is selected from one or more of glucosyl steviol glycoside, sucralose, steviol glycoside, fruit flavor, milk flavor, and cream flavor.
  • the flavoring agent is selected from one or more of glucosyl steviol glycoside, sucralose, and steviol glycoside.
  • the flavoring agent includes not only sweeteners but also flavors.
  • the sweetener includes one or more selected from glucosyl steviol glycoside, sucralose, and steviol glycoside;
  • the flavor includes one or more selected from fruit flavor, milk flavor, and cream flavor.
  • the sum of the weight percentages of fruit flavor and/or milk flavor and/or cream flavor in the dry suspension is 0.8%-4.0%; more preferably 1.0%-3.0%; and even more preferably 1.5%-2.5%.
  • the flavoring agent does not contain any flavor, such as fruit flavor, milk flavor, or cream flavor.
  • the flavoring agent includes glucosyl steviol glycoside.
  • the weight percentage of glucosyl steviol glycoside in the dry suspension is 0.8%-4.0%, more preferably 1.0%-3.0%, and even more preferably 1.5%-2.5%.
  • the flavoring agent includes glucosyl stevioside, and one or two or three selected from fruit flavor, milk flavor, and cream flavor.
  • the weight percentage of glucosyl stevioside in the dry suspension is 0.8%-4.0%, and the sum of the weight percentages of fruit flavor and/or milk flavor and/or cream flavor in the dry suspension is 0.8%-4.0%.
  • the weight percentage of glucosyl stevioside in the dry suspension is 1.0%-3.0%, and the sum of the weight percentages of fruit flavor and/or milk flavor and/or cream flavor in the dry suspension is 1.0%-3.0%.
  • the weight percentage of glucosyl stevioside in the dry suspension is 1.5%-2.5%, and the sum of the weight percentages of fruit flavor and/or milk flavor and/or cream flavor in the dry suspension is 1.5%-2.5%.
  • the flavoring agent includes sucralose.
  • the weight percentage of sucralose in the dry suspension is 0.1%-0.5%, preferably 0.15%-0.3%.
  • the flavoring agent includes steviol glycoside.
  • the weight percentage of steviol glycoside in the dry suspension is 1%-5%, preferably 2%-5%.
  • the dry suspension may further include one or more of an antibacterial agent, a buffer, and a pigment. Whether to add the antibacterial agent, buffer, and pigment, the type of addition, and the amount thereof may be routinely screened and determined by those skilled in the art.
  • the dry suspension can be administered to a patient including minors, adults and the elderly.
  • the dry suspension has excellent taste masking effect and satisfactory mouthfeel, and is particularly suitable for infants, toddlers or children.
  • the infant refers to a minor under 1 year old
  • the toddler refers to a minor between 1 and 3 years old
  • the child refers to a minor between 3 and 6 years old.
  • the dry suspension can achieve low osmotic pressure administration.
  • the osmotic pressure is preferably less than 300mOsm/L, more preferably less than 250mOsm/L, and further close to 245mOsm/L. In some embodiments, the osmotic pressure is close to 240mOsm/L; preferably less than 240mOsm/L.
  • the dry suspension has excellent dispersibility, and the dispersion time is no more than 90s, preferably no more than 50s, and more preferably no more than 20s.
  • the dispersion does not require additional tools, and the patient can quickly disperse it by gently stirring with daily tools such as chopsticks and spoons.
  • the gentle stirring is a stirring speed of 10-90rpm, 10-60rpm, 10-30rpm, or 10-20rpm.
  • the second aspect of the present application provides a method for preparing the dipyridamole suspension described in the first aspect of the present application, comprising: weighing the prescribed amount of raw materials and auxiliary materials according to the first aspect of the present application, and mixing them to obtain a dry suspension.
  • the preparation method further comprises the following steps: using a pharmaceutical composite film as an inner packaging material, and packing the total mixed material into bags according to unit dosage.
  • the pharmaceutical composite film is an ester/aluminum/polyethylene pharmaceutical composite film.
  • the unit dosage is 0.5 g to 2 g, preferably 1 g.
  • a screening operation is further included before mixing.
  • the sieving is through a 30-100 mesh sieve, preferably through a 40-80 mesh sieve, for example, through a 40 mesh sieve, or preferably through an 80 mesh sieve.
  • the sieving is that the filler is sieved through a 60-100 mesh sieve, preferably a 80 mesh sieve; and other raw materials are sieved through a 30-50 mesh sieve, preferably a 40 mesh sieve.
  • the preparation method comprises: weighing the prescribed amount of raw materials and excipients, and passing the filler through a 60-100 mesh sieve; crushing the filler on the sieve, and premixing the crushed filler with the raw material through a 30-50 mesh sieve; mixing the premix with the filler under the 60-100 mesh sieve and other excipients through a 30-50 mesh sieve.
  • the preparation method includes: weighing the prescribed amount of raw materials and excipients, and passing the filler (such as glucose, etc.) through an 80-mesh sieve; crushing the filler on the sieve, and premixing the crushed filler with the raw material through a 40-mesh sieve; mixing the premix with the filler under the 80-mesh sieve and other excipients through a 40-mesh sieve.
  • the filler such as glucose, etc.
  • the third aspect of the present application provides a method for preparing a suspension, comprising taking the dry suspension described in the first aspect of the present application, dissolving the dry suspension corresponding to 25 mg of dipyridamole in 1-50 mL of solvent, mixing the two, and stirring.
  • a method for preparing a suspension comprises taking the dry suspension described in the first aspect of the present application, mixing the dry suspension with a solvent in a ratio of 1 g of the dry suspension being dissolved in 1-50 mL of the solvent, and stirring.
  • the ratio is that every 25 mg of dipyridamole corresponding to the dry suspension is dissolved in 10-40 mL of solvent, preferably in 15-25 mL of solvent.
  • the ratio is that 1 g of the dry suspension is dissolved in 10-40 mL of solvent, preferably 15-25 mL of solvent.
  • the solvent is selected from one or more of water, juice, and milk, such as warm water.
  • the fourth aspect of the present application provides a suspension obtained by the preparation method of the third aspect of the present application.
  • the suspension comprises the dry suspension described herein and a solvent (e.g., one or more selected from water, juice, and milk).
  • a solvent e.g., one or more selected from water, juice, and milk.
  • the mass volume ratio of the dry suspension and the solvent is 1g:1mL to 1g:50mL, preferably 1g:1mL to 1g:25mL.
  • the suspension has excellent taste masking effect and satisfactory mouthfeel, and is particularly suitable for infants, toddlers or children.
  • the infant refers to a minor under 1 year old
  • the toddler refers to a minor between 1 and 3 years old
  • the child refers to a minor between 3 and 6 years old.
  • the suspension can achieve low osmotic pressure administration.
  • the osmotic pressure is preferably less than 300mOsm/L, more preferably less than 250mOsm/L, and further close to 245mOsm/L. In some embodiments, the osmotic pressure is close to 240mOsm/L, preferably less than 240mOsm/L.
  • the suspension has excellent dispersibility, and the dispersing time is no more than 90s, preferably no more than 50s, and more preferably no more than 20s.
  • the dispersion does not require additional tools, and the patient can quickly disperse it with daily tools such as chopsticks and spoons at a stirring speed of 30-90rpm.
  • the slight stirring is a stirring speed of 10-90rpm, 10-60rpm, 10-30rpm, or 10-20rpm.
  • the fifth aspect of the present application provides use of the dipyridamole dry suspension described in the first aspect of the present application, the dipyridamole suspension described in the fourth aspect of the present application, or the pharmaceutical composition described in the sixth aspect of the present application in preparing a drug.
  • the drug is used to prevent and/or treat one or more of digestive system diseases, kidney diseases, respiratory diseases, heart diseases, brain diseases and cardiovascular and cerebrovascular diseases, blood diseases, skin diseases, and ENT diseases.
  • the medicament is used to prevent and/or treat one or more of the following digestive system diseases: viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons), biliary atresia, gastroenteritis (such as acute gastroenteritis), duodenal enteritis, gastrointestinal bleeding, infectious enteritis (viral enteritis or bacterial enteritis), cholangitis, common bile duct cyst, inguinal hernia, infantile hepatitis syndrome, gallstones, liver insufficiency, umbilical hernia, intussusception, intestinal obstruction, hepatoblastoma, hepatitis, cirrhosis, liver fibrosis, small intestine or colon ulcer, peritonitis
  • the medicament is used to prevent and/or treat one or more of the following kidney diseases: renal syndrome, purpuric nephritis, lupus nephritis, IgA nephropathy, glomerulonephritis, renal hypertension, renal failure, renal injury.
  • kidney diseases renal syndrome, purpuric nephritis, lupus nephritis, IgA nephropathy, glomerulonephritis, renal hypertension, renal failure, renal injury.
  • the drug is used to prevent and/or treat one or more of the following respiratory diseases: respiratory tract infection (e.g., acute upper respiratory tract infection), respiratory distress syndrome, COVID-19, bronchitis, bronchopneumonia, community-acquired pneumonia, pleural effusion, respiratory failure, influenza, asthma, pulmonary fibrosis, pulmonary hypertension, and lung cancer.
  • respiratory tract infection e.g., acute upper respiratory tract infection
  • respiratory distress syndrome e.g., chronic upper respiratory tract infection
  • COVID-19 bronchitis
  • bronchopneumonia bronchopneumonia
  • community-acquired pneumonia e.g., pleural effusion
  • respiratory failure e.g., influenza, asthma, pulmonary fibrosis, pulmonary hypertension, and lung cancer.
  • the drug is used to prevent and/or treat one or more of the following heart diseases, brain diseases and cardiovascular and cerebrovascular diseases: congenital heart disease, coronary heart disease, angina pectoris, myocardial infarction, hypertension, vascular stones, thrombotic microangiopathy, nutcracker syndrome, portal vein cavernous change, myocardial damage, Kawasaki disease, portal hypertension, atrial/ventricular septal defect, congenital great artery malformation, angioneurotic edema, vasculitis, coronary artery aneurysm, congenital ventricular malformation, arrhythmia, thrombosis, stroke, meningitis, encephalitis, encephalomyelitis, hydrocephalus, epidemic encephalitis B, and dementia.
  • congenital heart disease congenital heart disease
  • coronary heart disease angina pectoris
  • myocardial infarction hypertension
  • vascular stones thrombotic microangiopathy
  • nutcracker syndrome portal vein cavernous change
  • the medicament is used to prevent and/or treat one or more of the following blood diseases: hyponatremia, iron deficiency anemia, hypogammaglobulinemia, thalassemia, hemolytic anemia, favism, thrombocytosis, sepsis, hypoproteinemia, leukemia, dyslipidemia.
  • blood diseases hyponatremia, iron deficiency anemia, hypogammaglobulinemia, thalassemia, hemolytic anemia, favism, thrombocytosis, sepsis, hypoproteinemia, leukemia, dyslipidemia.
  • the medicament is used to prevent and/or treat one or more of the following skin diseases: acne, rosacea, urticaria, fungal infection, herpes, solar dermatitis, atopic dermatitis, chickenpox, allergic purpura, vitiligo, psoriasis, nevus, melanoma, alopecia, seborrheic dermatitis, mite allergy, folliculitis, pemphigus, epidermal blisters, erythema and cutaneous eosinophilia.
  • skin diseases acne, rosacea, urticaria, fungal infection, herpes, solar dermatitis, atopic dermatitis, chickenpox, allergic purpura, vitiligo, psoriasis, nevus, melanoma, alopecia, seborrheic dermatitis, mite allergy, folliculitis, pemphigus, epidermal blisters, erythem
  • the drug is used to prevent and/or treat one or more of the following ENT diseases: glaucoma, cataract, conjunctivitis, sty, keratitis, rhinitis, sinusitis, caries, oral ulcers, tonsillitis, laryngitis, pharyngitis, tinnitus, and otitis media.
  • ENT diseases glaucoma, cataract, conjunctivitis, sty, keratitis, rhinitis, sinusitis, caries, oral ulcers, tonsillitis, laryngitis, pharyngitis, tinnitus, and otitis media.
  • the medicament is used to prevent and/or treat one or more of the following diseases: hydrocele, prostatitis, dwarfism, arthritis, inflammatory wrist disease, tendinitis, cytomegalovirus disease, adenovirus infection, hemodialysis status, stem cell transplant status, protein-energy malnutrition, growth retardation, glycogen storage disease, hypothyroidism, cellulitis, epilepsy, mineral metabolism disorders, fever, convulsions, shock, systemic inflammatory response syndrome, mastitis, vulvar pruritus, vaginitis, urethritis, hemorrhoids, mumps, breast cancer, ovarian cancer, hyperandrogenemia, ovarian polycystic changes, ovulation abnormalities and early embryonic maldevelopment, promotion of oocyte maturation, diabetic gangrene, diabetic neuropathy, leg ulcers, scleroderma, neurological diseases, dizziness, sleep disorders, pain, erectile dysfunction, graft-host disease, multiple s
  • the medicament is also used for preventing and/or treating allergic diseases and inflammatory diseases.
  • the sixth aspect of the present application provides a pharmaceutical composition, comprising the dry suspension described in the first aspect of the present application or the suspension described in the fourth aspect, and at least a second active ingredient.
  • the second active ingredient includes another ingredient for treating viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons), and biliary atresia.
  • viral enteritis including but not limited to rotavirus enteritis
  • inflammatory bowel disease including ulcerative colitis, Crohn's disease and indeterminate colitis
  • abdominal pain and diarrhea including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection-type diarrhea and abdominal pain and diarrhea caused by other reasons
  • biliary atresia including but not limited to biliary atresia.
  • Viral enteritis is usually an acute intestinal inflammatory lesion caused by a variety of viruses, including rotavirus, norovirus, canine parvovirus, and adenovirus.
  • the viral enteritis includes rotavirus enteritis, norovirus enteritis, and adenovirus enteritis.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn’s disease
  • IC indeterminate colitis
  • Biliary atresia is the most common cause of neonatal pathological jaundice and the most important influencing indicator of pediatric liver transplantation in the world. It is a common bile duct occlusive disease.
  • the at least one other ingredient for treating viral enteritis, abdominal pain and diarrhea is selected from one or more of oral/intravenous rehydration salts, ribavirin, zinc oxide, zinc gluconate, calcium gluconate, calcium carbonate, calcium citrate, heparin calcium, cimetidine, famotidine, montmorillonite, probiotics (such as Bacillus subtilis dual live bacteria, Bifidobacterium, Bifidobacterium-Lactobacillus-Thermophilus Triple Live Bacteria, Bifidobacterium-Lactobacillus acidophilus-Enterococcus faecalis-Bacillus cereus Quadruple Live Bacteria), cimetidine, folic acid, gentamicin, scopolamine, morpholino, and ampicillin.
  • probiotics such as Bacillus subtilis dual live bacteria, Bifidobacterium, Bifidobacterium-Lactobacillus-
  • the at least one other ingredient for treating inflammatory bowel disease is selected from one or more of aminosalicylic acid drugs (such as 5-aminosalicylic acid, sulfasalazine, etc.), glucocorticoids (such as prednisone, methylprednisolone, betamethasone, beclomethasone propionate, prednisolone, hydrocortisone, dexamethasone, etc.), immunosuppressants (such as azathioprine, mercaptopurine, methotrexate, etc.), monoclonal antibodies (such as infliximab), antibiotics, diphenoxylate, and anticholinergic drugs (such as loperamide, etc.).
  • aminosalicylic acid drugs such as 5-aminosalicylic acid, sulfasalazine, etc.
  • glucocorticoids such as prednisone, methylprednisolone, betamethasone, beclomethasone propionate
  • the at least another drug for treating biliary atresia includes one or more selected from water-soluble and fat-soluble vitamins (vitamin A, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B12, vitamin C, folic acid), taurine, jaundice-reducing drugs, liver protection drugs, albumin, immunoglobulin, antibiotics (e.g., ceftriaxone, cefoperazone, sulbactam, metronidazole, ornidazole, amipenem, meropenem, aspirin, etc.), ursodeoxycholic acid, and glucocorticoids.
  • water-soluble and fat-soluble vitamins vitamin A, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B3, vitamin B5, vitamin B6, vitamin B7, vitamin B12, vitamin C, folic acid
  • taurine e.g., f6, vitamin B7, vitamin B12, vitamin C, folic acid
  • jaundice-reducing drugs
  • the second active ingredient includes oral/intravenous rehydration salts, ribavirin, zinc oxide, zinc gluconate, calcium gluconate, calcium carbonate, calcium citrate, heparin calcium, cimetidine, famotidine, montmorillonite, probiotics (such as Bacillus subtilis, bifidobacterium, bifidobacterium-Lactobacillus-Thermophilus Streptococcus triple live bacteria, bifidobacterium-Lactobacillus acidophilus-Enterococcus faecalis-Bacillus cereus quadruple live bacteria), cimetidine, gentamicin, scopolamine, morpholino, ampicillin, aminosalicylic acid drugs (such as 5-aminosalicylic acid, sulfasalazine, etc.), immunomodulators.
  • probiotics such as Bacillus subtilis, bifidobacterium, bifi
  • Immunosuppressants such as azathioprine, mercaptopurine, methotrexate, etc.
  • monoclonal antibodies such as infliximab
  • diphenoxylate such as anticholinergic drugs (such as loperamide, etc.)
  • water-soluble and fat-soluble vitamins vitamin A, vitamin D, vitamin E, vitamin B1, vitamin B2, vitamin B3 (niacinamide), vitamin B5, vitamin B6, vitamin B7, vitamin B12, vitamin C, folic acid), taurine, jaundice-reducing drugs, liver protection drugs, albumin, immunoglobulin, antibiotics (such as ciprofloxacin, metronidazole, etc.), ursodeoxycholic acid, and one or more glucocorticoids.
  • the second active ingredient further comprises at least one of an active ingredient for anti-inflammatory diseases, an active ingredient for anti-allergic diseases, an anti-inflammatory active ingredient, and an anti-allergic active ingredient.
  • the anti-inflammatory active ingredients include: steroidal anti-inflammatory drugs or non-steroidal anti-inflammatory drugs.
  • the non-steroidal anti-inflammatory drugs include aspirin, benolate, salicylic acid, acetaminophen, indomethacin, diclofenac, sulindac, nemetbutalone, ibuprofen, naproxen, piroxicam, meloxicam, celecoxib, etoricoxib, and nimesulide.
  • the steroidal anti-inflammatory drugs include adrenal cortical hormones, androgens, estrogens, such as hydrocortisone, prednisone, dexamethasone, and the like.
  • the dry suspension described in the first aspect or the suspension described in the fourth aspect of the present application, and the second active ingredient may exist in the same drug or in different drugs.
  • the dry suspension described in the first aspect or the suspension described in the fourth aspect of the present application, and the second active ingredient may be in the same dosage form or in different dosage forms.
  • the dry suspension or suspension in the pharmaceutical composition and the second active ingredient can be packaged together or separately, and the two can be administered simultaneously, sequentially, or separately at regular or irregular intervals.
  • the seventh aspect of the present application provides the use of the pharmaceutical composition of the sixth aspect of the present application in the preparation of drugs for preventing and/or treating viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection diarrhea), and biliary atresia.
  • viral enteritis including but not limited to rotavirus enteritis
  • inflammatory bowel disease including ulcerative colitis, Crohn's disease and indeterminate colitis
  • abdominal pain and diarrhea including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection diarrhea
  • biliary atresia including but not limited to biliary atresia.
  • the dry suspension described in the first aspect of the present application, the suspension described in the fourth aspect, or the pharmaceutical composition of the sixth aspect can be used in combination with surgery to treat viral enteritis, inflammatory bowel disease, abdominal pain and diarrhea, and biliary atresia.
  • the surgery includes but is not limited to portojejunostomy, liver transplantation, ileostomy, diseased intestinal resection, selective leukocyte adsorption, and fecal microbiota transplantation.
  • the eighth aspect of the present application provides a method for preventing and/or treating a disease, comprising administering a preventively and/or therapeutically effective amount of dipyridamole and a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug thereof, the dry suspension described in the first aspect, the suspension described in the fourth aspect or the pharmaceutical composition described in the sixth aspect to a patient in need, wherein the disease includes one or more of the diseases described in the fifth aspect of the present application.
  • the disease is one or more of viral enteritis (including but not limited to rotavirus enteritis), inflammatory bowel disease (including ulcerative colitis, Crohn's disease and indeterminate colitis), abdominal pain and diarrhea (including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection diarrhea), and biliary atresia.
  • viral enteritis including but not limited to rotavirus enteritis
  • inflammatory bowel disease including ulcerative colitis, Crohn's disease and indeterminate colitis
  • abdominal pain and diarrhea including but not limited to viral diarrhea, allergic diarrhea, antibiotic diarrhea, upper respiratory tract infection diarrhea
  • biliary atresia including but not limited to biliary atresia.
  • the disease is an inflammatory disease and/or an allergic disease.
  • the drug is applicable to animals selected from humans, cats, cows, sheep, pigs, dogs, chickens, ducks, geese, rabbits, and mice; preferably, the animals are humans, including minors, adults, and the elderly; more preferably, infants, toddlers, and children.
  • the administration method is oral administration or rectal administration.
  • the administration route can be selected by the clinician according to actual needs, such as intravenous, intraperitoneal, oral, parenteral, etc.
  • the administration frequency is 1 to 3 times every 8 to 24 hours.
  • the drug is used 1-3 times a day; preferably 1-2 times a day; more preferably once a day.
  • the dosage is 1-500 mg/kg, 3-400 mg/kg, 6-300 mg/kg, 10-300 mg/kg, 30-300 mg/kg, 50-300 mg/kg or 50-100 mg/kg per day of dipyridamole.
  • the dosage when the subject is a human, is 0.1-50 mg/kg, 0.3-40 mg/kg, 0.6-30 mg/kg, 1-30 mg/kg, 3-30 mg/kg, 5-30 mg/kg or 5-10 mg/kg per time in terms of dipyridamole.
  • the dosage is 1-500 mg/kg, 3-400 mg/kg, 6-300 mg/kg, 10-300 mg/kg, 30-300 mg/kg, 50-300 mg/kg or 50-100 mg/kg per day; or 3-100 mg/kg, 3-60 mg/kg, 15-60 mg/kg, or 30-60 mg/kg per day.
  • the dosage is 0.1-50 mg/kg, 0.3-40 mg/kg, 0.6-30 mg/kg, 1-30 mg/kg, 3-30 mg/kg, 5-30 mg/kg or 5-10 mg/kg per day; or 0.3-10 mg/kg, 0.3-6 mg/kg, 1.5-6 mg/kg, or 3-6 mg/kg per day in terms of dipyridamole.
  • the dosage is based on dipyridamole and is 1-500 mg/kg, 3-400 mg/kg, 6-300 mg/kg, 10-300 mg/kg, 30-300 mg/kg, 50-300 mg/kg or 50-100 mg/kg per day; or 6-500 mg/kg, 30-300 mg/kg, or 200-400 mg/kg.
  • the dosage is 0.1-50 mg/kg, 0.3-40 mg/kg, 0.6-30 mg/kg, 1-30 mg/kg, 3-30 mg/kg, 5-30 mg/kg or 5-10 mg/kg per day; or 0.6-50 mg/kg, 3-30 mg/kg, or 20-40 mg/kg per day in terms of dipyridamole.
  • the method for preventing and/or treating a disease further comprises administering the second active ingredient described in the sixth aspect of the present application.
  • the second active ingredient is administered in combination with the dry suspension or suspension described in the present application to jointly prevent and/or treat the disease.
  • the method for preventing and/or treating the disease further comprises surgery.
  • the surgery includes but is not limited to hepatic portojejunostomy, liver transplantation, ileostomy, diseased intestinal resection, selective leukocyte adsorption, and fecal microbiota transplantation.
  • the surgery is combined with the dry suspension or suspension described in the present application to prevent and/or treat the disease.
  • a dipyridamole flavoring composition comprising or consisting of 0.1-20 parts by weight of a main drug and 0.1-10 parts by weight of a flavoring agent, wherein the main drug is selected from dipyridamole or a pharmaceutically acceptable salt, hydrate, solvate, polymorph, tautomer or prodrug thereof, and the flavoring agent includes one or more selected from glucosyl steviol glycoside, sucralose, and steviol glycoside.
  • the flavor-correcting composition is composed of 2-5 parts by weight of a main drug and 1-8 parts by weight of a flavoring agent.
  • the main drug is selected from dipyridamole or a pharmaceutically acceptable salt thereof.
  • the flavoring agent is glucosyl steviol glycoside.
  • the flavoring agent is glucosyl steviol glycoside; wherein the flavoring composition consists of 0.1-20 parts by weight of the main drug and 0.1-10 parts by weight of glucosyl steviol glycoside; preferably, the flavoring composition consists of 2-5 parts by weight of the main drug and 1-8 parts by weight of glucosyl steviol glycoside; more preferably, the flavoring composition consists of 2-3 parts by weight of the main drug and 1-4 parts by weight of glucosyl steviol glycoside; further preferably, the flavoring composition consists of 2.5 parts by weight of the main drug and 1-3 parts by weight of glucosyl steviol glycoside.
  • the flavoring agent is sucralose.
  • the flavoring agent is sucralose; wherein the flavoring composition consists of 0.1-20 parts by weight of the main drug and 0.1-10 parts by weight of sucralose; preferably, the flavoring composition consists of 1-8 parts by weight of the main drug and 0.1-2 parts by weight of sucralose; more preferably, the flavoring composition consists of 2-5 parts by weight of the main drug and 0.2-1 parts by weight of sucralose; further preferably, the flavoring composition consists of 5 parts by weight of the main drug and 0.4 parts by weight of sucralose.
  • the flavoring agent is steviol glycoside.
  • the flavoring agent is steviol glycoside; wherein the flavoring composition consists of 0.1-20 parts by weight of the main drug and 0.1-10 parts by weight of steviol glycoside; preferably, the flavoring composition consists of 1-5 parts by weight of the main drug and 0.5-8 parts by weight of steviol glycoside; more preferably, the flavoring composition consists of 2-3 parts by weight of the main drug and 1-6 parts by weight of steviol glycoside; further preferably, the flavoring composition consists of 2.5 parts by weight of the main drug and 3-5 parts by weight of steviol glycoside.
  • the flavoring composition further includes one or more of a fruit flavor, a milk flavor, and a cream flavor.
  • the weight fraction of the fruit flavor, milk flavor, and cream flavor is 0.1-10 parts, preferably 1-8 parts.
  • the flavoring agent is glucosyl steviol glycoside; and at least one of a fruit flavor, a milk flavor, and a cream flavor.
  • the flavoring agent is composed of glucosyl steviol glycoside and flavor.
  • the flavor includes at least one selected from fruit flavor, milk flavor, and cream flavor.
  • the flavoring composition is composed of 0.1-20 parts by weight of the main drug, 0.1-10 parts by weight of glucosyl steviol glycoside, and 0.1-10 parts by weight of flavor (composed of one or more of fruit flavor, milk flavor, and cream flavor); preferably, the flavoring composition is composed of 2-5 parts by weight of the main drug, 1-8 parts by weight of glucosyl steviol glycoside, and 1-8 parts by weight of flavor (composed of one or more of fruit flavor, milk flavor, and cream flavor).
  • the flavoring composition consists of 2-3 parts by weight of the main drug, 1-4 parts by weight of glucosyl stevioside, and 1-4 parts by weight of flavor (consisting of one or more of fruit flavor, milk flavor, and cream flavor); further preferably, the flavoring composition consists of 2.5 parts by weight of the main drug, 1-3 parts by weight of glucosyl stevioside, and 2 parts of flavor (consisting of one or more of fruit flavor, milk flavor, and cream flavor).
  • the flavoring composition does not contain flavors, such as one or more of fruit flavors, milk flavors, and cream flavors.
  • the flavoring composition further includes a suspending agent and a filler.
  • the suspending agent for example, includes one or more selected from hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, and carbomer.
  • the filler for example, includes one or more selected from sucrose, glucose, lactose, maltodextrin, mannitol, sorbitol, starch, pregelatinized starch, and microcrystalline cellulose.
  • dipyridamole flavor-correcting composition in the preparation of an oral preparation.
  • dipyridamole flavor-correcting composition in the preparation of a dry suspension, granules, orally disintegrating tablets, dispersible tablets and/or chewable tablets.
  • Example 1 A dipyridamole dry suspension
  • Preparation method Weigh the prescribed amount of raw and auxiliary materials, pass the filler (glucose) through an 80-mesh sieve, crush the glucose on the sieve, premix the crushed glucose with the raw material through a 40-mesh sieve, mix the premix with the glucose under the 80-mesh sieve and other auxiliary materials passing through a 40-mesh sieve in a mixer, use polyester/aluminum/polyethylene pharmaceutical composite film as the inner packaging material, and bag the total mixed material according to the unit dosage of 1g.
  • Example 18 A dipyridamole dry suspension
  • Example 20 A dipyridamole dry suspension
  • Example 21 A dipyridamole dry suspension
  • Example 22 A dipyridamole dry suspension
  • Example 25 A dipyridamole dry suspension
  • Example 26 A dipyridamole dry suspension
  • Example 28 A dipyridamole dry suspension
  • Examples 2-29 are similar to those of Example 1, except that the components and amounts of the auxiliary materials are different.
  • the flavor-correcting composition contains dipyridamole as an active ingredient (main drug) and can be used to treat various indications of dipyridamole known clinically, such as one or more selected from digestive system diseases, kidney diseases, respiratory diseases, heart diseases, brain diseases and cardiovascular and cerebrovascular diseases, blood diseases, skin diseases, and ENT diseases.
  • the dry suspension prepared in the present application has high purity and few impurities. Even under accelerated and accelerated exposure conditions, the content of the main drug, each impurity and the total impurity content are basically unchanged, showing extremely high stability.
  • the dry suspension of the present application has the need to achieve multiple modes of administration (especially hypotonic administration), so that the same mass of dry suspension can be dissolved in a wide range of volumes of solvent, such as 1-50mL of solvent; at the same time, in order to provide a higher administration concentration, it is necessary to choose to increase the content of the suspending agent accordingly when the main drug content is high, but a high content of the suspending agent often leads to poor dispersion and agglomeration.
  • hypotonic administration especially hypotonic administration
  • the dry suspension obtained by the ratio described in Table 3 was checked for sedimentation volume ratio according to the general rules of the four parts of the 2020 edition of the Chinese Pharmacopoeia. Three bags of dry suspension were taken, 50 mL of water was added, and stirred to make it evenly dispersed. The experimenter used a medicine spoon to stir manually and detect its stirring and dispersion speed. After uniform dispersion, 50 mL was taken, left to stand for 3 hours, and its sedimentation was detected (sedimentation volume ratio ⁇ 0.9 was considered qualified). The test results are shown in Table 3.
  • suspending agents including hydroxypropyl methylcellulose, sodium carboxymethylcellulose, povidone, tragacanth, gum arabic, carrageenan, sodium alginate, and they were adjusted within various content ranges, but none of them could obtain a dry suspension that met the requirements.
  • the inventor also screened common suspending agents on the market, such as Tween, Span, etc., but none of them could obtain a dry suspension with easy-to-disperse and easy-to-take characteristics, such as hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, carbomer or a combination thereof as suspending agents in the present application.
  • common suspending agents on the market such as Tween, Span, etc.
  • Example 1 hydroxyethyl cellulose, xanthan gum, microcrystalline cellulose-sodium carboxymethyl cellulose, and carbomer were used alone or in partial combination as suspending agents.
  • Example 1 i.e., Verification Example 1
  • Example 3 only the suspending agents were replaced to obtain the dipyridamole dry suspensions shown in Verification Example 2 (i.e., Example 3), Verification Example 3, Verification Example 4, and Verification Example 5.
  • the dispersion and sedimentation results are shown in the following table.
  • choosing a suitable suspending agent can not only disperse the drug quickly, but also meet the requirements of the pharmacopoeia on the sedimentation volume ratio of the suspension.
  • Example 1 1 g of the dry suspensions of Example 1, Example 17, Example 18 and Example 19 were added into 20 mL of water, and the osmotic pressure was tested as shown in Table 6.
  • glucose and maltodextrin are not only easily absorbed, but also more able to achieve the purpose of hypotonic solution administration (osmotic pressure close to 245mOsm/L), avoiding the risk of enteritis dehydration symptoms.
  • mice Male BALB/c pregnant mice, specific pathogen-free (SPF) grade, were purchased from Guangdong Medical Laboratory Animal Center. They were kept in the SPF grade environment of the Laboratory Animal Center of Guangzhou Medical University. The pregnant mice gave birth to newborn mice (each pregnant mouse gave birth to an average of 8 newborn mice), with an average weight of 1.5g. Newborn mice were randomly selected for the experiment according to the experimental groups.
  • SPF pathogen-free
  • the normal control group was given an equal volume of normal saline; the model control group was given the same solvent (i.e., water) as the preparation; the DIP low-dose suspension, DIP medium-dose suspension, and DIP high-dose suspension in the DIP-1 group, DIP-2 group, and DIP-3 group were respectively prepared by mixing the dry suspension with an API content of 0.5% in Example 24 with water to 0.125 mg/mL, 0.5 mg/mL, and 2 mg/mL to prepare the corresponding suspensions, and then administered according to the dosage.
  • the solvent i.e., water
  • Model preparation method Newborn BALB/c mice were intraperitoneally injected with 20 ⁇ L of monkey MMU18006 rotavirus (RV) (titer 1.0 ⁇ 10 6 PFU) within 24 hours after birth to establish the BA mouse animal model.
  • RV monkey MMU18006 rotavirus
  • Drug administration and index investigation After the animal model was prepared, the drugs were divided into groups and administered for 11 days, with oral administration and gavage once a day. Multiple clinical indicators were detected and recorded to evaluate the therapeutic effect of the drug.
  • RNA of the liver was extracted for qPCR detection, and the results are shown in Figure 3.
  • the results showed that the gene NSP3, which reflects the replication of the virus in vivo, was significantly increased in the model mice, and DIP-1, DIP-2, and DIP-3 could inhibit the replication of the virus in the liver at different levels, indicating that the dipyridamole dry suspension of the present application has an improving effect on liver damage in model mice.
  • mice were taken from each group for HE staining of liver paraffin sections and Ishak scoring of pathological staining. The results are shown in Figures 4 and 5. Comparison of HE staining of liver paraffin sections showed that RV model mice had more liver necrotic foci, increased infiltration of inflammatory cells in the portal area, and aggravated fibrosis around the portal area. After treatment with DIP-1, DIP-2, and DIP-3, it was found that the three DIP concentrations of drugs significantly reduced the number of liver necrotic foci, reduced the infiltration of inflammatory cells and the degree of fibrosis. The scores showed that each drug treatment group achieved significant differences from the model group.
  • dipyridamole has the efficacy of preventing and treating viral enteritis. Therefore, in order to prove the efficacy of the dipyridamole dry suspension of the present application and to study whether it also has the efficacy of preventing and treating viral enteritis and its dosage, the following experiment was conducted.
  • mice 84 suckling mice (7 days and 168 hours after birth) were randomly divided into 7 groups, 12 mice in each group. They were the normal group, the negative control group, the placebo control group, the dipyridamole 9.4 mg/kg group, the dipyridamole 37.5 mg/kg group, the dipyridamole 300 mg/kg group, and the racecadotril positive control group (Positive control racecadotril 300 mg/kg). Except for the blank control group, all animals were gavaged with rotavirus MA-104 to prepare the animal disease model of viral enteritis. Symptoms were evaluated 20 ⁇ 4 hours after infection, and the animals were divided into groups according to body weight and diarrhea score before drug administration.
  • the blank control group was given an equal volume of normal saline; the model control group was given the same solvent (i.e., water) as the preparation; the dipyridamole 9.4 mg/kg group, the dipyridamole 37.5 mg/kg group, and the dipyridamole 300 mg/kg group were respectively prepared by mixing the dry suspension with an API content of 2.5% in Example 3 with water to prepare 0.312 mg/mL, 1.25 mg/mL, and 10 mg/mL to prepare the corresponding suspensions, and then administered according to the dosage.
  • solvent i.e., water
  • Preparation of viral enteritis model All animals except the blank group; suckling mice were 7 days old and weighed about 4g. They were abstinent from milk for 4 ⁇ 0.5 hours before oral administration. Then, the amount of virus was 25 ⁇ L each time, administered once every 2 hours, for a total of 3 times, totaling 75 ⁇ L. Then, they were randomly divided into groups according to the diarrhea scoring criteria and weight differences, and the test drugs were administered after grouping. The administration time was 7 days.
  • Figure 6 and the scoring results show that compared with the model group in the same period, the animals given racecadotril and dipyridamole showed obvious inhibitory effects on diarrhea.
  • the scores of the drug intervention groups were all less than 3 points.
  • the dipyridamole 9.4 mg/kg group had a stool score range of 2-3 points
  • the dipyridamole 37.5 mg/kg group showed a good inhibitory effect on diarrhea, with a score below 2 points
  • the dipyridamole 300 mg/kg group was close to the normal score of 0-1 points.
  • the neonatal mouse diarrhea model prepared by rotavirus shows that the dipyridamole dry suspension of the present application, especially dipyridamole at a dose range of 9.4-300 mg/kg, has a good effect in preventing and treating viral diarrhea diseases (gastrointestinal cold) in mice (suckling mice).
  • the dry suspension of the present application is also effective for other diseases that have been reported to be effective with dipyridamole, and based on the characteristics of the dry suspension that does not require disintegration, has a large gastrointestinal distribution area, and is rapidly absorbed, it can be expected that the dosage form of the present application will have a bioavailability of 100%.
  • the cost is higher than other oral dosage forms and the efficacy is better.
  • the dry suspension prepared in the present application selects suitable suspending agents and fillers through prescription screening, so that the dry suspension has good dispersion effect and fast dispersion speed, and can be administered in a hypotonic solution (osmotic pressure is close to 245mOsm/L). Furthermore, by screening the flavoring agent, the bitter taste can be successfully masked, and a satisfactory taste for the patient can be obtained, thereby greatly improving the compliance of the patient (especially the young patient).

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Ophthalmology & Optometry (AREA)
  • Pulmonology (AREA)
  • Dermatology (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Inorganic Chemistry (AREA)
  • Cardiology (AREA)
  • Otolaryngology (AREA)
  • Hematology (AREA)
  • Molecular Biology (AREA)
  • Reproductive Health (AREA)
  • Vascular Medicine (AREA)
  • Diabetes (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Pregnancy & Childbirth (AREA)
  • Biochemistry (AREA)
  • Gynecology & Obstetrics (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Biophysics (AREA)
  • Dispersion Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)

Abstract

一种双嘧达莫干混悬剂及其制备方法和应用。制备的干混悬剂通过处方筛选而选择合适的助悬剂和填充剂，使得干混悬剂的分散效果好，分散速度快，并且可以低渗溶液给药（渗透压接近245mOsm/L）。进一步地，通过对矫味剂的筛选，能够成功掩盖苦味，取得令患者满意的口感，从而极大提高患者（特别是婴幼儿患者）的顺应性。

Description

一种双嘧达莫干混悬剂及其制备方法和应用 技术领域
本申请属于医药领域，具体涉及一种双嘧达莫干混悬剂及其制备方法和应用。
背景技术
双嘧达莫的化学名称为2,2',2”,2”',-[(4,8-二哌啶基嘧啶并[5,4-d]嘧啶-2,6-二基)双次氮基]-四乙醇，英文名Dipyridamole，分子式：C24H40N8O4，分子量：504.63，化学结构式如下：
双嘧达莫为黄色结晶性粉末；无臭，味苦。在三氯甲烷中易溶，在乙醇中溶解，在丙酮中微溶；在水中几乎不溶，在稀酸中易溶，呈pH依赖。pKa1：6.30±0.05，pKa2：0.8±0.1，分配系数：8250±300(辛醇/缓冲液pH7)，BCS分类为II类。
双嘧达莫由勃林格殷格翰公司开发，1961年FDA批准口服双嘧达莫片上市，商品名：(潘丁生)。双嘧达莫具有抑制磷酸二酯酶、抑制血小板聚集、强化前列环素等作用，临床上主要用于抗血栓形成和防治血栓性疾病。1969年发现双嘧达莫可以抑制腺苷再摄取，扩张冠状动脉。1990年勃林格殷格翰公司开发了双嘧达莫注射剂FDA获批，临床上用于诊断心肌缺血的药物试验。双嘧达莫作为抗血栓药物被临床广泛使用，常与阿司匹林联用，1999年勃林格殷格翰公司开发的阿司匹林双嘧达莫缓释胶囊FDA批准上市，用于降低因血栓形成而患有短暂性脑缺血或完全缺血性中风的患者的中风风险。
多年来双嘧达莫在全球范围上市，虽然说明书中没有儿童用药的描述，但是其真实世界中安全性较好，因此，目前临床上已有累积高达上百种超说明书用药的情况，一直广泛应用于儿童。然而，现临床剂型仅为片剂、胶囊剂这样的不易吞咽、剂量不灵活，以及有窒息、误吸风险和咀嚼等引入的风险的可接受性差的剂型，并没有适合儿童口服的剂型，临床上只能由患儿的监护人根据医生指示设法将现有剂型进行应用，例如双嘧达莫片碾碎加水混合或双嘧达莫胶囊拆开兑水后喂服，不仅给药过程繁琐而且苦味非常浓烈，常导致服药失败；剂量不易准确控制，影响药效或导致安全性风险，顺应性很差。
因此，急需开发一种具有人群顺应性好、剂量易于控制等优点的双嘧达莫口服新剂型。
发明内容
本申请为了克服现有技术的不足，提供了一种双嘧达莫干混悬剂及其制备方法和应用，具有优异的分散效果和掩味效果，且能实现低渗透压给药；从而极大地提高了患者的顺应性，提高给药疗效。
本申请上述方面通过如下技术方案实现：
本申请的第一方面，提供了一种双嘧达莫干混悬剂，由包括以下重量百分比的组分制成：0.1％-20％主药，0.1％-40％助悬剂，50％-99％填充剂。
在一些实施方式中，所述助悬剂包括选自黄原胶、卡波姆、羟丙甲基纤维素、甲基纤维素、羟乙基纤维素、聚维酮、羧甲基纤维素钠、微晶纤维素-羧甲基纤维素钠、阿拉伯胶、西黄蓍胶、卡拉胶、海藻酸钠、羧甲基淀粉钠中的一种或多种。
在一些实施方式中，所述助悬剂包括以下中的至少一种：羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆。
在一些实施方式中，所述助悬剂为羟乙基纤维素；优选为0.1％-10％的羟乙基纤维素。
在一些实施方式中，所述助悬剂为黄原胶；优选为0.1％-5％的黄原胶。
在一些实施方式中，所述助悬剂为微晶纤维素-羧甲基纤维素钠；优选为1％-30％的微晶纤维素-羧甲基纤维素钠。
在一些实施方式中，所述助悬剂为卡波姆；优选为0.1％-5％的卡波姆。
在一些实施方式中，所述助悬剂为羟乙基纤维素和黄原胶的组合；其中，羟乙基纤维素为0.1％-10％，黄原胶为0.1％-5％。
在一些实施方式中，所述助悬剂为微晶纤维素-羧甲基纤维素钠和卡波姆的组合；其中，微晶纤维素-羧甲基纤维素钠为1％-30％，卡波姆为0.1％-5％。
在一些实施方式中，所述主药的重量百分比为0.5％-10％。
在一些实施方式中，所述主药为双嘧达莫及其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药。
在一些实施方式中，所述药学上可接受的盐包括但不限于双嘧达莫钠盐或无机酸盐。
在一些实施方式中，所述药学上可接受的盐包括但不限于双嘧达莫氯化钠、双嘧达莫盐酸盐。
在一些实施方式中，所述填充剂在干混悬剂中的重量百分比为60％-98％；更优选为68％-95％。
在一些实施方式中，所述填充剂选自蔗糖、葡萄糖、乳糖、麦芽糊精、甘露醇、山梨醇、淀粉、预胶化淀粉、微晶纤维素中的一种或多种。
在一些实施方式中，所述填充剂选自葡萄糖、麦芽糊精、甘露醇和山梨醇中的一种或多种。
在一些实施方式中，所述填充剂选自葡萄糖和麦芽糊精中的一种或两种。
在一些实施方式中，所述干混悬剂还包括润湿剂、助流剂、抑菌剂、缓冲剂、色素、矫味剂中的一种或多种。
在一些实施方式中，所述干混悬剂还包括润湿剂、助流剂、矫味剂中的一种或多种。
在一些实施方式中，所述干混悬剂还包括润湿剂。
在一些实施方式中，所述干混悬剂还包括0％-5％的润湿剂。优选地，润湿剂在干混悬剂的重量百分比为0.1％-5％；更优选为0.1％-3％；更进一步优选为0.1％-1％。
在一些实施方式中，所述润湿剂选自泊洛沙姆、十二烷基硫酸钠中的一种或两种。
在一些实施方式中，所述润湿剂为十二烷基硫酸钠。
在一些实施方式中，所述干混悬剂还包括助流剂。
在一些实施方式中，所述干混悬剂还包括0％-5％的助流剂。优选地，助流剂在干混悬剂的重量百分比为0.1％-5％；更优选为0.5％-4％；更进一步优选为1.0％-3％。
在一些实施方式中，所述助流剂选自二氧化硅、硬脂酸镁、滑石粉、硬脂富马酸钠的中的一种或多种。
在一些实施方式中，所述助流剂选自二氧化硅。
在一些实施方式中，所述干混悬剂还包括矫味剂。
在一些实施方式中，所述干混悬剂还包括0.1％-10％的矫味剂。优选地，所述矫味剂在干混悬剂中的重量百分比是0.1％-8％，更优选是0.15％-5％。
在一些实施方式中，所述矫味剂选自甜味剂和/或香精中的一种或多种。
在一些实施方式中，所述甜味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷、安赛蜜、蔗糖、阿斯巴甜、山梨糖醇、麦芽糖醇、木糖醇、糖精钠、甜蜜素、山梨醇或甘露醇中的一种或多种。
在一些实施方式中，所述香精选自水果味香精、牛奶味香精、奶油味香精中的一种或多种。
在一些实施方式中，所述矫味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷、水果味香精、牛奶味香精、奶油味香精中的一种或多种。
在一些实施方式中，所述矫味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷中的一种或多种。
在一些实施方式中，所述干混悬剂还可以加入抑菌剂、缓冲剂、色素中的一种或多种。
在一些实施方式中，所述抑菌剂、缓冲剂、色素是否添加、添加的种类、含量可以由本领域技术人员常规筛选确定。
本申请的第二方面，提供了本申请第一方面所述双嘧达莫混悬剂的制备方法，包括：按照本申请的第一方面，称取处方量原辅料，混合得到干混悬剂。
本申请的第三方面，提供了一种混悬剂的配制方法，包括，取本申请第一方面所述干混悬剂，按照每25mg双嘧达莫对应干混悬剂溶解于1-50mL溶剂中的比例将二者混合，搅拌。
在一些实施方式中，提供了一种混悬剂的配制方法，包括，取本申请第一方面所述干混悬剂，按照每1g干混悬剂溶解于1-50mL溶剂中的比例将所述干混悬剂与溶剂混合，搅拌。
本申请的第四方面，提供了本申请第三方面配制方法得到的混悬剂。
本申请的第五方面，提供了本申请第一方面所述双嘧达莫干混悬剂和本申请第四方面所述双嘧达莫混悬剂在制备药物中的用途。
在一些实施方式中，所述药物用于预防和/或治疗消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种。
在一些实施方式中，所述药物用于预防和/或治疗以下消化系统疾病中的一种或多种：病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻和其他原因导致的腹痛腹泻)、胆道闭锁、胃肠炎(例如急性肠胃炎)、十二指肠肠炎、消化道出血、感染性肠炎(病毒性或细菌性肠炎)、胆管炎、胆总管囊肿、腹股沟疝气、婴儿肝炎综合征、胆囊结石、肝功能不全、脐疝、肠套叠、肠梗阻、肝母细胞瘤、肝炎、肝硬化、肝纤维化、小肠或结肠溃疡、腹膜炎、脾先天性畸形、食管静脉曲张、胃底静脉曲张、脾肿大、脾功能亢进、胃癌、肠癌、肝癌、食物过敏、胰腺炎。
在一些实施方式中，所述药物用于预防和/或治疗以下肾脏疾病中的一种或多种：肾脏综合征、紫癜性肾炎、狼疮性肾炎、IgA肾病、肾小球肾炎、肾性高血压、肾衰竭、肾损伤。
在一些实施方式中，所述药物用于预防和/或治疗以下呼吸道疾病中的一种或多种：呼吸道感染(例如急性上呼吸道感染)、呼吸窘迫症、新冠肺炎、支气管炎、支气管肺炎、社区获得性肺炎、胸腔积液、呼吸衰竭、流行性感冒、哮喘、肺纤维化、肺动脉高压、肺癌。
在一些实施方式中，所述药物用于预防和/或治疗以下心脏疾病、脑部疾病和心脑血管疾病中的一种或多种：先天性心脏病、冠心病、心绞痛、心梗、高血压、血管结石、血栓性微血管病、胡桃夹综合征、门静脉海绵样变、心肌损害、川崎病、门静脉高压、房/室间隔缺损、先天性大动脉畸形、血管神经性水肿、血管炎、冠状动脉瘤、心室先天畸形、心律失常、血栓、卒中、中风、脑膜炎、脑炎、脑脊髓炎、脑积水、流行性乙型脑炎、痴呆。
在一些实施方式中，所述药物用于预防和/或治疗以下血液疾病中的一种或多种：低钠血症、缺铁性贫血、低丙种球蛋白血症、地中海贫血、溶血性贫血、蚕豆病、血小板增多、败血症、低蛋白血症、白血病、血脂异常。
在一些实施方式中，所述药物用于预防和/或治疗以下皮肤疾病中的一种或多种：痤疮、玫瑰痤疮、荨麻疹、真菌感染、疱疹、日光性皮炎、特应性皮炎、水痘、过敏性紫癜、白癜风、银屑病、痣、黑素瘤、脱发、脂溢性皮炎、螨虫过敏、毛囊炎、天疱疮、表皮水疱、红斑和皮肤嗜酸性粒细胞增多症。
在一些实施方式中，所述药物用于预防和/或治疗以下五官科疾病中的一种或多种：青光眼、白内障、结膜炎、麦粒肿、角膜炎、鼻炎、鼻窦炎、龋齿、口腔溃疡、扁桃体炎、喉炎、咽炎、耳鸣、中耳炎。
在一些实施方式中，所述药物用于预防和/或治疗以下疾病中的一种或多种：鞘膜积液、前列腺炎、矮小症、关节炎、炎性手腕疾病、肌腱炎、巨细胞病毒病、腺病毒感染、血液透析状态、干细胞移植状态、蛋白质-能量营养不良、生长发育迟缓、糖原贮积病、甲状腺功能减退症、蜂窝织炎、癫痫、矿物质代谢异常、发烧、惊厥、休克、全身炎症反应综合征、乳腺炎、外阴瘙痒、阴道炎、尿道炎、痔疮、腮腺炎、乳腺癌、卵巢癌、高雄激素血症、卵巢多囊改变、排卵异常和早期胚胎发育不良、促进卵母细胞成熟、糖尿病坏疽、糖尿病神经病变、小腿溃疡、硬皮病、神经疾病、旋晕、睡眠障碍、疼痛、勃起障碍、移植物与 宿主疾病、多发性硬化、疱疹性咽峡炎。
在一些实施方式中，所述药物还用于预防和/或治疗过敏性疾病和/或炎症性疾病。
本申请的第六方面，提供了一种药物组合物，包括本申请第一方面所述干混悬剂或第四方面所述混悬剂，以及第二活性成分。
在一些实施方式中，所述第二活性成分包括至少另一种用于治疗病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻和其他原因导致的腹痛腹泻)、胆道闭锁的成分。
在一些实施方式中，所述药物组合物还包括药学上可接受的辅料。
本申请的第七方面，提供了本申请第六方面的药物组合物在制备预防和/或治疗病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻和其他原因导致的腹痛腹泻)、胆道闭锁药物中的应用。
在一些实施方式中，本申请第一方面所述干混悬剂或第四方面所述混悬剂或第六方面的药物组合物，可以与手术联用，用于治疗胆道闭锁。
本申请的第八方面，提供了一种预防和/或治疗疾病的方法，包括将预防和/或治疗有效量的双嘧达莫及其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药、上述的双嘧达莫干混悬剂或双嘧达莫混悬剂给予有需要的患者，所述疾病包括本申请第五方面所述的疾病中的一种或多种。或者，本申请提供了用于预防和/或治疗消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种的上述的双嘧达莫干混悬剂或双嘧达莫混悬剂、药物组合物、或包含它们的药物。
本申请的第九方面，提供了一种双嘧达莫的矫味组合物，包括重量份为0.1-20份的主药和重量份为0.1-10份的矫味剂或由重量份为0.1-20份的主药和重量份为0.1-10份的矫味剂组成，其中，主药选自双嘧达莫或其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，矫味剂包括选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷中的一种或多种。
在一些实施方式中，所述矫味组合物由重量份为2-5份的主药和重量份为1-8份的矫味剂组成，其中，主药选自双嘧达莫或其药学上可接受的盐，矫味剂为葡萄糖基甜菊糖苷。
在一些实施方式中，所述矫味剂还包括水果味香精、牛奶味香精、和奶油味香精中的一种或多种。
在一些实施方式中，所述水果味香精、牛奶味香精、和奶油味香精的重量份数为0.1-10份；优选为1-8份。
在一些实施方式中，所述矫味组合物不含水果味香精、牛奶味香精、和奶油味香精中的任一种。
在一些实施方式中，提供了上述双嘧达莫的矫味组合物在制备口服制剂中的应用。
在一些实施方式中，提供了上述双嘧达莫的矫味组合物在制备干混悬剂、混悬剂、颗粒剂、口腔崩解片、分散片和/或咀嚼片剂型中的应用。
本申请具有如下有益效果：
(1)本申请的干混悬剂集合了固体和液体制剂的特点，肠胃分布面积大、吸收快，而且是服用前配制所以一般不需要加入抑菌剂，对于儿童安全性好，相比普通片剂(原料药物或与适宜的辅料制成的圆形或异形的片状固体制剂)、胶囊剂(原料药物或与适宜辅料充填于空心胶囊或密封于软质囊材中制成的固体制剂)、分散片(在水中能迅速崩解并均匀分散的片剂，分散片中的原料药物是难溶性的，分散片可加水分散后口服)、散剂(原料药物或与适宜的辅料经粉碎、均匀混合制成的干燥粉末状制剂，一般溶于或分散于水、稀释液或者其他液体中服用，也可直接用水送服)、混悬剂(难溶性固体原料药物分散在液体介质中制成的混悬液体制剂)等口服剂型，克服了：片剂或胶囊剂不易吞咽的缺点；分散片剂量不灵活、加水分散后不如混悬剂均匀、口感差，分散片使用崩解剂量较大，吸湿性较强，对包装材料的阻湿效果要求更高，包装及贮藏成本高的缺点；散剂加水分散后为不均匀混悬状态，口服时容易沉积粘附在口腔，口 感差的缺点；混悬剂稳定性差、需要加入抑菌剂、安全性较差的缺点。
(2)为了应用到双嘧达莫的多种适应症中实现多种给药需求，包括低渗、等渗、高渗给药，例如对消化系统疾病患者或具有消化系统基础疾病的患者进行低渗给药(避免脱水、肠道不适等副作用)，本申请所述干混悬剂通过对各辅料的优化筛选(特别是助悬剂的优化筛选)，实现了相同质量的干混悬剂可以溶解于更大范围体积的溶剂中，例如在现有技术中，1g干混悬剂通常仅适用于溶解于相对较窄容量范围的溶剂中，例如1-5mL溶剂中，而本申请的1g干混悬剂不仅可以溶解于1-5mL溶剂中，还可以溶解于高达10mL、20mL、25mL、50mL的溶剂中，并且仍然可以获得优异的分散效果，可以在数十秒内溶解在水等溶剂中，便于携带、调配以及服用；此外，为了保证给药浓度，本申请的1g干混悬剂也往往含有更多含量主药及相应的更多含量的助悬剂，高含量的助悬剂往往导致分散效果不好、成团，因此，本申请的干混悬剂对于助悬剂的效果具有更高的要求。
(3)本申请所述干混悬剂通过对矫味剂的优化筛选，成功掩盖了原料药的苦味，取得了令人满意的口感，极大提高了患者，特别是婴幼儿、儿童以及老年人患者的顺应性，从而提高药物治疗效果。同时，也能够将本申请的矫味组合物应用到颗粒剂、口腔崩解片、分散片和/或咀嚼片剂型的口服需要掩味的剂型中。
(4)本申请创造性地针对双嘧达莫开发了干混悬剂这种新剂型，填补了用药市场，特别是婴幼儿和儿童用药市场的空白，通过对辅料的类型、具体种类、具体用量的确定、各原辅料的配伍、以及制备方法的确定：不仅制备方法极其简单，而且制备得到的干混悬剂具有优良的各项药剂学指标(溶出度、含量、杂质、稳定性、分散速度、沉降体积比等)。
(5)进一步地，本申请所述的干混悬剂能够防治胆道闭锁、病毒性肠炎等双嘧达莫能够防治的疾病，从而也反映了本申请所述的干混悬剂能够广泛应用到各种双嘧达莫有效的适应症中，具有广泛的应用前景。
附图说明
图1是实施例1所述干混悬剂在pH 4.0介质中溶出曲线。
图2是效果例5的胆道闭锁药效学研究实验中各组的黄疸率结果图。
图3是效果例5的胆道闭锁药效学研究实验中各组的NSP3结果图。
图4是效果例5的胆道闭锁药效学研究实验中各组的肝脏石蜡切片HE染色图。
图5是效果例5的胆道闭锁药效学研究实验中各组的病理染色Ishak评分图。
图6是效果例5的双嘧达莫干混悬制剂用于病毒性肠炎药效学研究实验中各组的腹泻拍照结果图。
图7是效果例5的双嘧达莫干混悬制剂用于病毒性肠炎药效学研究实验中各组的十二指肠病理切片HE染色观察图。
具体实施方式
下面对上述的发明作进一步的说明。
在本申请中，如无特别说明，所述“一种或多种”以及“至少一种”的含义相同，指的是可以选自任一种，或者任意多种的组合；所述“多种”指的是大于或等于2的，且小于可选范围的所有自然数。如无特别说明，所述百分比是重量比分比，所述重量百分比指的是各组分相对于干混悬剂总重量的重量百分比。除非另有说明，本文所使用的表示成分的量、测量值或测试条件的所有数字应理解为在所有情况下均由术语“约”修饰。当与百分比相连时，术语“约”可以表示例如±1％、优选±0.5％、更优选±0.1％。除非另有明确指示，本文中的单数术语涵盖复数的指示对象，反之亦然。除非另有明确指示，本文中的词语“或”意在包括“和”。本文中的术语“任选”或“任选地”意味着其所修饰的对象可以但不必然存在，例如，“干混悬剂包括任选的药用辅料”是指干混悬剂包括或不包括药用辅料。
本文中的术语“预防和/或治疗有效量”是指足以预防或者迟滞疾病或病症的发生或发展、或者对受试者提供临床上的治疗益处(包括但不限于改善、缓解或减轻疾病或病症，延缓或停止疾病或病症的进展)的活性成分或药物的量。
在本文中，除非另有说明，否则术语“包含、包括和含有(comprise、comprises和comprising)”或等同物为开放式表述，意味着除所列出的要素、组分和步骤外，还可涵盖其它未指明的要素、组分和步骤。
本文中所述的药学上可接受的药用辅料可选自例如但不限于溶剂、抛射剂、增溶剂、助溶剂、乳化剂、着色剂、崩解剂、填充剂、润滑剂、润湿剂、渗透压调节剂、稳定剂、助流剂、矫味剂、防腐剂、助悬剂、抗氧剂、渗透促进剂、pH值调节剂、表面活性剂、稀释剂等。关于其它可用的药学上可接受的药用辅料，可参见例如《药用辅料手册》(第4版)，R.C.罗等著，郑泽民主译，2005年，化学工业出版社。
为了描述和公开的目的，以引用的方式将所有的专利、专利申请和其它已确定的出版物在此明确地并入本文。这些出版物仅因为它们的公开早于本申请的申请日而提供。所有关于这些文件的日期的声明或这些文件的内容的表述是基于申请者可得的信息，并且不构成任何关于这些文件的日期或这些文件的内容的正确性的承认。而且，在任何国家，在本中对这些出版物的任何引用并不构成关于该出版物成为本领域的公知常识的一部分的认可。
(一)双嘧达莫干混悬剂
本申请的第一方面，提供了一种双嘧达莫干混悬剂，由包括以下重量百分比的组分制成：0.1％-20％主药，0.1％-40％助悬剂，50％-99％填充剂。
在一些实施方式中，所述助悬剂包括选自黄原胶、卡波姆、羟丙甲基纤维素、甲基纤维素、羟乙基纤维素、聚维酮、羧甲基纤维素钠、微晶纤维素-羧甲基纤维素钠、阿拉伯胶、西黄蓍胶、卡拉胶、海藻酸钠、羧甲基淀粉钠中的一种或多种。
在一些实施方式中，所述助悬剂包括以下中的至少一种：羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆。
在一些实施方式中，所述助悬剂为羟乙基纤维素，以重量百分比计，优选为0.1％-10％的羟乙基纤维素。优选的，羟乙基纤维素重量百分比是2％-10％，更优选为4％-10％。
在一些实施方式中，所述助悬剂为黄原胶，以重量百分比计，优选为0.1％-5％的黄原胶。优选地，黄原胶的重量百分比是1％-5％，更优选为2％-5％。
在一些实施方式中，所述助悬剂为微晶纤维素-羧甲基纤维素钠，以重量百分比计，优选为1％-30％的微晶纤维素-羧甲基纤维素钠。优选地，微晶纤维素-羧甲基纤维素钠的重量百分比是10％-30％，更优选为20％-30％。
在一些实施方式中，所述助悬剂为卡波姆，以重量百分比计，优选为0.1％-5％的卡波姆。优选地，卡波姆的重量百分比是1％-5％，更优选为2％-5％。
在一些实施方式中，所述助悬剂为羟乙基纤维素和黄原胶的组合，其中，羟乙基纤维素的重量百分比为0.1％-10％，黄原胶的重量百分比为0.1％-5％。优选地，羟乙基纤维素的重量百分比为2％-10％，黄原胶的重量百分比为0.2％-2％。优选地，羟乙基纤维素的重量百分比为4％-10％，黄原胶的重量百分比为0.4％-1.0％。
在一些实施方式中，以重量百分比计，所述助悬剂为6.5％的羟乙基纤维素和0.5％-0.8％的黄原胶的组合。
在一些实施方式中，所述助悬剂为羟乙基纤维素和黄原胶；及微晶纤维素-羧甲基纤维素钠、卡波姆中的至少一种。
在一些实施方式中，所述助悬剂为羟乙基纤维素、黄原胶，及卡波姆的组合。
在一些实施方式中，所述助悬剂为羟乙基纤维素、黄原胶，及微晶纤维素-羧甲基纤维素钠的组合。
在一些实施方式中，所述助悬剂为羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆的组合。
在一些实施方式中，所述助悬剂为卡波姆和黄原胶的组合，其中，卡波姆的重量百分比为0.1％-5％，黄原胶的重量百分比为0.1％-5％。优选地，卡波姆的重量百分比为1％-8％，黄原胶的重量百分比为0.2％-2％。优选地，卡波姆的重量百分比为3％-5％，黄原胶的重量百分比为0.4％-1.0％。
在一些实施方式中，所述助悬剂为微晶纤维素-羧甲基纤维素钠和卡波姆的组合，其中，微晶纤维素-羧甲基纤维素钠的重量百分比为1％-30％，卡波姆的重量百分比为0.1％-5％。优选地，微晶纤维素-羧甲基纤维素钠的重量百分比为5％-20％，卡波姆的重量百分比为0.5％-3％。优选地，微晶纤维素-羧甲基纤维素钠的重量百分比为8％-15％，卡波姆的重量百分比为1％-2％。
在一些实施方式中，以重量百分比计，所述助悬剂为10％的微晶纤维素-羧甲基纤维素钠和1.5％的卡波姆。
在一些实施方式中，所述助悬剂为卡波姆、黄原胶、微晶纤维素-羧甲基纤维素钠的组合，其中，微晶纤维素-羧甲基纤维素钠的重量百分比为1％-30％，卡波姆的重量百分比为0.1％-5％，黄原胶的重量百分比为0.1％-5％。优选地，微晶纤维素-羧甲基纤维素钠的重量百分比为5％-20％，卡波姆的重量百分比为0.5％-3％，黄原胶的重量百分比为0.2％-2.0％。优选地，微晶纤维素-羧甲基纤维素钠的重量百分比为8％-15％，卡波姆的重量百分比为1％-2％，黄原胶的重量百分比为0.4％-1.0％。
在一些实施方式中，所述主药在干混悬剂中的重量百分比为0.5％-10％，例如10％；优选为1-5％；更优选为5％、2.5％。
在一些实施方式中，所述主药为双嘧达莫及其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药。
在一些实施方式中，所述药学上可接受的盐包括但不限于双嘧达莫钠盐或无机酸盐。
在一些实施方式中，所述药学上可接受的盐包括但不限于双嘧达莫氯化钠、双嘧达莫盐酸盐。
在一些实施方式中，所述填充剂在干混悬剂中的重量百分比为60％-98％；更优选为68％-95％。
在一些实施方式中，所述填充剂选自蔗糖、葡萄糖、乳糖、麦芽糊精、甘露醇、山梨醇、淀粉、预胶化淀粉、微晶纤维素中的一种或多种。
在一些实施方式中，所述填充剂选自葡萄糖、麦芽糊精、甘露醇、山梨醇中的一种或多种。
在一些实施方式中，所述填充剂选自葡萄糖和麦芽糊精中的一种或两种。
在一些实施方式中，所述填充剂包括葡萄糖。优选地，葡萄糖在干混悬剂中的重量百分比50％-99％；更优选为60％-98％；更进一步优选为68％-95％。
在一些实施方式中，所述填充剂包括麦芽糊精。优选地，麦芽糊精在干混悬剂中的重量百分比50％-99％；更优选为60-98％；更进一步优选为68％-95％。
在一些实施方式中，所述填充剂包括葡萄糖和麦芽糊精的组合。优选地，葡萄糖和麦芽糊精在干混悬剂中的重量百分比50％-99％；更优选为60％-98％；更进一步优选为68％-95％。所述葡萄糖和麦芽糊精可以是任意比例混合。优选地，葡萄糖和麦芽糊精地重量比为(1-3):(3-1)；优选为(1-2):(2-1)；更优选为1:1。
在一些实施方式中，所述干混悬剂包括任选的药用辅料。
在一些实施方式中，所述干混悬剂包括润湿剂、助流剂、矫味剂中的一种或多种。
在一些实施方式中，所述干混悬剂还包括润湿剂。
在一些实施方式中，所述干混悬剂还包括重量百分比0％-5％的润湿剂。优选地，润湿剂在干混悬剂的重量百分比为0.1％-5％；优选为0.1％-3％；更优选为0.1％-1％。
在一些实施方式中，所述润湿剂包括选自泊洛沙姆、十二烷基硫酸钠中的一种或多种。
在一些实施方式中，所述润湿剂为十二烷基硫酸钠。
在一些实施方式中，所述润湿剂为重量百分比0％-5％的十二烷基硫酸钠、或0.1％-5％的十二烷基硫酸钠，或0.1％-3％的十二烷基硫酸钠，0.1％-1％的十二烷基硫酸钠，或0.2％的十二烷基硫酸钠。
在一些实施方式中，所述干混悬剂还包括助流剂。
在一些实施方式中，所述干混悬剂还包括重量百分比0％-5％的助流剂。优选地，助流剂在干混悬剂的重量百分比为0.1％-5％；优选为0.5％-4％；更优选为1.0％-3％。
在一些实施方式中，所述助流剂选自二氧化硅、硬脂酸镁、滑石粉、硬脂富马酸钠的中的一种或多种。
在一些实施方式中，所述助流剂为二氧化硅。
在一些实施方式中，所述助流剂为重量百分比0％-5％的二氧化硅、或0.1％-5％的二氧化硅、或0.5％-4％的二氧化硅、或1.0％-3％的二氧化硅、或2％的二氧化硅。
在一些实施方式中，所述干混悬剂还包括矫味剂。
在一些实施方式中，所述干混悬剂还包括重量百分比0.1％-10％的矫味剂。优选地，所述矫味剂在干混悬剂中的重量百分比是0.1％-8％，更优选是0.15％-5％。
在一些实施方式中，所述矫味剂选自甜味剂和/或香精的一种或多种。
在一些实施方式中，所述甜味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷、安赛蜜、蔗糖、阿斯巴甜、山梨糖醇、麦芽糖醇、木糖醇、糖精钠、甜蜜素、山梨醇或甘露醇中的一种或多种。
在一些实施方式中，所述香精选自水果味香精、牛奶味香精、奶油味香精中的一种或多种。
在一些实施方式中，所述矫味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷、水果味香精、牛奶味香精、奶油味香精中的一种或多种。
在一些实施方式中，所述矫味剂选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷中一种或多种。
在一些实施方式中，所述矫味剂在包括甜味剂的基础上，还包括香精。优选的，所述甜味剂包括选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷一种或多种；所述香精包括选自水果味香精、牛奶味香精、奶油味香精的一种或多种。优选地，水果味香精和/或牛奶味香精和/或奶油味香精在干混悬剂的重量百分比之和为0.8％-4.0％；更优选为1.0％-3.0％；更进一步优选为1.5％-2.5％。
在一些实施方式中，所述矫味剂不含香精，如不含水果味香精、牛奶味香精、奶油味香精中的任一种。
在一些实施方式中，所述矫味剂包括葡萄糖基甜菊糖苷。优选地，其在干混悬剂的重量百分比为0.8％-4.0％；更优选为1.0％-3.0％；更进一步优选为1.5％-2.5％。
在一些实施方式中，所述矫味剂包括葡萄糖基甜菊糖苷，和选自水果味香精、牛奶味香精、奶油味香精的一种或二种或三种。优选地，葡萄糖基甜菊糖在干混悬剂的重量百分比为0.8％-4.0％，水果味香精和/或牛奶味香精和/或奶油味香精在干混悬剂的重量百分比之和是0.8％-4.0％。优选地，葡萄糖基甜菊糖在干混悬剂的重量百分比为1.0％-3.0％，水果味香精和/或牛奶味香精和/或奶油味香精在干混悬剂的重量百分比之和是1.0％-3.0％。更优选地，葡萄糖基甜菊糖在干混悬剂的重量百分比为1.5％-2.5％，水果味香精和/或牛奶味香精和/或奶油味香精在干混悬剂的重量百分比之和是1.5％-2.5％。
在一些实施方式中，所述矫味剂包括三氯蔗糖。优选地，其在干混悬剂的重量百分比为0.1％-0.5％；优选为0.15％-0.3％。
在一些实施方式中，所述矫味剂包括甜菊糖苷。优选地，其在干混悬剂的重量百分比为1％-5％；优选为2％-5％。
在一些实施方式中，所述干混悬剂还可以加入抑菌剂、缓冲剂、色素中的一种或多种。所述抑菌剂、缓冲剂、色素是否添加、添加种类、含量可以由本领域技术人员常规筛选确定。
在一些实施方式，所述干混悬剂给予的患者可以是未成年人，成年人和老年人。
在一些实施方式中，所述干混悬剂具有卓越的掩味效果和令人满意的口感，特别适用于婴儿、幼儿或儿童。所述婴儿是指小于1周岁的未成年人，所述幼儿是指1周岁-3周岁的未成人，所述儿童是指3周岁-6周岁的未成年人。
在一些实施方式中，所述干混悬剂可以实现低渗透压给药。所述渗透压优选小于300mOsm/L，更优选小于250mOsm/L，更进一步为接近245mOsm/L。在一些实施方式中，所述渗透压接近240mOsm/L；优选小于240mOsm/L。
在一些实施方式中，所述干混悬剂具有优异的分散能力，分散时间不大于90s，优选不大于50s，更优选不大于20s。所述分散不需要额外工具，仅是患者用筷子、勺子等日常工具在轻微搅拌即可快速分散。在一些实施方式中，所述轻微搅拌是搅拌速度为10-90rpm、10-60rpm、10-30rpm、或10-20rpm。
(二)混悬剂的制备
本申请的第二方面，提供了本申请第一方面所述双嘧达莫混悬剂的制备方法，包括：按照本申请的第一方面，称取处方量原辅料，混合得到干混悬剂。
在一些实施方式中，制备方法还包括以下步骤：采用药用复合膜为内包装材料，将总混物料按单位制剂量装入袋包。
在一些实施方式中，所述药用复合膜是酯/铝/聚乙烯药用复合膜。
在一些实施方式中，单位制剂量是0.5g-2g，优选1g。
在一些实施方式中，混合前还包括过筛操作。
在一些实施方式中，所述过筛是过30-100目筛；优选过40目-80目筛。例如过40目筛，或者优选为过80目筛。
在一些实施方式中，所述过筛为填充剂过60-100目筛，优选过80目筛；其他原料过30-50目筛，优选40目筛。
在一些实施方式中，所述制备方法包括：称取处方量原辅料，填充剂过60-100目筛；筛上填充剂粉碎，粉碎后填充剂与原料药过30-50目筛预混；预混物与60-100目筛下填充剂及过30-50目筛的其它辅料混合。
在一些实施例中，所述制备方法包括：称取处方量原辅料，填充剂(例如葡萄糖等)过80目筛；筛上填充剂粉碎，粉碎后填充剂与原料药过40目筛预混；预混物与80目筛下填充剂及过40目筛的其它辅料混合。
(三)混悬剂的使用
本申请的第三方面，提供了一种混悬剂的配制方法，包括，取本申请第一方面所述干混悬剂，按照每25mg双嘧达莫对应的干混悬剂溶解于1-50mL溶剂中的比例将二者混合，搅拌。
在一些实施方式中，一种混悬剂的配制方法，包括，取本申请第一方面所述干混悬剂，按照每1g干混悬剂溶解于1-50mL溶剂中的比例将所述干混悬剂与溶剂混合，搅拌。
在一些实施方式中，所述比例为每25mg双嘧达莫对应的干混悬剂溶解于10-40mL溶剂中，优选溶解于15-25mL溶剂中。
在一些实施方式中，所述比例为每1g干混悬剂溶解于10-40mL溶剂中，优选溶解于15-25mL溶剂中。
在一些实施方式中，所述溶剂选自水、果汁、牛奶的一种或多种，例如温水。
(四)混悬剂
本申请的第四方面，提供了本申请第三方面配制方法得到的混悬剂。在一些实施方式中，所述混悬剂包括本文所述的干混悬剂和溶剂(例如选自水、果汁、牛奶中的一种或多种)。优选地，所述干混悬剂和溶剂的质量体积比为1g:1mL至1g:50mL、优选1g:1mL至1g:25mL。
在一些实施方式中，所述混悬剂具有卓越的掩味效果和令人满意的口感，特别适用于婴儿、幼儿或儿童。所述婴儿是指小于1周岁的未成年人，所述幼儿是指1周岁-3周岁的未成人，所述儿童是指3周岁-6周岁的未成年人。
在一些实施方式中，所述混悬剂可以实现低渗透压给药。所述渗透压优选小于300mOsm/L，更优选小于250mOsm/L，更进一步为接近245mOsm/L。在一些实施方式中，所述渗透压接近240mOsm/L，优选小于240mOsm/L。
在一些实施方式中，所述混悬剂具有优异的分散能力，分散时间不大于90s，优选不大于50s，更优选不大于20s。所述分散不需要额外工具，仅是患者用筷子、勺子等日常工具在30-90rpm的搅拌速度下即可快速分散。在一些实施方式中，所述轻微搅拌是搅拌速度为10-90rpm、10-60rpm、10-30rpm、或10-20rpm。
(五)应用
本申请的第五方面，提供了本申请第一方面所述双嘧达莫干混悬剂、本申请第四方面所述双嘧达莫混悬剂、或本申请第六方面所述药物组合物在制备药物中的用途。
在一些实施方式中，所述药物用于预防和/或治疗消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种。
在一些实施方式中，所述药物用于预防和/或治疗以下消化系统疾病中的一种或多种：病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻和其他原因导致的腹痛腹泻)、胆道闭锁、胃肠炎(例如急性肠胃炎)、十二指肠肠炎、消化道出血、感染性肠炎(病毒性肠炎或细菌性肠炎)、胆管炎、胆总管囊肿、腹股沟疝气、婴儿肝炎综合征、胆囊结石、肝功能不全、脐疝、肠套叠、肠梗阻、肝母细胞瘤、肝炎、肝硬化、肝纤维化、小肠或结肠溃疡、腹膜炎、脾先天性畸形、食管静脉曲张、胃底静脉曲张、脾肿大、脾功能亢进、胃癌、肠癌、肝癌、食物过敏、胰腺炎。
在一些实施方式中，所述药物用于预防和/或治疗以下肾脏疾病中的一种或多种：肾脏综合征、紫癜性肾炎、狼疮性肾炎、IgA肾病、肾小球肾炎、肾性高血压、肾衰竭、肾损伤。
在一些实施方式中，所述药物用于预防和/或治疗以下呼吸道疾病中的一种或多种：呼吸道感染(例如急性上呼吸道感染)、呼吸窘迫症、新冠肺炎、支气管炎、支气管肺炎、社区获得性肺炎、胸腔积液、呼吸衰竭、流行性感冒、哮喘、肺纤维化、肺动脉高压、肺癌。
在一些实施方式中，所述药物用于预防和/或治疗以下心脏疾病、脑部疾病和心脑血管疾病中的一种或多种：先天性心脏病、冠心病、心绞痛、心梗、高血压、血管结石、血栓性微血管病、胡桃夹综合征、门静脉海绵样变、心肌损害、川崎病、门静脉高压、房/室间隔缺损、先天性大动脉畸形、血管神经性水肿、血管炎、冠状动脉瘤、心室先天畸形、心律失常、血栓、卒中、中风、脑膜炎、脑炎、脑脊髓炎、脑积水、流行性乙型脑炎、痴呆。
在一些实施方式中，所述药物用于预防和/或治疗以下血液疾病中的一种或多种：低钠血症、缺铁性贫血、低丙种球蛋白血症、地中海贫血、溶血性贫血、蚕豆病、血小板增多、败血症、低蛋白血症、白血病、血脂异常。
在一些实施方式中，所述药物用于预防和/或治疗以下皮肤疾病中的一种或多种：痤疮、玫瑰痤疮、荨麻疹、真菌感染、疱疹、日光性皮炎、特应性皮炎、水痘、过敏性紫癜、白癜风、银屑病、痣、黑素瘤、脱发、脂溢性皮炎、螨虫过敏、毛囊炎、天疱疮、表皮水疱、红斑和皮肤嗜酸性粒细胞增多症。
在一些实施方式中，所述药物用于预防和/或治疗以下五官科疾病中的一种或多种：青光眼、白内障、结膜炎、麦粒肿、角膜炎、鼻炎、鼻窦炎、龋齿、口腔溃疡、扁桃体炎、喉炎、咽炎、耳鸣、中耳炎。
在一些实施方式中，所述药物用于预防和/或治疗以下疾病中的一种或多种：鞘膜积液、前列腺炎、矮小症、关节炎、炎性手腕疾病、肌腱炎、巨细胞病毒病、腺病毒感染、血液透析状态、干细胞移植状态、蛋白质-能量营养不良、生长发育迟缓、糖原贮积病、甲状腺功能减退症、蜂窝织炎、癫痫、矿物质代谢异常、发烧、惊厥、休克、全身炎症反应综合征、乳腺炎、外阴瘙痒、阴道炎、尿道炎、痔疮、腮腺炎、乳腺癌、卵巢癌、高雄激素血症、卵巢多囊改变、排卵异常和早期胚胎发育不良、促进卵母细胞成熟、糖尿病坏疽、糖尿病神经病变、小腿溃疡、硬皮病、神经疾病、旋晕、睡眠障碍、疼痛、勃起障碍、移植物与宿主疾病、多发性硬化、疱疹性咽峡炎。
在一些实施方式中，所述药物还用于预防和/或治疗过敏性疾病和炎症性疾病。
(六)药物组合物
本申请的第六方面，提供了一种药物组合物，包括本申请第一方面所述干混悬剂或第四方面所述混悬剂，以及至少第二活性成分。
在一些实施方式中，所述第二活性成分包括另一种用于治疗病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻和其他原因导致的腹痛腹泻)、胆道闭锁的成分。
病毒性肠炎通常是由多种病毒引起的急性肠道炎症性病变，包括轮状病毒、诺如病毒、犬细小病毒、腺病毒，例如在本申请的一些实施方式中，所述病毒性肠炎包括轮状病毒肠炎、诺如病毒肠炎、腺病毒肠炎。
炎症性肠病(IBD)是指原因不明的一组非特异性慢性胃肠道炎症性疾病，包括溃疡性结肠炎(Ulcerative colitis,UC)、克罗恩病(Crohn’s disease,CD)和未定型结肠炎(Indeterminate colitis,IC)。IBD病因与发病机制至今仍未完全明确，但公认系遗传、环境及免疫等多种因素综合作用的结果。目前认为其发病机制是由大量肠道细菌诱发的过度肠黏膜免疫反应，在具有遗传易感性的人群中导致肠黏膜损伤。
胆道闭锁(Biliary Atresia,BA)是引起新生儿病理性黄疸的最常见原因，也是目前世界小儿肝移植的最主要影响指标，是一种常见的胆管闭塞性疾病。
在一些实施方式中，所述至少另一种用于治疗病毒性肠炎、腹痛腹泻的成分选自口服/静脉补液盐、利巴韦林、氧化锌、葡萄糖酸锌、葡萄糖酸钙、碳酸钙、柠檬酸钙、肝素钙、西咪替丁、法莫替丁、蒙脱石、益生菌(如枯草杆菌二联活菌、双歧杆菌、双歧杆菌-乳杆菌-嗜热链球菌三联活菌、双歧杆菌-嗜酸乳杆菌-粪肠球菌-蜡样芽孢杆菌四联活菌)、甲氰咪胍、叶酸、庆大霉素、山莨菪碱、吗啉呱、氨苄青霉素的一种或多种。
在一些实施方式中，所述至少另一种用于治疗炎症性肠病的成分选自氨基水杨酸类药物(例如5-氨基水杨酸、柳氮磺吡啶等)、糖皮质激素(例如泼尼松、甲泼尼龙、倍他米松、丙酸倍氯米松、泼尼松龙、氢化可的松、地塞米松等)、免疫抑制剂(例如硫唑嘌呤、巯嘌呤、甲氨蝶呤等)、单抗(如英夫利西单抗)、抗生素、地芬诺酯，抗胆碱能药物(如洛哌丁胺等)中一种的或多种。
在一些实施方式中，所述至少另一种用于治疗胆道闭锁的药物包括选自水溶性和脂溶性维生素(维生素A、维生素D、维生素E、维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B7、维生素B12、维生素C、叶酸)、牛磺酸、退黄药物、护肝药物、白蛋白、免疫球蛋白、抗生素(例如头孢曲松、头孢哌酮、舒巴坦、甲硝唑、奥硝唑、胺培南、美罗培南、阿司匹林等)、熊去氧胆酸、糖皮质激素一种或多种。
在一些实施方式中，所述第二活性成分包括选自口服/静脉补液盐、利巴韦林、氧化锌、葡萄糖酸锌、葡萄糖酸钙、碳酸钙、柠檬酸钙、肝素钙、西咪替丁、法莫替丁、蒙脱石、益生菌(如枯草杆菌二联活菌、双歧杆菌、双歧杆菌-乳杆菌-嗜热链球菌三联活菌、双歧杆菌-嗜酸乳杆菌-粪肠球菌-蜡样芽孢杆菌四联活菌)、甲氰咪胍、庆大霉素、山莨菪碱、吗啉呱、氨苄青霉素、氨基水杨酸类药物(例如5-氨基水杨酸、柳氮磺吡啶等)、免疫抑制剂(例如硫唑嘌呤、巯嘌呤、甲氨蝶呤等)、单抗(如英夫利西单抗)、地芬诺酯，抗胆碱能药物(如洛哌丁胺等)、水溶性和脂溶性维生素(维生素A、维生素D、维生素E、维生素B1、维生素B2、维生素B3(烟酰胺)、维生素B5、维生素B6、维生素B7、维生素B12、维生素C、叶酸)、牛磺酸、退黄药物、护肝药物、白蛋白、免疫球蛋白、抗生素(例如环丙沙星、甲硝唑等)、熊去氧胆酸、糖皮质激素一种或者多种。
在本申请的一些实施方式中，所述第二活性成分还包括抗炎症性疾病的活性成分、抗过敏性疾病的活性成分、抗炎活性成分、抗过敏活性成分中的至少一种。
在本申请的一些实施方式中，所述抗炎活性成分包括：甾体抗炎药、或非甾体抗炎药。
在本申请的一些实施方式中，所述非甾体抗炎药包括阿司匹林、贝诺酯、水杨酸、对乙酰氨基酚、吲哚美辛、双氯芬酸、舒林酸、奈美丁酮、布洛芬、萘普生、吡罗昔康、美洛昔康、塞来昔布、依托考昔、尼美舒利。
在本申请的一些实施方式中，所述甾体抗炎药包括肾上腺皮质激素、雄激素、雌激素，例如氢化考的松、强的松、地塞米松等。
在一些实施方式中，本申请第一方面所述干混悬剂或第四方面所述混悬剂，以及第二活性成分可以存在于相同药品中，也可以存在于不同药品中。
在一些实施方式中，本申请第一方面所述干混悬剂或第四方面所述混悬剂，以及第二活性成分可以为相同剂型，也可以为不同剂型。
在一些实施方式中，所述药物组合物中的干混悬剂或混悬剂与第二活性成分可包装在一起或分别包装，并且二者可同时、序贯、以规律或不规律的间隔分别给药。
(七)药物联用
本申请的第七方面，提供了本申请第六方面的药物组合物在制备预防和/或治疗病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻)、胆道闭锁的药物中的应用。
在一些实施方式中，本申请第一方面所述干混悬剂或第四方面所述混悬剂或第六方面的药物组合物，可以与手术联用，用于治疗病毒性肠炎、炎症性肠病、腹痛腹泻、胆道闭锁。所述手术包括但不限于肝门空肠吻合手术、肝移植手术、回肠造瘘术、病变肠道切除术、选择性白细胞吸附法、粪菌移植治疗。
在一些实施方式中，提供了本申请第六方面的药物组合物在制备预防和/或治疗炎症性疾病和/或过敏性疾病的药物中的应用。
(八)预防和/或治疗方法
本申请的第八方面，提供了一种预防和/或治疗疾病的方法，包括将预防和/或治疗有效量的双嘧达莫及其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药、第一方面所述干混悬剂、第四方面所述混悬剂或第六方面所述药物组合物给予有需要的患者，所述疾病包括本申请第五方面所述的疾病中的一种或多种。
在一些实施方式中，所述疾病为病毒性肠炎(包括但不限于轮状病毒肠炎)、炎症性肠病(包括溃疡性结肠炎、克罗恩病和和未定型结肠炎)、腹痛腹泻(包括但不限于病毒性腹泻、过敏性腹泻、抗生素腹泻、上呼吸道感染型腹泻)、胆道闭锁中的一种或多种。
在一些实施方式中，所述疾病为炎症性疾病和/或过敏性疾病。
在一些实施方式中，所述药物的适用对象为动物，所述动物选自人、猫、牛、羊、猪、狗、鸡、鸭、鹅、兔、鼠；优选所述动物为人，包括未成年人、成年人和老人；更优选为婴儿、幼儿、儿童。
在一些实施方式中，所述给药方式为口服给药或直肠给药。给药途径可由临床医师根据实际需要选择，例如静脉内、腹膜内、口服、胃肠外等。
在一些实施方式中，所述给药频率为每8～24小时使用1-3次。
在本申请的一些实施方式中，所述药物的使用频率为每天使用1-3次；优选每天1-2次；更优选每天1次。
在一些实施方式中，当给药对象为小鼠时，所述给药剂量以双嘧达莫计，每天1-500mg/kg、3-400mg/kg、6-300mg/kg、10-300mg/kg、30-300mg/kg、50-300mg/kg或50-100mg/kg。
在一些实施方式中，当给药对象为人时，所述给药剂量以双嘧达莫计，每次0.1-50mg/kg、0.3-40mg/kg、0.6-30mg/kg、1-30mg/kg、3-30mg/kg、5-30mg/kg或5-10mg/kg。
在一些实施方式中，当疾病为胆道闭锁，给药对象为小鼠时，所述给药剂量以双嘧达莫计，每天1-500mg/kg、3-400mg/kg、6-300mg/kg、10-300mg/kg、30-300mg/kg、50-300mg/kg或50-100mg/kg；或者3-100mg/kg、3-60mg/kg、15-60mg/kg、或30-60mg/kg。
在一些实施方式中，当疾病为胆道闭锁，给药对象为人时，所述给药剂量以双嘧达莫计，每天0.1-50mg/kg、0.3-40mg/kg、0.6-30mg/kg、1-30mg/kg、3-30mg/kg、5-30mg/kg或5-10mg/kg；或者0.3-10mg/kg、0.3-6mg/kg、1.5-6mg/kg、或3-6mg/kg。
在一些实施方式中，当疾病为病毒性肠炎，给药对象为小鼠时，所述给药剂量以双嘧达莫计，每天1-500mg/kg、3-400mg/kg、6-300mg/kg、10-300mg/kg、30-300mg/kg、50-300mg/kg或50-100mg/kg；或6-500mg/kg、30-300mg/kg、或200-400mg/kg。
在一些实施方式中，当疾病为病毒性肠炎，给药对象为人时，所述给药剂量以双嘧达莫计，每天0.1-50mg/kg、0.3-40mg/kg、0.6-30mg/kg、1-30mg/kg、3-30mg/kg、5-30mg/kg或5-10mg/kg；或0.6-50mg/kg、3-30mg/kg、或20-40mg/kg。
在一些实施方式中，所述预防和/或治疗疾病的方法还包括给予本申请第六方面所述的第二活性成分。所述第二活性成分与本申请所述干混悬剂或混悬剂联合给药共同预防和/或治疗所述疾病。
在一些实施方式中，所述预防和/或治疗疾病的方法还包括手术。优选地，所述手术包括但不限于肝门空肠吻合手术、肝移植手术、回肠造瘘术、病变肠道切除术、选择性白细胞吸附法、粪菌移植治疗。所述手术与与本申请所述干混悬剂或混悬剂联合，共同预防和/或治疗所述疾病。
(九)矫味组合物
本申请的第九方面，提供了一种双嘧达莫的矫味组合物，包括重量份为0.1-20份的主药和重量份为0.1-10份的矫味剂或由重量份为0.1-20份的主药和重量份为0.1-10份的矫味剂组成，其中，主药选自双嘧达莫或其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，矫味剂包括选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷的一种或多种。
在一些实施方式中，所述矫味组合物由重量份为2-5份的主药和重量份为1-8份的矫味剂组成。
在一些实施方式中，主药选自双嘧达莫或其药学上可接受的盐。
在一些实施方式中，矫味剂为葡萄糖基甜菊糖苷。
在一些实施方式中，矫味剂是葡萄糖基甜菊糖苷；其中，矫味组合物由重量份为0.1-20份的主药和重量份为0.1-10份的葡萄糖基甜菊糖苷组成；优选地，矫味组合物由重量份为2-5份的主药和重量份为1-8份的葡萄糖基甜菊糖苷组成；更优选地，矫味组合物由重量份为2-3份的主药和重量份为1-4份的葡萄糖基甜菊糖苷组成；更进一步优选地，矫味组合物由重量份为2.5份的主药和重量份为1-3份的葡萄糖基甜菊糖苷组成。
在一些实施方式中，矫味剂为三氯蔗糖。
在一些实施方式中，矫味剂是三氯蔗糖；其中，矫味组合物由重量份为0.1-20份的主药和重量份为0.1-10份的三氯蔗糖组成；优选地，矫味组合物由重量份为1-8份的主药和重量份为0.1-2份的三氯蔗糖组成；更优选地，矫味组合物由重量份为2-5份的主药和重量份为0.2-1份的三氯蔗糖组成；更进一步优选地，矫味组合物由重量份为5份的主药和重量份为0.4份的三氯蔗糖组成。
在一些实施方式中，矫味剂为甜菊糖苷。
在一些实施方式中，矫味剂是甜菊糖苷；其中，矫味组合物由重量份为0.1-20份的主药和重量份为0.1-10份的甜菊糖苷组成；优选地，矫味组合物由重量份为1-5份的主药和重量份为0.5-8份的甜菊糖苷组成；更优选地，矫味组合物由重量份为2-3份的主药和重量份为1-6份的甜菊糖苷组成；更进一步优选地，矫味组合物由重量份为2.5份的主药和重量份为3-5份的甜菊糖苷组成。
在一些实施方式中，所述矫味组合物还包括水果味香精、牛奶味香精、和奶油味香精中的一种或多种。
在一些实施方式中，所述水果味香精、牛奶味香精、和奶油味香精的重量分数为0.1-10份；优选为1-8份。
在一些实施方式中，矫味剂为葡萄糖基甜菊糖苷；和水果味香精、牛奶味香精、和奶油味香精中的至少一种。
在一些实施方式中，矫味剂由葡萄糖基甜菊糖苷和香精组成。所述香精包括选自水果味香精、牛奶味香精、和奶油味香精中的至少一种。其中，矫味组合物由重量份为0.1-20份的主药，重量份为0.1-10份的葡萄糖基甜菊糖苷，和重量份为0.1-10份的香精(由水果味香精、牛奶味香精、和奶油味香精的中的一种或几种组成)组成；优选地，矫味组合物由重量份为2-5份的主药，重量份为1-8份的葡萄糖基甜菊糖苷，和重量份为1-8份的香精(由水果味香精、牛奶味香精、和奶油味香精的中的一种或几种组成)组成；更优选地，矫味组合物由重量份为2-3份的主药，重量份为1-4份的葡萄糖基甜菊糖苷，和重量份为1-4份的香精(由水果味香精、牛奶味香精、和奶油味香精的中的一种或几种组成)组成；更进一步优选地，矫味组合物由重量份为2.5份的主药，重量份为1-3份的葡萄糖基甜菊糖苷，和2份的香精(由水果味香精、牛奶味香精、和奶油味香精的中的一种或几种组成)组成。
在一些实施方式中，所述矫味组合物不含香精，例如不含水果味香精、牛奶味香精、和奶油味香精中的一种或多种。
在一些实施方式中，所述矫味组合物进一步包括助悬剂和填充剂。所述助悬剂例如包括选自羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆中的一种或多种。所述填充剂例如包括选自蔗糖、葡萄糖、乳糖、麦芽糊精、甘露醇、山梨醇、淀粉、预胶化淀粉、微晶纤维素中的一种或多种。
在一些实施方式中，提供了上述双嘧达莫矫味组合物在制备口服制剂中的应用。
在一些实施方式中，提供了上述双嘧达莫矫味组合物在制备干混悬剂、颗粒剂、口腔崩解片、分散片和/或咀嚼片剂型中的应用。
以下通过具体的实施例对本申请的内容作进一步详细的说明。
下面将结合本申请实施例具体介绍本申请实质性内容，但以下实施例仅是用以理解本申请，而不能限制本申请，本申请可以由权利要求限定和覆盖的多种不同方式实施。本申请中使用的原料均为普通市售产品，因此对其来源不做具体限定。
实施例1一种双嘧达莫干混悬剂
规格：25mg/1g/袋
制备方法：称取处方量原辅料，填充剂(葡萄糖)过80目筛，筛上葡萄糖粉碎，粉碎后葡萄糖与原料药过40目筛预混，预混物与80目筛下葡萄糖及过40目筛的其它辅料混合机混合，采用聚酯/铝/聚乙烯药用复合膜为内包装材料，将总混物料按单位制剂装量1g袋包。
实施例2一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例3一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例4一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例5一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例6一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例7一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例8一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例9一种双嘧达莫干混悬剂
规格：25mg/1g/袋

实施例10-17双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例18一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例19一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例20一种双嘧达莫干混悬剂
规格：25mg/1g/袋

实施例21一种双嘧达莫干混悬剂
实施例22一种双嘧达莫干混悬剂
实施例23一种双嘧达莫干混悬剂
实施例24一种双嘧达莫干混悬剂
实施例25一种双嘧达莫干混悬剂
实施例26一种双嘧达莫干混悬剂
实施例27一种双嘧达莫干混悬剂
实施例28一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例29一种双嘧达莫干混悬剂
规格：25mg/1g/袋
实施例2-29的制备方法与实施例1相似，区别仅在于辅料的组分和用量不同。
实施例30-58双嘧达莫混悬剂
取实施例1-29的双嘧达莫干混悬剂，按照需要将每1g干混悬剂溶解于1-50mL溶剂中的比例将二者混合，搅拌，得到相应的双嘧达莫混悬剂。例如，作为示例，将实施例1、2、3、4、5、17、18、19、27的干混悬剂溶解于20mL、25mL、15mL、30mL、10mL、20mL、20mL、20mL、40mL的温水中，得到相应的混悬剂。
实施例59-76矫味组合物
按照下表所示的处方，将双嘧达莫与各矫味剂混合来配制矫味组合物。


注：“-”表示未添加。
所述矫味组合物包含双嘧达莫作为活性成分(主药)，能够用于治疗作为临床上已知的双嘧达莫的各适应症，例如选自消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种。
实施例77-106药物组合物
按照下表所示的处方，将实施例1-29制备的双嘧达莫干混悬剂、实施例30的双嘧达莫混悬剂分别与不同的第二活性成分作为药物组合物联用，相对于所述组合物的总重量，二者占比在0.1-99.9％：99.9％-0.1％之间，具体分别为表格中所示。

所述药物组合物除了包含双嘧达莫作为活性成分外，还含有第二活性成分，能够用于治疗作为临床上已知的双嘧达莫和第二活性成分的各适应症，例如选自消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种；特别是发明人已经在动物模型中验证这些药物组合物可有效用于治疗病毒性肠炎、腹痛腹泻、炎症性肠病、胆道闭锁等。
效果例1溶出度和稳定性测定
取实施例1制备得到的干混悬剂，按照溶出度与释放度测定法(中国药典2020年版四部通则0931第二法)，900mL介质(pH 4.0醋酸盐缓冲液，配制方法为：称取醋酸钠1.22g，至1000mL水中溶解，再加入2.337mL冰醋酸混匀，用冰醋酸调节pH值至4.0，脱气备用)，50rpm，在pH 4.0介质中检测溶出，平行试验3组(n＝3)，结果如表1和图1所示。
表1双嘧达莫干混悬剂pH 4.0介质中累积溶出结果
从表1和图1可以看出，15分钟时已经溶出80％以上，在30分钟可溶出90％以上，1小时内基本溶出完全；各平行试验组的RSD差异小；溶出曲线缓和没有突释。
取实施例1制备得到的干混悬剂，按照中国药典2020年版测定稳定性数据，平行试验3组(n＝3)，结果如表2所示。
表2双嘧达莫干混悬剂的稳定性数据

从表2可以看出，本申请制得的干混悬剂纯度高，杂质少。即使在加速以及加速敞口的条件下，主药含量、各杂质以及总杂质含量也基本没有变化；显示了极高的稳定性。
效果例2不同助悬剂对搅拌分散速度和沉降体积比的影响
干混悬剂在服用前需要溶于水中，搅拌均匀后喝下。由于加入水后搅拌分散的速度关系到给药的便捷性，分散的均匀性关系到口服剂量的准确性。因而干混悬剂的质量首先需要通过分散速度和沉降体积比来评价。
进一步地，本申请的干混悬剂存在实现多种方式给药的需求(尤其是低渗给药)，使得相同质量的干混悬剂可以溶解于大范围体积的溶剂中，例如1-50mL的溶剂中；同时为了提供更高的给药浓度，会需要选择在高主药含量情形时相应增高助悬剂的含量，但高含量的助悬剂往往导致分散效果不好，成团。针对上述需求，进行如下实验。
如表3中所述的配比得到的干混悬剂，按照中国药典2020年版四部通则检查沉降体积比，取干混悬剂3袋，加水50mL，搅拌使其分散均匀，实验人员使用药匙手动搅拌，检测其搅拌分散速度。均匀分散后，取50mL，静置3小时，检测其沉降情况(沉降体积比≥0.9视为合格)。检测结果如表3所示。
表3：不同助悬剂的分散和沉降情况

从上表可以看出，在为了实现大溶剂范围给药需求的前提下，本申请筛选了多种助悬剂，包括羟丙甲基纤维素、羧甲基纤维素钠、聚维酮、西黄芪胶、阿拉伯胶、卡拉胶、海藻酸钠，它们在各种含量范围内调整，都无法得到符合要求的干混悬剂。按此方法，发明人还对市面上常见的助悬剂进行了筛选，例如吐温、司盘(Span)等，都无法得到如本申请中采用羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆或其组合作为助悬剂的、具有易分散、易服用特性的干混悬剂。
在此基础上，对羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆单独或部分组合作为助悬剂，在实施例1(即验证例1)的基础上，仅仅替换助悬剂，得到了验证例2(即实施例3)、验证例3、验证例4和验证例5所示的双嘧达莫干混悬剂，分散和沉降结果如下表所示。
表4双嘧达莫干混悬剂的分散和沉降结果
从表4可以看出，选择合适的助悬剂不仅可以快速分散药物，而且也能满足药典中关于混悬剂沉降体积比的要求。
将实施例17、18、19、28、29的干混悬剂，按照效果例2记载的方法检测搅拌分散速度、和沉降体积比，其沉降体积比均合格，搅拌分散速度分别为20s、20s、23s、21s和20s。可见，填充剂在本申请所述的特定范围内的替换，以及所述润湿剂和助流剂的加入与否，对最终分散和沉降结果影响不大。
效果例3不同矫味剂对口感的影响
通过加入不同的矫味剂及其组合来掩盖双嘧达莫的苦味。征集50名受试者，同一名受试者分别给予等量的各实施例制备得到的混悬剂，进行口感测试，包括对口感、掩味效果用数字1-5进行打分评估。其中1＝口感差；2＝口感稍差；3＝口感可接受；4＝口感满意；5＝口感非常满意。各打分值取平均数，最终得到的口感测试的结果如表5所示。
表5使用不同矫味剂制得的双嘧达莫混悬剂的口感测试结果

从表5可看出，通过不同矫味剂的对比发现，葡萄糖基甜菊糖苷、三氯蔗糖以及甜菊糖均可有效的掩盖双嘧达莫的苦味。发明人意外地发现再加入果味和奶味香精后掩味效果却会变差，自由甜味会比较柔和。
效果例4不同填充剂对渗透压的影响
将所述实施例1、实施例17、实施例18、实施例19的干混悬剂，按照1g干混悬剂加入到20mL水中，测试渗透压如表6所示。
表6渗透压测试结果
从表6可以看出，与甘露醇、山梨醇相比，葡萄糖、麦芽糊精不仅易吸收，而且更能够达到低渗溶液给药的目的(渗透压接近245mOsm/L)，避免肠炎脱水症状的风险。
效果例5药效学试验
(1)双嘧达莫(DIP)干混悬制剂用于胆道闭锁药效学研究实验
目前应用猴轮状病毒(Rotavirus，RV)制备胆道闭锁(Biliary Atresia,BA)动物模型接近实际的药物病理发生过程、是常见的药效研究方法。已有文献报导双嘧达莫具有防治胆道闭锁功效，因此，为了证明本申请的双嘧达莫干混悬剂的药效，研究其是否同样具有防治胆道闭锁的功效及其剂量，进行如下实验。
实验动物：成年BALB/c孕鼠，无特定病原体级(SPF级)，购自广东省医学实验动物中心。饲养在广州医科大学实验动物中心SPF级环境。待孕鼠产下新生小鼠(每只孕鼠平均产8只新生鼠)，平均体重1.5g，根据实验分组随机选取新生小鼠进行实验。
实验分组：
其中，正常对照组给予等体积的生理盐水；模型对照组给予制剂相同的溶媒(即水)；DIP-1组、DIP-2组、DIP-3组中的DIP低剂量混悬、DIP中剂量混悬、DIP高剂量混悬分别由实施例24中API含量为0.5％的干混悬剂与水勾兑成0.125mg/mL、0.5mg/mL和2mg/mL来配制相应的混悬液后根据给药剂量给药。
模型制备方法：将新生的BALB/c小鼠，于出生24小时内腹腔注射猴MMU18006轮状病毒(RV)20μL(滴度1.0×106PFU)，建立BA小鼠动物模型。详细步骤见已发表的文章“不同滴度轮状病毒对新生小鼠肝胆系统损伤的比较.中华实验和临床病毒学杂志.2017.01.1003-9279”，其内容全部在此引用作为参考。
给药以及指标考察：动物模型制备后，进行分组给药，给药时间11日，口服灌胃每日一次，检测多个临床指标进行记录和对药物的治疗作用进行评价。
其中，黄疸率结果见图2。结果表明，DIP-1、DIP-2、DIP-3可将轮状病毒感染引起的小鼠(RV组)黄疸由100％分别降至75％、66.7％以及33.3％。因此，本申请的干混悬剂具有明显的抑制胆道闭锁小鼠模 型黄疸率的效果。
提取肝脏的RNA进行qPCR的检测，结果见图3。结果显示，反映病毒体内复制的基因NSP3在模型小鼠显著升高，DIP-1、DIP-2、DIP-3可以不同水平的抑制病毒在肝脏的复制，提示本申请的双嘧达莫干混悬剂对模型小鼠肝脏损伤的改善作用。
从每组取8只小鼠进行肝脏石蜡切片HE染色实验并及病理染色Ishak评分，结果见图4-图5，对比肝脏石蜡切片HE染色发现，RV模型小鼠肝脏坏死灶多、炎症细胞在汇管区浸润增加、门脉汇管区周围纤维化程度加重；进行DIP-1、DIP-2、DIP-3治疗后，发现三种DIP浓度的药物均显著减少肝脏坏死灶数量，减少炎症细胞的浸润以及纤维化的程度降低，评分显示达到各药物治疗组均达到与模型组的显著差异。
结论：以上结果表明，本申请的双嘧达莫干混悬剂与文献已报道的双嘧达莫对胆道闭锁的防治功效吻合，而且对胆道闭锁及其所导致的肝脏损伤、黄疸等具有显著的预防和治疗作用。
(2)双嘧达莫(DIP)干混悬制剂用于病毒性肠炎药效学研究实验
已有文献报导双嘧达莫具有防治病毒性肠炎的功效，因此，为了证明本申请的双嘧达莫干混悬剂的药效，研究其是否同样具有防治病毒性肠炎的功效及其剂量，进行如下实验。
实验方法：入选84只乳鼠(出生后7天，168小时)，随机分为7组，12只/组。分别为空白对照组(Normal group)、模型对照组(Negative control)、安慰剂模型对照组(Placebo control)、双嘧达莫9.4mg/kg组、双嘧达莫37.5mg/kg组、双嘧达莫300mg/kg组、以及消旋卡多曲散阳性对照组(Positive control消旋卡多曲300mg/kg)。除空白对照组之外，所有动物灌胃给予轮状病毒MA-104制备病毒性肠炎动物疾病模型。感染后20±4小时进行症状评估，按照体重结合腹泻评分进行分组后给药。实验期间每天对实验动物进行一般临床观察，D1、D3、D5的时候称量各组动物体重，操作时间为当天的08:30，每次给药后60±15min记录动物的粪便重量和状态评分(参考表7的评分表)，受试药物按照每日一次灌胃给予实验动物，实验结束后，安乐死处理，4％多聚甲醛固定，石蜡包埋、3-5微米切片，染色观察。
其中，空白对照组给予等体积的生理盐水；模型对照组给予制剂相同的溶媒(即水)；双嘧达莫9.4mg/kg组、双嘧达莫37.5mg/kg组、双嘧达莫300mg/kg组分别由实施例3中API含量为2.5％的干混悬剂与水勾兑成0.312mg/mL、1.25mg/mL和10mg/mL来配制相应的混悬液后根据给药剂量给药。
病毒性肠炎模型制备：除空白组动物外所有动物；乳鼠出生后7天，体重约为4g，灌胃给药前禁奶4±0.5小时，然后每次给予病毒的量为25μL，每2小时给药一次，共计给药3次，计75μL。然后按照根据腹泻的评分标准和体重差异为指标进行随机分组，分组后给予测试药物。给药时间7天。
表7.腹泻评分表
备注：轻柔动物腹部，观察粪便状态，3分以上(包含3分)定义为腹泻，4-5级为腹泻为严重腹泻。
从图6并且结合评分结果显示，与同期的模型组相比，给予消旋卡多曲散和双嘧达莫的动物表现明显的抑制腹泻作用，对粪便状态评估，药物干预组评分均小于3分；与同期给药的消旋卡多曲散组比较，双嘧达莫9.4mg/kg组在粪便的评分范围在2-3分，双嘧达莫37.5mg/kg组表现出良好的抑制腹泻效果，评分在2分以下，双嘧达莫300mg/kg组接近正常0-1分。
从图7可以看出，通过对十二指肠组织的石蜡包埋，HE染色的结果观察，在炎性细胞侵润、上皮结构改变以及黏膜结构和基底膜细胞的指标上，空白对照组没有变化，模型对照组和安慰剂对照组均出现上皮细胞炎症、脱落和基底膜细胞空泡化现象，双嘧达莫和阳性对照药物消旋卡多曲散干预后，上述现象改善，给药组双嘧达莫37.5mg/kg和300mg/kg，炎症明显降低，上皮细胞空泡不明显。
结论：通过轮状病毒制备的新生小鼠腹泻模型显示，本申请的双嘧达莫干混悬剂，尤其是双嘧达莫在9.4-300mg/kg范围剂量下，对小鼠(乳鼠)有良好防治病毒性腹泻疾病(胃肠型感冒)的作用。
由此，本领域技术人员可以预期，对于其他已报道的用双嘧达莫有效的疾病，本申请的干混悬剂同样有效，而且基于干混悬剂不需要崩解、在肠胃分布面积大、吸收快等特性，能够预期本申请的剂型生物利 用度比其他口服剂型更高、药效更优。本申请制备的干混悬剂通过处方筛选选择合适的助悬剂和填充剂使得干混悬剂的分散效果好，分散速度快，并且可以低渗溶液给药(渗透压接近245mOsm/L)。进一步地，通过对矫味剂的筛选，能够成功掩盖苦味，取得令患者满意的口感，从而极大提高患者(特别是幼儿患者)的顺应性。
以上仅为本申请的优选实施例而已，并不用于限制本申请，对于本领域的技术人员来说，本申请可以有各种更改和变化。凡在本申请的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本申请的保护范围之内。

Claims (38)

  1. 一种双嘧达莫干混悬剂，由包括以下重量百分比的组分制成：0.1％-20％主药，0.1％-40％助悬剂，50％-99％填充剂；
    其中，所述主药为双嘧达莫或其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药。
  2. 根据权利要求1所述的干混悬剂，其中，所述主药为双嘧达莫钠盐或无机酸盐。
  3. 根据权利要求2所述的干混悬剂，其中，所述主药为双嘧达莫氯化钠或双嘧达莫盐酸盐。
  4. 根据权利要求1-3任一项所述的干混悬剂，其中，所述主药的重量百分比为0.5％-10％。
  5. 根据权利要求1-3任一项所述的干混悬剂，其中，所述助悬剂选自黄原胶、卡波姆、羟丙甲基纤维素、甲基纤维素、羟乙基纤维素、聚维酮、羧甲基纤维素钠、微晶纤维素-羧甲基纤维素钠、阿拉伯胶、西黄蓍胶、卡拉胶、海藻酸钠、羧甲基淀粉钠中的一种或多种。
  6. 根据权利要求5所述的干混悬剂，其中，所述助悬剂包括选自羟乙基纤维素、黄原胶、微晶纤维素-羧甲基纤维素钠、卡波姆中的一种或多种。
  7. 根据权利要求6所述的干混悬剂，其中，羟乙基纤维素的重量百分比为0.1％-10％；黄原胶的重量百分比为0.1％-5％；微晶纤维素-羧甲基纤维素钠的重量百分比为1.0％-30％；和/或，卡波姆的重量百分比为0.1％-5％。
  8. 根据权利要求7所述的干混悬剂，其中，所述助悬剂为微晶纤维素-羧甲基纤维素钠；羟乙基纤维素；或黄原胶；或羟乙基纤维素和黄原胶的组合；或微晶纤维素-羧甲基纤维素钠和卡波姆的组合。
  9. 根据权利要求7所述的干混悬剂，其中，所述助悬剂为1％-30％微晶纤维素-羧甲基纤维素钠；或0.1％-10％羟乙基纤维素；或0.1％-5％黄原胶；或0.1％-10％羟乙基纤维素和0.1％-5％黄原胶的组合；或1％-30％微晶纤维素-羧甲基纤维素钠和0.1％-5％卡波姆的组合。
  10. 根据权利要求7所述的干混悬剂，其中，所述助悬剂为10％-30％微晶纤维素-羧甲基纤维素钠；或2％-10％羟乙基纤维素；或1％-5％黄原胶；或2％-10％羟乙基纤维素和0.2％-2％黄原胶的组合；或0.5％-3％卡波姆和5％-20％微晶纤维素-羧甲基纤维素钠的组合。
  11. 根据权利要求7所述的干混悬剂，其中，所述助悬剂为20％-30％微晶纤维素-羧甲基纤维素钠；或4％-10％羟乙基纤维素；或2％-5％黄原胶；或4％-10％羟乙基纤维素和0.4％-1％黄原胶的组合；或1％-2％卡波姆和8％-15％微晶纤维素-羧甲基纤维素钠的组合。
  12. 根据权利要求7所述的干混悬剂，其中，所述助悬剂为6.5％的羟乙基纤维素和0.5％-0.8％的黄原胶的组合。
  13. 根据权利要求1-3任一项所述的干混悬剂，其中，所述填充剂包括选自蔗糖、葡萄糖、乳糖、麦芽糊精、甘露醇、山梨醇、淀粉、预胶化淀粉、微晶纤维素中的一种或多种。
  14. 根据权利要求13所述的干混悬剂，其中，所述填充剂选自葡萄糖和麦芽糊精中的一种或两种。
  15. 根据权利要求1-14任一项所述的干混悬剂，其中，所述干混悬剂还包括润湿剂、助流剂、抑菌剂、缓冲剂、色素、矫味剂中的一种或多种。
  16. 根据权利要求15所述的干混悬剂，其中，所述润湿剂的重量百分比为0％-5％，和/或者所述助流剂的重量百分比为0％-5％。
  17. 根据权利要求16所述的干混悬剂，其中，所述润湿剂包括泊洛沙姆、十二烷基硫酸钠中的一种或两种。
  18. 根据权利要求16所述的干混悬剂，其中，所述助流剂选自二氧化硅、硬脂酸镁、滑石粉、硬脂富马酸钠中的一种或多种。
  19. 根据权利要求15所述的干混悬剂，其中，所述矫味剂的重量百分比是0.1％-10％。
  20. 根据权利要求19所述的干混悬剂，其中，所述矫味剂为甜味剂和/或香精。
  21. 根据权利要求20所述的干混悬剂，其中，所述矫味剂包括葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷、水果味香精、牛奶味香精、奶油味香精中的一种或多种。
  22. 一种权利要求1-21任一项所述的双嘧达莫干混悬剂的制备方法，包括：称取处方量的原辅料，混合得到干混悬剂。
  23. 一种双嘧达莫混悬剂的配制方法，包括：取权利要求1-21任一项所述的双嘧达莫干混悬剂，按照每1g干混悬剂溶解于1-50mL溶剂中的比例混合，搅拌。
  24. 根据权利要求23所述的配制方法，其中，按照每1g干混悬剂溶解于15-25mL溶剂中的比例混合。
  25. 一种双嘧达莫混悬剂，其中，所述混悬剂是由权利要求23或24所述配制方法得到。
  26. 根据权利要求25所述的双嘧达莫混悬剂，其中，所述混悬剂的渗透压小于250mOsm/L。
  27. 一种权利要求1-21任一项所述的双嘧达莫干混悬剂或权利要求25-26任一项所述的双嘧达莫混悬剂在制备药物中的用途。
  28. 根据权利要求27所述的用途，其中，所述药物用于预防和/或治疗如下疾病中的一种或多种：
    1)炎症性肠病、腹痛腹泻、胆道闭锁、胃肠炎、十二指肠肠炎、消化道出血、病毒性肠炎、细菌性肠炎、真菌性肠炎、胆管炎、胆总管囊肿、腹股沟疝气、婴儿肝炎综合征、胆囊结石、肝功能不全、脐疝、肠套叠、肠梗阻、肝母细胞瘤、肝炎、肝硬化、肝纤维化、小肠或结肠溃疡、腹膜炎、脾先天性畸形、食管静脉曲张、胃底静脉曲张、脾肿大、脾功能亢进、胃癌、肠癌、肝癌、食物过敏、胰腺炎；
    2)肾脏综合征、紫癜性肾炎、狼疮性肾炎、IgA肾病、肾小球肾炎、肾性高血压、肾衰竭、肾损伤；
    3)呼吸道感染、呼吸窘迫症、新冠肺炎、支气管炎、支气管肺炎、社区获得性肺炎、胸腔积液、呼吸衰竭、流行性感冒、哮喘、肺纤维化、肺动脉高压、肺癌；
    4)先天性心脏病、冠心病、心绞痛、心梗、高血压、血管结石、血栓性微血管病、胡桃夹综合征、门静脉海绵样变、心肌损害、川崎病、门静脉高压、房/室间隔缺损、先天性大动脉畸形、血管神经性水肿、血管炎、冠状动脉瘤、心室先天畸形、心律失常、血栓、卒中、中风、脑膜炎、脑炎、脑脊髓炎、脑积水、流行性乙型脑炎、痴呆；
    5)低钠血症、缺铁性贫血、低丙种球蛋白血症、地中海贫血、溶血性贫血、蚕豆病、血小板增多、败血症、低蛋白血症、白血病、血脂异常；
    6)痤疮、玫瑰痤疮、荨麻疹、真菌感染、疱疹、日光性皮炎、特应性皮炎、水痘、过敏性紫癜、白癜风、银屑病、痣、黑素瘤、脱发、脂溢性皮炎、螨虫过敏、毛囊炎、天疱疮、表皮水疱、红斑和皮肤嗜酸性粒细胞增多症；
    7)青光眼、白内障、结膜炎、麦粒肿、角膜炎、鼻炎、鼻窦炎、龋齿、口腔溃疡、扁桃体炎、喉炎、咽炎、耳鸣、中耳炎；
    8)鞘膜积液、前列腺炎、矮小症、关节炎、炎性手腕疾病、肌腱炎、巨细胞病毒病、腺病毒感染、血液透析状态、干细胞移植状态、蛋白质-能量营养不良、生长发育迟缓、糖原贮积病、甲状腺功能减退症、蜂窝织炎、癫痫、矿物质代谢异常、发烧、惊厥、休克、全身炎症反应综合征、乳腺炎、外阴瘙痒、阴道炎、尿道炎、痔疮、腮腺炎、乳腺癌、卵巢癌、高雄激素血症、卵巢多囊改变、排卵异常和早期胚胎发育不良、促进卵母细胞成熟、糖尿病坏疽、糖尿病神经病变、小腿溃疡、硬皮病、神经疾病、旋晕、睡眠障碍、疼痛、勃起障碍、移植物与宿主疾病、多发性硬化、疱疹性咽峡炎。
  29. 一种药物组合物，包括权利要求1-21任一项所述的双嘧达莫干混悬剂或权利要求25-26任一项所述的双嘧达莫混悬剂，以及第二活性成分。
  30. 根据权利要求29所述的药物组合物，所述第二活性成分包括至少另一种用于治疗病毒性肠炎、炎症性肠病、腹痛腹泻、胆道闭锁的成分。
  31. 根据权利要求30所述的药物组合物，其中，所述另一种用于治疗病毒性肠炎、炎症性肠病、腹痛腹泻、胆道闭锁的成分选自口服/静脉补液盐、利巴韦林、氧化锌、葡萄糖酸锌、葡萄糖酸钙、碳酸钙、柠檬酸钙、肝素钙、益生菌、西咪替丁、法莫替丁、蒙脱石、甲氰咪胍、叶酸、庆大霉素、山莨菪碱、吗啉呱、氨苄青霉素、氨基水杨酸类药物、免疫抑制剂、英夫利西单抗、地芬诺酯，抗胆碱能药物、维生素A、维生素D、维生素E、维生素B1、维生素B2、维生素B3、维生素B5、维生素B6、维生素B7、维生素B12、维生素C、牛磺酸、白蛋白、免疫球蛋白、抗生素、熊去氧胆酸、糖皮质激素中的一种或多种。
  32. 权利要求29-31任一项所述的药物组合物在制备预防和/或治疗病毒性肠炎、炎症性肠病、腹痛腹泻、胆道闭锁中的应用。
  33. 一种双嘧达莫的矫味组合物，其中，包括重量份为0.1-20份的主药和重量份为0.1-10份的矫味剂，其中，所述主药选自双嘧达莫或其药学上可接受的盐、水合物、溶剂化物、多晶型物、互变异构体或前药，所述矫味剂包括选自葡萄糖基甜菊糖苷、三氯蔗糖、甜菊糖苷中的一种或多种。
  34. 根据权利要求33所述的双嘧达莫的矫味组合物，其中，由重量份为2-5份的所述主药和重量份为1-8份的所述矫味剂组成，所述矫味剂为葡萄糖基甜菊糖苷。
  35. 根据权利要求33或34所述的双嘧达莫的矫味组合物，其中，所述矫味剂还包括水果味香精、牛奶味香精、和奶油味香精中的一种或多种。
  36. 权利要求33-35任一项所述的双嘧达莫的矫味组合物在制备干混悬剂、混悬剂、颗粒剂、口腔崩解片、分散片和/或咀嚼片剂型中的应用。
  37. 一种预防和/或治疗如下疾病的方法，包括将预防和/或治疗有效量的权利要求1-21任一项所述的双嘧达莫干混悬剂、权利要求25-26任一项所述的双嘧达莫混悬剂、权利要求29-31任一项所述的药物组合物、或权利要求33-35任一项所述的双嘧达莫的矫味组合物给予有需要的患者，所述疾病选自消化系统疾病、肾脏疾病、呼吸道疾病、心脏疾病、脑部疾病和心脑血管疾病、血液疾病、皮肤疾病、五官科疾病中的一种或多种。
  38. 权利要求37所述的方法，其中，所述疾病选自如下中的一种或多种：
    1)炎症性肠病、腹痛腹泻、胆道闭锁、胃肠炎、十二指肠肠炎、消化道出血、病毒性肠炎、细菌性肠炎、真菌性肠炎、胆管炎、胆总管囊肿、腹股沟疝气、婴儿肝炎综合征、胆囊结石、肝功能不全、脐疝、肠套叠、肠梗阻、肝母细胞瘤、肝炎、肝硬化、肝纤维化、小肠或结肠溃疡、腹膜炎、脾先天性畸形、食管静脉曲张、胃底静脉曲张、脾肿大、脾功能亢进、胃癌、肠癌、肝癌、食物过敏、胰腺炎；
    2)肾脏综合征、紫癜性肾炎、狼疮性肾炎、IgA肾病、肾小球肾炎、肾性高血压、肾衰竭、肾损伤；
    3)呼吸道感染、呼吸窘迫症、新冠肺炎、支气管炎、支气管肺炎、社区获得性肺炎、胸腔积液、呼吸衰竭、流行性感冒、哮喘、肺纤维化、肺动脉高压、肺癌；
    4)先天性心脏病、冠心病、心绞痛、心梗、高血压、血管结石、血栓性微血管病、胡桃夹综合征、门静脉海绵样变、心肌损害、川崎病、门静脉高压、房/室间隔缺损、先天性大动脉畸形、血管神经性水肿、血管炎、冠状动脉瘤、心室先天畸形、心律失常、血栓、卒中、中风、脑膜炎、脑炎、脑脊髓炎、脑积水、流行性乙型脑炎、痴呆；
    5)低钠血症、缺铁性贫血、低丙种球蛋白血症、地中海贫血、溶血性贫血、蚕豆病、血小板增多、败血症、低蛋白血症、白血病、血脂异常；
    6)痤疮、玫瑰痤疮、荨麻疹、真菌感染、疱疹、日光性皮炎、特应性皮炎、水痘、过敏性紫癜、白癜风、银屑病、痣、黑素瘤、脱发、脂溢性皮炎、螨虫过敏、毛囊炎、天疱疮、表皮水疱、红斑和皮肤嗜酸性粒细胞增多症；
    7)青光眼、白内障、结膜炎、麦粒肿、角膜炎、鼻炎、鼻窦炎、龋齿、口腔溃疡、扁桃体炎、喉炎、咽炎、耳鸣、中耳炎；
    8)鞘膜积液、前列腺炎、矮小症、关节炎、炎性手腕疾病、肌腱炎、巨细胞病毒病、腺病毒感染、血液透析状态、干细胞移植状态、蛋白质-能量营养不良、生长发育迟缓、糖原贮积病、甲状腺功能减退症、蜂窝织炎、癫痫、矿物质代谢异常、发烧、惊厥、休克、全身炎症反应综合征、乳腺炎、外阴瘙痒、阴道炎、尿道炎、痔疮、腮腺炎、乳腺癌、卵巢癌、高雄激素血症、卵巢多囊改变、排卵异常和早期胚胎发育不良、促进卵母细胞成熟、糖尿病坏疽、糖尿病神经病变、小腿溃疡、硬皮病、神经疾病、旋晕、睡眠障碍、疼痛、勃起障碍、移植物与宿主疾病、多发性硬化、疱疹性咽峡炎。
PCT/CN2023/118527 2023-02-13 2023-09-13 一种双嘧达莫干混悬剂及其制备方法和应用 Ceased WO2024169170A1 (zh)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202310102658.2 2023-02-13
CN202310102658.2A CN115770219B (zh) 2023-02-13 2023-02-13 一种双嘧达莫干混悬剂及其制备方法和应用

Publications (1)

Publication Number Publication Date
WO2024169170A1 true WO2024169170A1 (zh) 2024-08-22

Family

ID=85393649

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/118527 Ceased WO2024169170A1 (zh) 2023-02-13 2023-09-13 一种双嘧达莫干混悬剂及其制备方法和应用

Country Status (2)

Country Link
CN (2) CN115770219B (zh)
WO (1) WO2024169170A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024125322A1 (zh) * 2022-12-16 2024-06-20 智泽童康(广州)生物科技有限公司 防治过敏性和/或炎症性疾病的双嘧达莫及其制剂
CN115770219B (zh) * 2023-02-13 2023-06-02 智泽童康(广州)生物科技有限公司 一种双嘧达莫干混悬剂及其制备方法和应用
CN116196314B (zh) * 2023-05-04 2023-08-15 广州市妇女儿童医疗中心 Ri-1或其盐在制备防治胃肠道疾病的药物中的应用
CN116270657B (zh) * 2023-05-18 2023-08-18 智泽童康(广州)生物科技有限公司 一种预防和/或治疗胃肠道疾病的药物组合物及其用途

Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030149058A1 (en) * 1999-10-22 2003-08-07 Wolfgang Eisert Use of dipyridamole or mopidamol for treatment and prevention of fibrin-dependent microcirculation disorders
KR20050018330A (ko) * 2003-08-13 2005-02-23 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 혈관장애의 치료 및 예방을 위한 디피리다몰,아세틸살리실산 및 안지오텐신 ⅱ 길항제의 용도
US20050282830A1 (en) * 2003-02-07 2005-12-22 Boehringer Ingelheim International Gmbh Use of dipyridamole or mopidamole for treatment and prevention of MMP-9-dependent disorders
CN106389329A (zh) * 2016-12-05 2017-02-15 黑龙江童医生儿童生物制药有限公司 一种双嘧达莫口服乳剂给药系统及其制备方法
CN113244395A (zh) * 2020-02-10 2021-08-13 广州市妇女儿童医疗中心 纤维化疾病机制及其治疗药物
CN114432241A (zh) * 2021-12-21 2022-05-06 上海奥全生物医药科技有限公司 一种快速分散的助悬组合物、制备方法及其应用
CN115770219A (zh) * 2023-02-13 2023-03-10 智泽童康(广州)生物科技有限公司 一种双嘧达莫干混悬剂及其制备方法和应用
CN116270657A (zh) * 2023-05-18 2023-06-23 智泽童康(广州)生物科技有限公司 一种预防和/或治疗胃肠道疾病的药物组合物及其用途

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5498613A (en) * 1994-06-07 1996-03-12 The University Of Southern California Dipyridamole and analogs thereof in preventing adhesion formation
CN111904942B (zh) * 2020-07-30 2021-08-20 上海奥科达生物医药科技有限公司 一种托吡酯干混悬剂、制备方法及其应用

Patent Citations (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030149058A1 (en) * 1999-10-22 2003-08-07 Wolfgang Eisert Use of dipyridamole or mopidamol for treatment and prevention of fibrin-dependent microcirculation disorders
US20050282830A1 (en) * 2003-02-07 2005-12-22 Boehringer Ingelheim International Gmbh Use of dipyridamole or mopidamole for treatment and prevention of MMP-9-dependent disorders
KR20050018330A (ko) * 2003-08-13 2005-02-23 베링거 잉겔하임 파르마 게엠베하 운트 코 카게 혈관장애의 치료 및 예방을 위한 디피리다몰,아세틸살리실산 및 안지오텐신 ⅱ 길항제의 용도
CN106389329A (zh) * 2016-12-05 2017-02-15 黑龙江童医生儿童生物制药有限公司 一种双嘧达莫口服乳剂给药系统及其制备方法
CN113244395A (zh) * 2020-02-10 2021-08-13 广州市妇女儿童医疗中心 纤维化疾病机制及其治疗药物
CN114432241A (zh) * 2021-12-21 2022-05-06 上海奥全生物医药科技有限公司 一种快速分散的助悬组合物、制备方法及其应用
CN115770219A (zh) * 2023-02-13 2023-03-10 智泽童康(广州)生物科技有限公司 一种双嘧达莫干混悬剂及其制备方法和应用
CN116270657A (zh) * 2023-05-18 2023-06-23 智泽童康(广州)生物科技有限公司 一种预防和/或治疗胃肠道疾病的药物组合物及其用途

Also Published As

Publication number Publication date
CN115770219B (zh) 2023-06-02
CN118477044A (zh) 2024-08-13
CN115770219A (zh) 2023-03-10

Similar Documents

Publication Publication Date Title
CN115770219B (zh) 一种双嘧达莫干混悬剂及其制备方法和应用
JP6092629B2 (ja) リファキシミン使用準備済懸濁液
TWI782982B (zh) Hsp90抑制劑口服調配物及相關方法
JPH09509648A (ja) ミコフェノール酸モフェチル高用量経口用懸濁剤
WO2019208540A1 (ja) 安定性に優れた固形製剤
JP2022031345A (ja) Ｓｔ－２４６（テコビリマット一水和物）懸濁製剤
CN112312912B (zh) 含有二胺衍生物的颗粒
CN102860986A (zh) 一种稳定的掩味的左西替利嗪药物组合物及其制备方法
US20170157108A1 (en) Liquid formulation comprising montelukast or pharmaceutically acceptable salt thereof and method for preparing same
CN104507476B (zh) 含奈帕坦特的儿科口服液体组合物
HK40086709A (zh) 一种双嘧达莫干混悬剂及其制备方法和应用
HK40086709B (zh) 一种双嘧达莫干混悬剂及其制备方法和应用
CN115697344B (zh) 包含度鲁特韦的可分散片剂制剂
JP7766933B2 (ja) ウデナフィルを含む薬学的組成物
JPWO2019208540A1 (ja) 安定性に優れた固形製剤
WO2006109737A1 (ja) 苦味が低減されたプランルカスト水和物を含有する製剤
JP3899522B2 (ja) 苦味が低減されたプランルカスト水和物を含有する製剤
CN115803018A (zh) 制剂
US20190380965A1 (en) Quick Water-Dispersible Pharmaceutical Compositions of Flucytosine
CN111989102A (zh) 水性混悬液型药物制剂
JP2008094751A (ja) プランルカスト水和物含有医薬組成物
JP6853828B2 (ja) メマンチンまたはその薬学上許容される塩を含有する医薬組成物
GB2638418A (en) An orodispersible tablet of spironolactone and its process of preparation
JP2025525168A (ja) 新規処方
HK40053232A (zh) 含有二胺衍生物的颗粒

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: 23922289

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE