WO2022135331A1 - 一种稳定的含有苦丁皂苷类化合物的液体药物组合物 - Google Patents

一种稳定的含有苦丁皂苷类化合物的液体药物组合物 Download PDF

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WO2022135331A1
WO2022135331A1 PCT/CN2021/139611 CN2021139611W WO2022135331A1 WO 2022135331 A1 WO2022135331 A1 WO 2022135331A1 CN 2021139611 W CN2021139611 W CN 2021139611W WO 2022135331 A1 WO2022135331 A1 WO 2022135331A1
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pharmaceutical composition
liquid pharmaceutical
ring
residue
ethanol
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PCT/CN2021/139611
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French (fr)
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马明
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上海凯屹医药科技有限公司
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Priority to US18/258,628 priority Critical patent/US20240091146A1/en
Priority to EP21909327.5A priority patent/EP4265260A1/en
Priority to CN202180094287.7A priority patent/CN116916932A/zh
Priority to JP2023538063A priority patent/JP2024500166A/ja
Publication of WO2022135331A1 publication Critical patent/WO2022135331A1/zh

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    • A—HUMAN NECESSITIES
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    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
    • A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • 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
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
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    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/08—Solutions
    • 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
    • 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
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/06—Ampoules or carpules
    • A61J1/065—Rigid ampoules, e.g. glass ampoules
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/05—Containers specially adapted for medical or pharmaceutical purposes for collecting, storing or administering blood, plasma or medical fluids ; Infusion or perfusion containers
    • A61J1/10—Bag-type containers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/16—Holders for containers

Definitions

  • the invention belongs to the field of chemical pharmacy, and in particular relates to a stable liquid pharmaceutical composition containing picroside compounds.
  • COPD chronic obstructive pulmonary disease
  • the characteristic pathological changes of COPD include lung parenchyma damage and small airway fibrosis caused by the combined effects of bacteria and gas exposure leading to chronic inflammation of the small airways and lungs, oxidative stress and increased proteases.
  • the morbidity and mortality of COPD are increasing with the changes in the global environment and the age structure of the world population. The incidence rate of people over 40 years old in the world has reached 9% to 10%, which has a serious impact on the life and work of patients.
  • COPD is mainly treated with drugs, which can effectively control the progression of the disease and relieve symptoms.
  • the treatment drugs for COPD mainly include bronchodilators ( ⁇ 2-adrenergic receptor agonists, theophylline drugs and anticholinergic drugs), glucocorticoids, antibiotics, and mucoactive agents.
  • Bronchial asthma (asthma for short) is a disease characterized by chronic allergic airway inflammation, and many cells and cytokines are involved in this process. Asthma triggers airway hyperresponsiveness, causing recurrent episodes of wheezing, dyspnea, coughing, and its persistence can lead to death. Asthma often occurs at night and in the early morning and is often related to the environment, air currents, exposure to allergens such as dust mites and pollen, and autoimmunity. At present, there are about 300 million people suffering from asthma in the world, and more than 20 million people in my country are suffering from asthma, and the incidence rate is increasing day by day. Asthma has a high incidence and affects people's physical and mental health and quality of life. It has become one of the major chronic diseases that seriously threaten public health.
  • Kudingcha is a plant tea that people of all ethnic groups in southern my country often drink, and it is also a traditional medicinal plant. It is a general term for a large class of plants derived from herbs, vines, shrubs, small trees and tall trees, and has different degrees of bitter and sweet taste.
  • the native plants of Kudingcha involve 12 families and a total of more than 30 species.
  • the planting area is relatively large and two of these families are used more: one is the Ilex family Ilex genus Kudingcha, which mainly includes Kudingcha Ilex (Ilex kudingcha C.J.Tseng), large leaf holly (Ilex latifolia Thunb.), wolf bone (Ilex cornute Lindl.), Wuling Kudingcha (Ilex.Pentag-ona S.K.Chen.Y.X.Feng et C.F.Liang), Huazhong wolf bone (Ilex cent rochinensis S.Y.Hu) and Huoshan holly (I.houshanensis Y.H.He); the second is Oleaceae Kudingcha, which is mainly developed in southeastern provinces and cities such as Guizhou, Sichuan, Yunnan and Chongqing. Kuding tea is called "Ligustrum henryi Hemsl" (Ligustrum henryi
  • Kuding tea leaves contain caffeine, tannic acid, protein, ursolic acid, aromatic oil, Kuding saponin, alpha-balsam, beta-sitosterol, ursolic acid, as well as a variety of vitamins and trace elements It has medicinal and health care functions such as clearing heat and detoxifying, anti-inflammatory and sterilizing, relieving cough and reducing phlegm, strengthening stomach and eliminating accumulation, improving eyesight and thinking, lowering cholesterol, lowering blood pressure, lowering blood fat, anti-fatigue, and anti-aging.
  • Chinese patent CN106456657A discloses the application of kudzu saponins in the treatment of asthma, COPD and other pulmonary diseases. These compounds can be administered by inhalation, and have the advantages of fast onset of action and large contact surface area of the lungs.
  • the present invention provides a stable liquid pharmaceutical composition, which is characterized in that the liquid pharmaceutical composition comprises a therapeutically effective amount of a picroside compound, a buffered effective amount of a pH 6.5-7.5 buffer, and a pharmaceutically acceptable Carrier.
  • the kudzu saponins are isolated from the holly plant of the family Ilex; more preferably, the holly of the family holly is selected from the group consisting of Kudingcha holly, large leaf holly, wolfberry, Wuling Kudingcha, Huazhong wolf bone or Huoshan holly.
  • the picroside compound is the compound represented by the general formula (I):
  • the sugar residue is a monosaccharide residue or an oligosaccharide residue.
  • the monosaccharide is arabinose (Ara), glucuronic acid or 2-deoxy-glucuronic acid (GlcA), glucose (Glc) or rhamnose (Rha).
  • the oligosaccharide residue is a disaccharide residue, a trisaccharide residue, or a tetrasaccharide residue.
  • the oligosaccharide residues include any combination of glucose, arabinose, glucuronic acid, and rhamnose.
  • a ring, B ring, C ring and E ring are fully saturated rings
  • D ring is a partially saturated ring
  • C12 and C19 positions are independently substituted by -OH
  • R 1 is a monosaccharide residue or oligosaccharide residues
  • R3a and R3b are -CH3 .
  • a ring, B ring, C ring and E ring are fully saturated rings
  • D ring is a partially saturated ring
  • C11 and C19 positions are independently substituted by -OH, respectively
  • R 3a and R 3b are respectively is -CH 3
  • R 1 is a monosaccharide residue or an oligosaccharide residue.
  • ring A, ring B and ring E are fully saturated rings, ring C and ring D are partially saturated rings, C19 is substituted by -OH, R 3a and R 3b are respectively -CH 3 , R 1 is a monosaccharide residue or an oligosaccharide residue.
  • the compound represented by the general formula (I) has the structure represented by the following formula (II), (III) or (IV):
  • R 1 is a monosaccharide residue or an oligosaccharide residue.
  • the monosaccharide is arabinose (Ara), glucuronic acid, 2-deoxy-glucuronic acid (GlcA), glucose (Glc ) or rhamnose (Rha);
  • oligosaccharide residues are disaccharide residues, trisaccharide residues or tetrasaccharide residues; oligosaccharide residues include any combination of glucose, arabinose and rhamnose.
  • the saponin compound is selected from the group consisting of saponin A, saponin B, saponin C, saponin D, saponin E, saponin F, saponin Saponin I, Kuding Saponin J, Kudingcha Ilex H, Kudingcha Ilex I and Kudingcha Ilex J.
  • the kudrine compound is selected from kudrine A, kudosaponin B, kudrin C, kudosaponin D, kudosaponin I, kudrin I and kudrin I and Kudingcha Ilexin J.
  • the picroside compound is selected from the two isomers of picroside A: 3 ⁇ -12 ⁇ -19 ⁇ -trihydroxy-ursane-13(18)-ene -28,20 ⁇ -lactone-3-O-[ ⁇ -D-glucosyl-(1 ⁇ 3)-[ ⁇ -L-rhamnosyl-(1 ⁇ 2)]- ⁇ -L-arabinoside or 3 ⁇ -12 ⁇ -19 ⁇ -Trihydroxy-ursane-13(18)-ene-28,20 ⁇ -lactone-3-O-[ ⁇ -D-glucosyl-(1 ⁇ 3)-[ ⁇ -L- Rhamnosyl-(1 ⁇ 2)]- ⁇ -L-arabinoside.
  • the mass percentage content of the picroside saponins in the whole liquid pharmaceutical composition is 0.001%-0.050%, preferably 0.006%-0.030%, more preferably 0.010%-0.030%, most preferably 0.001%-0.050%. 0.015% is preferred.
  • the pH 6.5-7.5 buffer is selected from phosphate buffer, preferably sodium phosphate buffer, potassium phosphate buffer or a combination thereof, more preferably disodium hydrogen phosphate-diphosphate Potassium hydrogen buffer.
  • the pH 6.5-7.5 buffer is selected from the group consisting of disodium hydrogen phosphate phosphate-potassium dihydrogen phosphate buffer at pH 6.5, disodium hydrogen phosphate-potassium dihydrogen phosphate buffer at pH 6.9, Disodium hydrogen phosphate – potassium dihydrogen phosphate buffer at pH 7.0, disodium hydrogen phosphate – potassium dihydrogen phosphate buffer at pH 7.4, or disodium hydrogen phosphate – potassium dihydrogen phosphate buffer at pH 7.5.
  • the pharmaceutically acceptable carrier includes pharmaceutically acceptable vehicles, co-solvents, and stabilizers.
  • the pharmaceutically acceptable vehicle is selected from water, ethanol or a combination thereof, preferably an aqueous ethanol solution.
  • the mass percentage content of ethanol in the entire liquid pharmaceutical composition is 1.0%-5.0%, preferably 2.5-4.0%, more preferably 3.5%.
  • the co-solvent is selected from propylene glycol, glycerol, polyethylene glycol 200, polyethylene glycol 400 or Tween 80, preferably Tween 80.
  • the mass percentage content of the cosolvent in the entire liquid pharmaceutical composition is 0.1%-0.8%, preferably 0.2%-0.5%.
  • the cosolvent is Tween 80, and its mass percentage content in the entire liquid pharmaceutical composition is 0.1%-0.5%, preferably 0.2%-0.4%, more preferably 0.3%.
  • the stabilizer is selected from phenylethanol and disodium edetate, preferably disodium edetate.
  • the mass percentage content of the stabilizer in the entire liquid pharmaceutical composition is 0.05%-0.20%, preferably 0.05%-0.15%.
  • the mass percentage content of the disodium edetate in the entire liquid pharmaceutical composition is 0.05%-0.20%, preferably 0.05%-0.10%, more preferably 0.072%-0.088%.
  • the buffer system of the liquid pharmaceutical composition is disodium hydrogen phosphate-dipotassium hydrogen phosphate, and the pH of the composition is about 7.0; wherein, based on the total weight of the liquid pharmaceutical composition, the The liquid pharmaceutical composition contains: 0.006%-0.030% picroside A, about 3.5% ethanol, 0.1%-0.5% Tween 80 and 0.072%-0.088% disodium edetate.
  • the liquid pharmaceutical composition is characterized in that, based on the total weight of the liquid pharmaceutical composition, it contains: about 0.006% picroside A, about 3.5% ethanol, about 0.1% Tween 80, about 0.072% disodium edetate and about 96.2% water; or containing about 0.015% picroside A, about 3.5% ethanol, about 0.3% Tween 80, about 0.08% edetate disodium edetate and about 95.8% water; or containing about 0.03% picroside A, about 3.5% ethanol, about 0.5% Tween 80, about 0.088% disodium edetate and about 95.2% water.
  • the liquid pharmaceutical composition is a solution or suspension.
  • the dosage form of the liquid pharmaceutical composition is a solution for inhalation or a suspension for inhalation.
  • the liquid pharmaceutical composition is stored in a closed pharmaceutically acceptable packaging material.
  • the pharmaceutically acceptable packaging material includes polymeric material, glass bottle, aluminum foil material, or a combination thereof.
  • the polymer material includes low density polyethylene film, low density polyethylene bags, high density polyethylene films, low density polyethylene bottles, high density polyethylene bottles, polypropylene bottles, poly Ethylene terephthalate bottle, polyester/aluminum/polyethylene composite film, polyester/aluminum/polyethylene composite bag, or a combination thereof.
  • the aluminum foil material includes an aluminum foil bag, preferably a pharmaceutical aluminum foil bag.
  • the pharmaceutically acceptable packaging material is a combination of a low density polyethylene bottle and an aluminum foil bag.
  • a vacuum or a near-vacuum state is between the low density polyethylene bottle and the aluminum foil bag.
  • the thickness of the low density polyethylene bottle is 0.5-2.0mm, preferably 0.8-1.2mm, more preferably 1.0-1.2mm.
  • the preparation process of the liquid pharmaceutical composition of the present invention due to the low solubility of the trisaponin compounds (eg, tributaponin A), the preparation process needs to be continuously adjusted so that the compounds can be fully dissolved therein.
  • the trisaponin compounds eg, tributaponin A
  • the preparation process of the liquid pharmaceutical composition is as follows: take water (such as purified water or water for injection), add disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate, stir evenly, Adjust the pH to prepare a buffer solution; then weigh ethanol and Tween 80, add the above solution and stir evenly; finally add a picroside compound (eg picroside A) and stir until completely dissolved.
  • water such as purified water or water for injection
  • disodium hydrogen phosphate potassium dihydrogen phosphate
  • disodium edetate disodium edetate
  • Adjust the pH to prepare a buffer solution then weigh ethanol and Tween 80, add the above solution and stir evenly
  • a picroside compound eg picroside A
  • the preparation process of the liquid pharmaceutical composition is as follows: take water (such as purified water or water for injection), add disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate, and stir evenly , adjust the pH, and make a buffer solution; at the same time, weigh ethanol and Tween 80, add a part of the obtained buffer solution to it, stir evenly, and prepare a solution with an ethanol concentration of about 50%, and add picrosides to it. (for example, picroside A), stir until it is completely dissolved; finally add the remaining part of the buffer and stir evenly.
  • water such as purified water or water for injection
  • disodium hydrogen phosphate potassium dihydrogen phosphate
  • disodium edetate disodium edetate
  • the preparation process of the liquid pharmaceutical composition is as follows: take water (such as purified water or water for injection), add disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate, and stir evenly , adjust the pH, and make
  • the preparation process of the liquid pharmaceutical composition is as follows: taking water (such as purified water or water for injection), adding disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate, stirring uniformly, adjust the pH, and prepare a buffer solution; at the same time, weigh ethanol and Tween 80, add a part of the prepared buffer solution to it, stir evenly, and prepare a solution with an ethanol concentration of about 30%, and add picrosides to it. Compounds (such as picroside A) are stirred until completely dissolved; finally, the remaining part of the buffer is added and stirred evenly.
  • water such as purified water or water for injection
  • disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate stirring uniformly, adjust the pH, and prepare a buffer solution
  • weigh ethanol and Tween 80 add a part of the prepared buffer solution to it, stir evenly, and prepare a solution with an ethanol concentration of about 30%, and add picrosides to it.
  • Compounds (
  • the preparation process of the liquid pharmaceutical composition is as follows: weighing water (such as purified water or water for injection), adding disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate, adjusting pH, stir evenly, and prepare a buffer solution; at the same time, weigh ethanol and Tween 80, add picroside compounds (such as picroside A), stir until completely dissolved, and configure into a mother liquor; finally, mix the mother liquor with the buffer solution, Stir well.
  • FIG. 1A Changes in ethanol content (%) in samples 1-3 in a long-term test (temperature: 25°C ⁇ 2°C; humidity: 40% ⁇ 5%).
  • Figure 1B Changes in ethanol content (%) in samples 4-6 in long-term tests (temperature: 25°C ⁇ 2°C; humidity: 40% ⁇ 5%).
  • Figure 1C Changes in ethanol content (%) in samples 7-9 during long-term tests (temperature: 25°C ⁇ 2°C; humidity: 40% ⁇ 5%).
  • Figure 2A Changes in ethanol content (%) in samples 1-3 in an accelerated test (temperature: 40°C ⁇ 2°C; humidity: 22% ⁇ 5%).
  • Figure 2B Changes in ethanol content (%) in samples 4-6 in an accelerated test (temperature: 40°C ⁇ 2°C; humidity: 22% ⁇ 5%).
  • Figure 2C Changes in ethanol content (%) in samples 7-9 in an accelerated test (temperature: 40°C ⁇ 2°C; humidity: 22% ⁇ 5%).
  • Figure 3A Changes in ethanol content (%) in samples 1-3 in a high temperature test (temperature: 60°C ⁇ 2°C).
  • Figure 3B Changes in ethanol content (%) in samples 4-6 in a high temperature test (temperature: 60°C ⁇ 2°C).
  • Figure 3C Changes in ethanol content (%) in samples 7-9 in a high temperature test (temperature: 60°C ⁇ 2°C).
  • Fig. 4 shows the structure of kudzu saponins.
  • Figure 4A represents Kudingsaponin A, Kudingsaponin B, Kudingsaponin C, Kudingsaponin I, Kudingcha Ilex I, Kudingcha Ilex J
  • Figure 4B represents Kudingsaponin F, Kudingcha Ilexin Butanoside H
  • Fig. 4C represents butanoside D, butanoside E, and butanoside J.
  • the abscissa represents the time for detecting the ethanol content; the ordinate represents the mass percentage content of ethanol in the entire liquid pharmaceutical composition.
  • ranges are in the form of lower and upper limits. There can be one or more lower limits, and one or more upper limits, respectively.
  • the given range is defined by choosing a lower limit and an upper limit.
  • the selected lower and upper limits define the boundaries of the particular range. All ranges that can be defined in this manner are inclusive and combinable, ie, any lower limit can be combined with any upper limit to form a range.
  • the range defined by “about” is generally the range of experimental error. For example, "about 7" means 7 ⁇ 0.1 if the experimental error is 0.1.
  • the present invention provides a stable liquid pharmaceutical composition, which is characterized in that it comprises a therapeutically effective amount of a picroside compound, a buffered effective amount of a pH 6.5-7.5 buffer, and a pharmaceutically acceptable accepted vector.
  • a pharmaceutically acceptable accepted vector means that the drug may also contain any other components, and these components may be present in any amount, as long as the component present in the amount is acceptable to the human body and is not applicable to the present invention. It is sufficient that the biological activity of the active ingredient in the inventive pharmaceutical composition is not substantially affected.
  • the liquid pharmaceutical composition comprises a therapeutically effective amount of picrosides, a buffered effective amount of a buffer at pH 6.5-7.5, a cosolvent, a stabilizer, and a pharmaceutically acceptable vehicle .
  • the Kudingsaponin compounds of the present invention are in liquid or solid state. It can be purchased from commercial sources, and can also be isolated or chemically synthesized from Ilex plants of the family Ilex using existing techniques. Described holly family holly plant is selected from Kudingcha holly (llex kudingcha C.J.Tseng), large-leaf holly (Ilex.latifolia Thunb.), wolf bone (Ilex.cornute Lindl.), Wuling Kudingcha (Ilex.pentag) -ona S.K.Chen Y.X Feng et C.F.Liang), Chinese wolf bone (Ilex cent rochinensis S.Y.Hu), Huoshan holly (I.houshanensis Y.H.He) or a combination thereof.
  • the butanoside compounds are preferably butanoside A, butanoside B, butanoside C, butanoside D, butanoside E, butanoside F, butanoside I , Kudingcha Ilexin J, Kudingcha Ilexin H, Kudingcha Ilexin I, Kudingcha Ilexin J (its chemical structural formula is in CN106456657A and the document "Triterpenes and their saponin compounds in Ilex genus Kudingcha" 4A-C); more preferably 3 ⁇ -12 ⁇ -19 ⁇ -trihydroxy-ursane-13(18)-ene-28,20 ⁇ -lactone-3-O-[ ⁇ - D-glucosyl-(1 ⁇ 3)-[ ⁇ -L-rhamnosyl-(1 ⁇ 2)]- ⁇ -L-arabinoside or 3 ⁇ -12 ⁇ -19 ⁇ -trihydroxy-ursane-13( 18)-ene-28,20 ⁇ -lactone-3-O-[ ⁇ -D-glucosyl-(
  • the term "therapeutically effective amount” refers to the concentration (dose) at which the liquid pharmaceutical composition of the present invention is used to treat diseases such as asthma, COPD or other related diseases.
  • the mass percentage content of the "therapeutically effective amount” of the kudzu saponins in the whole liquid pharmaceutical composition is 0.001%-0.050%, such as 0.006-0.030%.
  • the mass percentage content of the "therapeutically effective amount” of the picrosides in the entire liquid pharmaceutical composition is 0.001%-0.050%, preferably 0.006%-0.030%, more preferably 0.010%-0.030%, 0.015% is also preferred.
  • a pharmaceutically acceptable carrier refers to a substance that will not greatly reduce the curative effect of the drug under normal circumstances after being blended with the picroside compound in the drug of the present invention, including but not limited to substances that have been regulated by the State Drug Administration.
  • a pharmaceutically acceptable carrier may include one or more inactive pharmaceutical ingredients.
  • Inactive pharmaceutical ingredients in pharmaceutically acceptable carriers include stabilizers, preservatives, additives, adjuvants, sprays, other inactive pharmaceutical ingredients suitable for use with the pharmacologically effective compound, compressed air or other suitable gases .
  • the pharmaceutically acceptable vehicle is selected from the group consisting of sterile water, decarbonated water, ethanol, aqueous ethanol, aqueous sorbitol, physiological saline, and combinations thereof.
  • the inventors mixed commonly used pharmaceutically acceptable vehicles, including sterile water, decarbonated water, ethanol, ethanol aqueous solution, sorbitol aqueous solution, and physiological saline, respectively, with the picroside compound. These compounds have the best solubility and can form stable solutions or suspensions.
  • the pharmaceutically acceptable vehicle is an aqueous ethanol solution.
  • the mass percentage content of ethanol in the entire liquid pharmaceutical composition is 1.0%-5.0%, preferably 2.5-4.0%, more preferably 3.5%.
  • a pharmaceutically acceptable cosolvent refers to, in order to increase the solubility of a drug in a solvent, adding a soluble intermolecular complex, an associate or a double salt, etc. with a poorly soluble drug, and it will not be large under normal circumstances. Compounds that significantly reduce the efficacy of a drug.
  • the pharmaceutically acceptable co-solvent is selected from propylene glycol, glycerol, polyethylene glycol 200, polyethylene glycol 400 or Tween 80, preferably Tween 80.
  • the mass percentage content of the co-solvent in the whole liquid pharmaceutical composition can be in the range of 0.1-1.0%, such as 0.1-0.8% or 0.1-0.5%.
  • the co-solvent is Tween 80, and its mass percentage content in the entire liquid pharmaceutical composition is 0.1%-0.5%, preferably 0.2%-0.4%, more preferably 0.3%.
  • Pharmaceutically acceptable stabilizers are compounds that increase the stability of solutions, colloids, solids, and mixtures. It can achieve stabilization by slowing down the reaction, maintaining chemical balance, reducing surface tension, and preventing light, thermal decomposition or oxidative decomposition. Under normal circumstances, stabilizers will not greatly reduce the efficacy of the drug.
  • the pharmaceutically acceptable stabilizer is selected from phenylethanol and disodium edetate, preferably disodium edetate.
  • the mass percentage content of the stabilizer in the whole liquid pharmaceutical composition can be in the range of 0.01-0.50%, such as 0.05-0.20%.
  • the stabilizer is disodium edetate, and its mass percentage content in the entire liquid pharmaceutical composition is 0.05%-0.20%, preferably 0.05%-0.10%, more preferably 0.072%-0.088 %.
  • the "buffer” of the present invention is well known to those skilled in the art and can be safely used in pharmaceutical preparations, including but not limited to: glycine-hydrochloric acid buffer, phthalic acid-hydrochloric acid buffer, disodium hydrogen phosphate – citrate buffer, citric acid – sodium hydroxide – hydrochloric acid buffer, citric acid – sodium citrate buffer, acetic acid – sodium acetate buffer, disodium hydrogen phosphate – sodium dihydrogen phosphate buffer, disodium hydrogen phosphate – Potassium dihydrogen phosphate buffer, potassium dihydrogen phosphate-sodium hydroxide buffer, sodium barbital-hydrochloric acid buffer, Tris-hydrochloric acid buffer, boric acid-borax buffer, glycine-sodium hydroxide buffer, borax-hydrogen Sodium oxide buffer, sodium carbonate-sodium bicarbonate buffer, PBS buffer (disodium hydrogen phosphate-sodium dihydrogen phosphate-s
  • a buffer of pH 6.5 to 7.5 is preferably used.
  • the pH 6.5-7.5 buffer is selected from phosphate buffer, preferably sodium phosphate buffer, potassium phosphate buffer or a combination thereof, more preferably disodium hydrogen phosphate-diphosphate Potassium hydrogen phosphate buffer, most preferably pH 6.5, disodium hydrogen phosphate - potassium dihydrogen phosphate buffer, pH 6.9 disodium hydrogen phosphate - potassium dihydrogen phosphate buffer, pH 7.0 disodium hydrogen phosphate - potassium dihydrogen phosphate Buffer, Disodium Hydrogen Phosphate – Potassium Dihydrogen Phosphate pH 7.4 or Disodium Hydrogen Phosphate – Potassium Dihydrogen Phosphate Buffer pH 7.5.
  • buffer-effective amount refers to the concentration of the buffer solution sufficient to maintain the pH value of the liquid pharmaceutical composition at a specific pH value (preferably pH 6.5-7.5) ⁇ 0.5 (more preferably ⁇ 0.3, still more preferably ⁇ 0.2, best ⁇ 0.1) within pH units.
  • a specific pH value preferably pH 6.5-7.5
  • 0.5 more preferably ⁇ 0.3, still more preferably ⁇ 0.2, best ⁇ 0.1
  • the concentration of the buffer is related to factors such as the type of the buffer, pH value, and the specific composition of the entire pharmaceutical composition, which can be conveniently determined by those skilled in the art based on limited routine experiments.
  • the concentration of the buffer is 5mM to 500mM (preferably 5mM to 100mM, more preferably 5mM to 50mM, still more preferably 5mM to 20mM).
  • the buffer system of the liquid pharmaceutical composition is disodium hydrogen phosphate-dipotassium hydrogen phosphate, and the pH of the composition is about 7.0; wherein, based on the total weight of the liquid pharmaceutical composition, the The liquid pharmaceutical composition contains: 0.006%-0.030% picroside A, about 3.5% ethanol, 0.1%-0.5% Tween 80 and 0.072%-0.088% disodium edetate.
  • the liquid pharmaceutical composition is characterized in that, based on the total weight of the liquid pharmaceutical composition, it contains: about 0.006% picroside A, about 3.5% ethanol, about 0.1% Tween 80, about 0.072% disodium edetate and about 96.2% water; or containing about 0.015% picroside A, about 3.5% ethanol, about 0.3% Tween 80, about 0.08% edetate disodium edetate and about 95.8% water; or containing about 0.03% picroside A, about 3.5% ethanol, about 0.5% Tween 80, about 0.088% disodium edetate and about 95.2% water.
  • the liquid pharmaceutical composition of the present invention can expand tracheal smooth muscle and is suitable for the treatment of diseases such as COPD and asthma, and inhalation therapy is currently the most commonly recommended method for the treatment of asthma. Aerosol, dry powder inhaler, nebulized inhaler, inhalation solution or suspension, etc.
  • the liquid pharmaceutical composition is a solution or suspension.
  • the dosage form of the liquid pharmaceutical composition is a solution for inhalation or a suspension for inhalation.
  • the long-term stability test mainly examines indexes such as the content of ethanol and picrosides.
  • the ethanol content in the liquid pharmaceutical composition is 100%, after a period of time under certain conditions, using the same detection method, the ethanol content is changed to more than 70% (preferably more than 80%, more preferably 90% of the initial content) above); and the content of kudzu saponins is 90%-110% (preferably 95%-105%, more preferably 98%-102%) of the initial content after a period of time under certain conditions;
  • the liquid pharmaceutical composition is deemed “stable" and reliable for the treatment of asthma, COPD or other related diseases.
  • the picroside compound in the liquid pharmaceutical composition of the present invention is picroside A, and the liquid pharmaceutical composition has one or more of the following characteristics:
  • the content of butyroside A is greater than or equal to 95%, and the content of butyroside D as an impurity is less than or equal to 0.30%, As an impurity, the content of tributaponin E is less than or equal to 0.30%, and the total amount of impurities does not exceed 1.0%;
  • the content of picroside A is ⁇ 100%, and the content of picroside D as an impurity is less than or equal to 100%. 0.10%, the content of picroside E as an impurity is less than or equal to 0.10%, and the total amount of impurities does not exceed 0.50%;
  • the content of picroside A is ⁇ 100%, and the content of picroside D as an impurity is less than or equal to 100%. 0.10%, the content of picroside E as an impurity is less than or equal to 0.05%, and the total amount of impurities does not exceed 0.30%.
  • the picroside compound in the liquid pharmaceutical composition of the present invention is picroside A, and the liquid pharmaceutical composition has one or more of the following characteristics:
  • liquid pharmaceutical composition of the present invention is stored in a closed pharmaceutically acceptable packaging material.
  • pharmaceutically acceptable packaging material means that there is no serious interaction between the container closure material and the contents, does not result in a change in product activity and stability, or creates a risk of toxicity, and under normal storage/use conditions, the packaging Packaging materials that do not cause unacceptable changes in product quality or packaging due to any impact between the material composition and the product.
  • the pharmaceutically acceptable packaging materials include polymeric materials, glass bottles, aluminum foil materials, or combinations thereof.
  • the polymer materials include but are not limited to: low density polyethylene films, low density polyethylene bags, low density polyethylene bottles, high density polyethylene films, high density polyethylene bottles, poly acrylic bottle, polyethylene terephthalate bottle, polyester/aluminum/polyethylene composite film, polyester/aluminum/polyethylene composite bag, aluminum foil bag, glass bottle, or a combination thereof;
  • the aluminum foil material includes Aluminum foil bags, preferably medicinal aluminum foil bags.
  • the present invention finds that during long-term storage (such as storage at room temperature for 180 days or even longer), if the volatilized amount of ethanol in the liquid pharmaceutical composition of the present invention (that is, the ratio of the volatilized ethanol content to its initial content) can be controlled within Within the range of 30% or less, preferably 20% or less, more preferably 10% or less, a stable liquid pharmaceutical composition can be provided.
  • the pharmaceutically acceptable packaging material is a combination of a low density polyethylene bottle and an aluminum foil bag, which can more effectively prevent the volatilization of ethanol.
  • the liquid pharmaceutical composition is packaged in a low-density polyethylene bottle, preferably a low-density polyethylene bottle with a thickness of 0.5-2.0 mm, more preferably a low-density polyethylene bottle with a thickness of 0.8-1.2 mm, Most preferably a 1.0-1.2 mm low density polyethylene bottle, which is then placed in an aluminum foil bag.
  • a vacuum or a near-vacuum state is established between the low-density polyethylene bottle and the aluminum foil bag.
  • the near-vacuum state described herein generally refers to pressure ⁇ 50Kpa, preferably pressure ⁇ 20Kpa, more preferably pressure ⁇ 10Kpa, most preferably pressure ⁇ 1Kpa.
  • the method for preparing a liquid pharmaceutical composition of the present invention comprises: preparing a buffer solution (such as disodium hydrogen phosphate-potassium dihydrogen phosphate buffer solution) in which a stabilizer (such as disodium edetate) is dissolved, and mixing all the vehicle (such as an aqueous ethanol solution) ) and a co-solvent (such as Tween 80) are dissolved in the buffer, add a picroside compound (such as picroside A), and stir until the dissolution is completed; or first add a solvent (such as an aqueous ethanol solution), a stabilizer (such as Disodium edetate) and cosolvents (such as Tween 80) and partial buffers (such as disodium hydrogen phosphate-potassium dihydrogen phosphate buffer), so that the mass percentage of ethanol in the entire liquid pharmaceutical composition in the resulting mixture
  • the content is less than 100% (preferably 50%), and then add picroside compounds (such as picroside A), stir until completely dissolved
  • the compound used in the examples of the present invention is picroside A, namely 3 ⁇ -12 ⁇ -19 ⁇ -trihydroxy-ursane-13(18)-ene-28,20 ⁇ -lactone-3-O-[ ⁇ -D -Glucosyl-(1 ⁇ 3)-[ ⁇ -L-rhamnosyl-(1 ⁇ 2)]- ⁇ -L-arabinoside (hereinafter referred to as KA), which can be obtained commercially, and its preparation method is also It is well known to those skilled in the art, for example, can refer to patent CN106456657A and document "Triterpenes and triterpenoid saponins from the leaves of Ilex kudincha".
  • the preparation formula of Table 1 take by weighing the water for injection of the formula amount, add disodium hydrogen phosphate, potassium dihydrogen phosphate, disodium edetate of the formula amount, stir evenly, adjust the pH to about 7, and make a buffer solution; Weigh the ethanol and Tween 80 of the formula amount, take a part of the buffer solution obtained and add it, stir evenly, be prepared into a solution with an ethanol concentration of about 50%, add the tricloside A of the formula amount to it, and stir until it is completely dissolved. ; Finally, add the rest of the buffer and stir well. Obtain 3 recipe preparations.
  • Blowing, filling and sealing (BFS) integrated production line is used for filling, and three kinds of low density polyethylene (Low Density Polyethylene, LDPE) bottles, 2ml each.
  • LDPE Low Density Polyethylene
  • Package 1 Fill samples without any processing.
  • Packing 2 The filling sample is packed in an aluminum foil bag and sealed.
  • Packaging 3 The filling samples are packed in aluminum foil bags, and vacuumed between the low-density polyethylene bottle and the aluminum foil bag to a pressure of ⁇ 20Kpa.
  • LDPE bottles low-density polyethylene bottles
  • LDPE bottles low-density polyethylene bottles
  • the semi-permeability of LDPE bottles can cause the content of certain solvents (eg, ethanol) stored in them to drop due to volatilization. Due to the decrease of the ethanol content, the solubility of the active compound KA decreases, which eventually leads to the precipitation of KA. Therefore, the inventors need to prevent the volatilization of ethanol to enhance the stability of the formulation and prolong its storage time. To this end, the inventors investigated the stability of the ethanol content in the different sample formulations in Table 2.
  • solvents eg, ethanol
  • the ethanol content was determined according to the quantitative analysis method of high performance liquid chromatography-external standard method recorded in the general technical requirements section of the 2020 Pharmacopoeia (Part Four). Wherein, the condition parameters used in high performance liquid chromatography are as follows:
  • Chromatographic column 30m ⁇ 0.53mm, film thickness 3.0 ⁇ m, capillary column with (6%) cyanopropylphenyl-(94%) dimethylpolysiloxane as the stationary liquid as the chromatographic column;
  • Carrier gas nitrogen; split ratio: 1:1;
  • Inlet temperature 200°C;
  • FID detector temperature 220°C.
  • Constant temperature furnace temperature 85°C;
  • the composite packaging of low-density polyethylene bottle and aluminum foil bag with a certain thickness (for example, 0.6mm or more, preferably 1.0mm or more) is used, and when the two are in a vacuum or close to vacuum state, the stored samples will be in a vacuum state.
  • the ethanol content of the sample can be basically maintained stable, and there will be no precipitation of picroside A, which is beneficial to the storage of the sample.
  • the content of KA was determined by external standard method according to the general rule 0512 of high performance liquid chromatography in the Chinese Pharmacopoeia (2020 edition, four volumes).
  • the chromatographic condition parameters used in high performance liquid chromatography are as follows:
  • the content of related substances in the preparation was determined by the principal component self-control method with correction factor added in high performance liquid chromatography.
  • the ultra-high pressure liquid chromatography chromatographic conditions are as follows:
  • Mobile phase A phase is water, B phase is acetonitrile;
  • the injection volume is 5 ⁇ l
  • the gradient elution conditions are as follows:
  • ND means not detected.
  • ND means not detected.
  • ND means not detected.

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Abstract

一种稳定的含有苦丁皂苷类化合物的液体药物组合物，其包含治疗有效量的苦丁皂苷类化合物、缓冲有效量的pH 6.5-7.5的缓冲液以及药学上可接受的载体。液体药物组合物适宜存放在半渗透性容器中进行长期保存。所述半渗透性容器优选低密度聚乙烯瓶与药用铝箔袋的组合，并且所述低密度聚乙烯瓶和药用铝箔袋之间为真空或接近真空状态。

Description

一种稳定的含有苦丁皂苷类化合物的液体药物组合物 技术领域
本发明属于化学制药领域，具体涉及一种稳定的含有苦丁皂苷类化合物的液体药物组合物。
背景技术
慢性阻塞性肺疾病(chronic obstructive pulmonary disease，COPD)为具有气流阻塞特征的慢性支气管炎或肺气肿，其可进一步发展为肺心病和呼吸衰竭。COPD的特征性病理改变包括由于病菌及气体暴露导致小气道及肺部的慢性炎症、氧化应激与蛋白酶增加等机制综合作用而导致的肺实质损伤及小气道纤维化等。COPD的发病率以及致死率随着全球环境以及世界人口年龄结构的改变不断上升，全球40岁以上的人群发病率达到了9％～10％，对患者的生活及工作造成严重影响。
目前，主要采用药物治疗COPD，其能有效控制病情发展，缓解症状。COPD的治疗药物主要包括支气管扩张剂(β2肾上腺素受体激动剂、茶碱类药物和抗胆碱能药物)、糖皮质激素、抗菌药、粘液活性剂。随着COPD发病机制和病理特征的进一步认识，出现了各种治疗COPD的新药，包括抗蛋白酶制剂、磷酸二酯酶抑制剂、P38丝裂原激活蛋白抑制因子以及磷酸肌醇-3激酶抑制剂。
支气管哮喘(简称哮喘)是一种以慢性过敏性呼吸道炎症为特征的疾病，许多细胞和细胞因子参与了此过程。哮喘会引发气道高反应性，导致喘鸣、呼吸困难、咳嗽的反复发作，并且它的持续发作会导致死亡。哮喘常发生在夜间和清晨，常与环境、气流、尘螨和花粉等过敏原接触以及自身的免疫有关。目前国际上约有3亿人患有哮喘病，而我国约有二千多万人患病，并且发病率呈日益上升趋势。哮喘的发病率高，影响着人们的身心健康与生活质量，它已成为严重威胁公众健康的主要慢性疾病之一。
目前国际上已研制成功的用于治疗哮喘的药物有呼吸道平滑肌松弛药和抗炎药两大类，主要包括β受体激动剂、糖皮质激素、氨茶碱等。虽然这些药物的近期疗效都很显著，但对提高生存率和改善生活质量的效果都不明显。其主要原因是此类药物的副作用大，对心肾功能有一定的损伤。为了解决这些问题，人们不断研制新剂型，期望获得毒性更低且疗效更好的抗哮喘药物。
苦丁茶是我国南方各族人民常饮用的植物茶，也是传统的药用植物。它是来源于草 本、藤本、灌木、小乔木与高大乔木等植物叶片，具有不同程度苦甘味口感的一大类植物的统称。苦丁茶的原生植物涉及12个科，共30余种，目前种植面积较大以及使用较多的是其中两个科：一是冬青科冬青属苦丁茶，主要包括苦丁茶冬青(Ilex kudingcha C.J.Tseng)，大叶冬青(Ilex latifolia Thunb.)，枸骨(Ilex cornute Lindl.)，五棱苦丁茶(Ilex.Pentag-ona S.K.Chen.Y.X.Feng et C.F.L iang)、华中枸骨(Ilex cent rochinensis S.Y.Hu)以及霍山冬青(I.houshanensis Y.H.He)；二是木犀科苦丁茶，即贵州、四川、云南和重庆等西南地区省市主要开发的女贞属苦丁茶，该属的苦丁茶被称为“小叶苦丁茶”(Ligustrum henryi Hemsl)。
经现代科学研究证实，苦丁茶叶片中含有咖啡碱、鞣酸、蛋白质、熊果酸、芳香油、苦丁皂苷、α-香树脂、β-谷甾醇、乌苏酸以及多种维生素和微量元素，具清热解毒、消炎杀菌、止咳化痰、健胃消积、明目益思、降胆固醇、降血压、降血脂、抗疲劳、抗衰老等药用保健功能。中国专利CN106456657A公布了苦丁皂苷类化合物在治疗哮喘、COPD等肺部疾病方面的应用，这些化合物可以通过吸入方式给药，具有起效速度快、肺部接触表面积大等优点。
针对这些化合物获得稳定的化学制剂是制药工业亟待解决的问题。
发明内容
本发明提供了一种稳定的液体药物组合物，其特征在于，该液体药物组合物包含治疗有效量的苦丁皂苷类化合物、缓冲有效量的pH 6.5～7.5的缓冲液、以及药学上可接受的载体。
在一个优选的实施方案中，所述苦丁皂苷类化合物分离自冬青科冬青属植物；更优选地，所述冬青科冬青属植物选自苦丁茶冬青、大叶冬青、枸骨、五棱苦丁茶、华中枸骨或霍山冬青。
在另一个优选的实施方案中，所述的苦丁皂苷类化合物为通式(Ⅰ)所示化合物：
Figure PCTCN2021139611-appb-000001
其中，A环、B环、C环、D环或E环各自独自为完全饱和或部分饱和环；C2、C11、C12和C19位分别独自任选地被-OH取代；R 1选自糖残基；R 2a及R 2b共同形成-CO 2-；R 3a和R 3b共同形成CH 2＝，或分别独自选自-CH 3或-CH 2-OH。
在一个较佳的实施方案中，所述糖残基为单糖残基或寡糖残基。在一个较佳的实施方案中，单糖为阿拉伯糖(Ara)、葡萄糖醛酸或2-脱氧-葡萄糖醛酸(GlcA)、葡萄糖(Glc)或者鼠李糖(Rha)。在一些实施方案中，寡糖残基是二糖残基、三糖残基或四糖残基。在一些实施方案中，所述寡糖残基包括葡萄糖、阿拉伯糖、葡萄糖醛酸与鼠李糖的任意组合。
在一个较佳的实施方案中，A环、B环、C环、E环为完全饱和环，D环为部分饱和环，C12和C19位分别独自被-OH取代，R 1为单糖残基或寡糖残基，R 3a和R 3b为-CH 3。
在一个较佳的实施方案中，A环、B环、C环、E环为完全饱和环，D环为部分饱和环，C11和C19位分别独自地被-OH取代，R 3a和R 3b分别为-CH 3，R 1为单糖残基或寡糖残基。
在一个较佳的实施方案中，A环、B环、E环为完全饱和环，C环、D环为部分饱和环，C19位被-OH取代，R 3a和R 3b分别为-CH 3，R 1为单糖残基或寡糖残基。
在一个较佳的实施方案中，通式(I)所示化合物具有下式(II)、(III)或(IV)所示结构：
Figure PCTCN2021139611-appb-000002
Figure PCTCN2021139611-appb-000003
各式中，R 1为单糖残基或寡糖残基。在一个较佳的实施方案中，式(II)、(III)和(IV)中，单糖为阿拉伯糖(Ara)、葡萄糖醛酸、2-脱氧-葡萄糖醛酸(GlcA)、葡萄糖(Glc)或者鼠李糖(Rha)；寡糖残基是二糖残基、三糖残基或四糖残基；寡糖残基包括葡萄糖、阿拉伯糖与鼠李糖的任意组合。
在一个较佳的实施方案中，所述苦丁皂苷类化合物选自苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷D、苦丁皂苷E、苦丁皂苷F、苦丁皂苷I、苦丁皂苷J、苦丁茶冬青苷H、苦丁茶冬青苷I和苦丁茶冬青苷J。
在一个较佳的实施方案中，所述苦丁皂苷类化合物选自自苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷D、苦丁皂苷I、苦丁茶冬青苷I和苦丁茶冬青苷J。
在一个更佳的实施方案中，所述苦丁皂苷类化合物选自苦丁皂苷A的2种同分异构体：3β-12α-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷或3β-12β-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷。
在一个最佳的实施方案中，所述苦丁皂苷类化合物在整个液体药物组合物中的质量百分比含量为0.001％-0.050％，优选0.006％-0.030％，更优选0.010％-0.030％，最优选0.015％。
在另一个较佳的实施方案中，所述pH 6.5～7.5的缓冲液选自磷酸盐缓冲液，优选磷酸钠缓冲液、磷酸钾缓冲液或它们的组合，更优选磷酸氢二钠-磷酸二氢钾缓冲液。
在一个更佳的实施方案中，所述pH 6.5～7.5的缓冲液选自pH 6.5的磷酸氢二钠磷酸–二氢钾缓冲液、pH 6.9的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.0的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.4的磷酸氢二钠–磷酸二氢钾缓冲液或pH 7.5的磷酸氢二钠–磷酸二氢钾缓冲液。
在一个优选的实施方案中，所述药学上可接受的载体包括药学上可接受的溶媒、助溶剂、稳定剂。
在一个较佳的实施方案中，所述药学上可接受的溶媒选自水、乙醇或其组合，优选乙 醇水溶液。
在一个更佳的实施方案中，所述药学上可接受的溶媒中，乙醇在整个液体药物组合物中的质量百分比含量为1.0％-5.0％，优选2.5-4.0％，更优选3.5％。
在另一个较佳的实施方案中，所述助溶剂选自丙二醇，丙三醇，聚乙二醇200，聚乙二醇400或吐温80，优选吐温80。
在一个更佳的实施方案中，所述助溶剂在整个液体药物组合物中的质量百分比含量为0.1％-0.8％，优选0.2％-0.5％。
在一个更佳的实施方案中，所述助溶剂为吐温80，其在整个液体药物组合物中的质量百分比含量为0.1％-0.5％，优选0.2％-0.4％，更优选0.3％。
在还有一个较佳的实施方案中，所述稳定剂选自苯基乙醇和依地酸二钠，优选依地酸二钠。
在一个较佳的实施方案中，所述稳定剂在整个液体药物组合物中的质量百分比含量为0.05％-0.20％，优选0.05％-0.15％。
在一个更佳的实施方案中，所述依地酸二钠在整个液体药物组合物中的质量百分比含量为0.05％-0.20％，优选0.05％-0.10％，更优选0.072％-0.088％。
在一个优选的实施方案中，所述液体药物组合物的缓冲体系为磷酸氢二钠-磷酸氢二钾，该组合物的pH约为7.0；其中，以该液体药物组合物总重计，所述液体药物组合物含有：0.006％-0.030％的苦丁皂苷A，约3.5％的乙醇，0.1％-0.5％的吐温80和0.072％-0.088％的依地酸二钠。
在一个较佳的实施方案中，所述液体药物组合物的特征在于，以液体药物组合物总重计，其含有：约0.006％的苦丁皂苷A，约3.5％的乙醇，约0.1％的吐温80，约0.072％的依地酸二钠和约96.2％的水；或含有约0.015％的苦丁皂苷A，约3.5％的乙醇，约0.3％的吐温80，约0.08％的依地酸二钠和约95.8％的水；或含有约0.03％的苦丁皂苷A，约3.5％的乙醇，约0.5％的吐温80，约0.088％的依地酸二钠和约95.2％的水。
在一个优选的实施方案中，所述液体药物组合物为溶液或混悬液。
在一个较佳的实施方案中，所述液体药物组合物的剂型为吸入用溶液或吸入用混悬液。
在一个优选的实施方案中，所述液体药物组合物存储于密闭的药学上可接受的包装材料中。
在一个较佳的实施方案中，所述药学上可接受的包装材料包括聚合物材料、玻璃瓶、铝箔材料或其组合。
在一个较佳的实施方案中，所述聚合物材料包括低密度聚乙烯膜、低密度聚乙烯 袋、高密度聚乙烯膜、低密度聚乙烯瓶、高密度聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、聚酯/铝/聚乙烯复合膜、聚酯/铝/聚乙烯复合袋或其组合。
在一个较佳的实施方案中，所述铝箔材料包括铝箔袋，优选药用铝箔袋。
在一个更佳的实施方案中，所述药学上可接受的包装材料为低密度聚乙烯瓶与铝箔袋的组合。
在一个还要佳的实施方案中，所述低密度聚乙烯瓶与铝箔袋之间为真空或接近真空状态。
在一个最佳的实施方案中，所述低密度聚乙烯瓶厚度为0.5-2.0mm，优选0.8-1.2mm，更优选1.0-1.2mm。
在本发明所述液体药物组合物的配制过程中，因苦丁皂苷类化合物(例如苦丁皂苷A)溶解度小，需不断调整制备工艺，使得该类化合物可以充分地溶解其中。
在一个优选的实施方案中，所述液体药物组合物的制备工艺为：称取水(如纯化水或注射用水)，加入磷酸氢二钠、磷酸二氢钾，依地酸二钠，搅拌均匀，调节pH，制成缓冲液；然后称取乙醇与吐温80，加入上述溶液并搅拌均匀；最后加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完全溶解。
在另一个优选的实施方案中，所述液体药物组合物的制备工艺为：称取水(如纯化水或注射用水)，加入磷酸氢二钠、磷酸二氢钾、依地酸二钠，搅拌均匀，调节pH，制成缓冲液；同时称取乙醇与吐温80，取一部分制得的缓冲液加入其中，搅拌均匀，配制成乙醇浓度约为50％的溶液，向其中加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完全溶解；最后加入剩余部分的缓冲液，搅拌均匀。
在还有一个优选的实施方案中，所述液体药物组合物的制备工艺为：称取水(如纯化水或注射用水)，加入磷酸氢二钠、磷酸二氢钾、依地酸二钠，搅拌均匀，调节pH，制成缓冲液；同时称取乙醇与吐温80，取一部分制得的缓冲液加入其中，搅拌均匀，配制成乙醇浓度约为30％的溶液，向其中加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完全溶解；最后加入剩余部分的缓冲液，搅拌均匀。
在还有一个优选的实施方案中，所述液体药物组合物的制备工艺为：称取水(如纯化水或注射用水)，加入磷酸氢二钠、磷酸二氢钾、依地酸二钠，调节pH，搅拌均匀，制成缓冲液；同时称取乙醇与吐温80，加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完全溶解，配置成母液；最后将母液与缓冲液混合，搅拌均匀。
附图说明
图1A：长期试验(温度:25℃±2℃；湿度:40％±5％)中，样本1-3中乙醇含量(％) 的变化。
图1B：长期试验(温度:25℃±2℃；湿度:40％±5％)中，样本4-6中乙醇含量(％)的变化。
图1C：长期试验(温度:25℃±2℃；湿度:40％±5％)中，样本7-9中乙醇含量(％)的变化。
图2A：加速试验(温度:40℃±2℃；湿度:22％±5％)中，样本1-3中乙醇含量(％)的变化。
图2B：加速试验(温度:40℃±2℃；湿度:22％±5％)中，样本4-6中乙醇含量(％)的变化。
图2C：加速试验(温度:40℃±2℃；湿度:22％±5％)中，样本7-9中乙醇含量(％)的变化。
图3A：高温试验(温度:60℃±2℃)中，样本1-3中乙醇含量(％)的变化。
图3B：高温试验(温度:60℃±2℃)中，样本4-6中乙醇含量(％)的变化。
图3C：高温试验(温度:60℃±2℃)中，样本7-9中乙醇含量(％)的变化。
图4表示苦丁皂苷类化合物的结构。其中，图4A代表了苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷I、苦丁茶冬青苷I、苦丁茶冬青苷J；图4B代表了苦丁皂苷F、苦丁茶冬青苷H；图4C代表了苦丁皂苷D、苦丁皂苷E、苦丁皂苷J。
图1A-1C、2A-2C和3A-3C中，横坐标代表检测乙醇含量的时间；纵坐标代表乙醇占整个液体药物组合物的质量百分比含量。
具体实施方案
在本说明书中，如果没有特别的说明，所涉及的各组分或其优选组分可以相互组合形成新的技术方案。
在本说明书中，如果没有特别的说明，本文所提到的所有实施方案以及优选实施方案可以相互组合形成新的技术方案。
在本说明书中，如果没有特别的说明，本文所提到的所有技术特征以及优选特征可以相互组合形成新的技术方案。
如果没有特别指出，本说明书所用的术语“一种”指“至少一种”。
本文所公开的“范围”以下限和上限的形式。可以分别为一个或多个下限，和一个或多个上限。给定范围是通过选定一个下限和一个上限进行限定的。选定的下限和上限限定了特别范围的边界。所有可以这种方式进行限定的范围是包含和可组合的，即任何下限可以与任何上限组合形成一个范围。本文中，“约”限定的范围通常为实验误差的范围。例 如，若实验误差为0.1，则“约7”指7±0.1。
具体而言，本发明提供了一种稳定的液体药物组合物，其特征在于，它包含了治疗有效量的苦丁皂苷类化合物、缓冲有效量的pH 6.5～7.5的缓冲液、以及药学上可接受的载体。此处的术语“包含……”指的是该药物中还可以含有任何其它组分，这些组分可以以任何含量存在，只要以该含量存在的该组分是人体可接受的，并对于本发明药物组合物中活性成分的生物活性没有实质性的影响即可。
在一个优选的实施方案中，所述液体药物组合物包含治疗有效量的苦丁皂苷类化合物、缓冲有效量的pH 6.5～7.5的缓冲液、助溶剂、稳定剂、以及药学上可接受的溶媒。
本发明所述苦丁皂苷类化合物呈液态或固态。其可从商业途径购买，也可利用现有技术从冬青科冬青属植物中分离或化学合成方法获得。所述冬青科冬青属植物选自苦丁茶冬青(llex kudingcha C.J.Tseng)，大叶冬青(Ilex.latifolia Thunb.)，枸骨(Ilex.cornute Lindl.)，五棱苦丁茶(Ilex.pentag-ona S.K.Chen Y.X Feng et C.F.L iang)，华中枸骨(Ilex cent rochinensis S.Y.Hu)、霍山冬青(I.houshanensis Y.H.He)或其组合。
在一个优选的实施方案中，所述苦丁皂苷类化合物优选苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷D、苦丁皂苷E、苦丁皂苷F、苦丁皂苷I、苦丁皂苷J、苦丁茶冬青苷H、苦丁茶冬青苷I、苦丁茶冬青苷J(其化学结构式在CN106456657A和文献“冬青属苦丁茶中的三萜及其皂苷类化合物”中已有说明，具体见附图4A-C)；更优选3β-12α-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷或3β-12β-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷。术语“治疗有效量”是指本发明的液体药物组合物应用于治疗疾病(例如哮喘、COPD或其他相关疾病)时的浓度(剂量)。一般而言，“治疗有效量”的苦丁皂苷类化合物在整个液体药物组合物中的质量百分比含量为0.001％-0.050％，如0.006-0.030％。在一些实施方案中，“治疗有效量”的苦丁皂苷类化合物在整个液体药物组合物中的质量百分比含量为0.001％-0.050％，优选0.006％-0.030％，更优选0.010％-0.030％，还要优选0.015％。
术语“药学上可接受的载体”是指与本发明药物中的苦丁皂苷类化合物共混后，在通常情况下不会大幅度降低药物疗效的物质，包括但不限于已经被国家药品监督管理局批准使用的佐剂、赋形剂、助溶剂、甜味剂、稀释剂、防腐剂、染料/着色剂、增味剂、表面活性剂、润湿剂、分散剂、悬浮剂、稳定剂、等渗剂、溶剂或乳化剂。在一些实施方案中，一种药学上可接受的载体可以包括一种或多种非活性药用组分。药学上可接受的载体中的非活性药用组分包括稳定剂、防腐剂、添加剂、佐剂、喷雾剂、其它适宜与药效化合物合用的非活性药用成分、压缩空气或其它适宜的气体。
在一个优选的实施方案中，所述药学上可接受的溶媒选自无菌水、脱二氧化碳水、乙醇、乙醇水溶液、山梨醇水溶液、生理盐水及其组合。
发明人将常用的药学上可接受的溶媒，包括无菌水、脱二氧化碳水、乙醇、乙醇水溶液、山梨醇水溶液、生理盐水分别与苦丁皂苷类化合物混合，结果显示乙醇水溶液与上述苦丁皂苷类化合物的溶解性最佳，可以形成稳定的溶液或混悬液。
故在一个优选的实施方案中，所述药学上可接受的溶媒为乙醇水溶液。
在一个更优选的实施方案中，所述药学上可接受的溶媒中，乙醇在整个液体药物组合物中的质量百分比含量为1.0％-5.0％，优选2.5-4.0％，更优选3.5％。
药学上可接受的助溶剂是指，为了增加药物在溶剂中的溶解度，加入其中与难溶性药物形成可溶性分子间的络合物、缔合物或复盐等，并且在通常情况下不会大幅度降低药物疗效的化合物。
在一个较佳的实施方案中，所述药学上可接受的助溶剂选自丙二醇，丙三醇，聚乙二醇200，聚乙二醇400或吐温80，优选吐温80。通常，根据所选助溶剂的种类，助溶剂在整个液体药物组合物中的质量百分数含量可在0.1-1.0％的范围内，如0.1-0.8％或0.1-0.5％。
在一个较佳的实施方案中，助溶剂是吐温80，其在整个液体药物组合物中的质量百分数含量为0.1％-0.5％，优选0.2％-0.4％，更优选0.3％。
药学上可接受的稳定剂是指能增加溶液、胶体、固体、混合物的稳定性能的化合物。其可通过减慢反应，保持化学平衡，降低表面张力，防止光、热分解或氧化分解来达到稳定作用，在通常情况下稳定剂不会大幅度降低药物疗效。
在一个较佳的实施方案中，所述药学上可接受的稳定剂选自苯基乙醇和依地酸二钠，优选依地酸二钠。通常，根据所选稳定剂的种类，稳定剂在整个液体药物组合物中的质量百分数含量可在0.01-0.50％的范围内，如0.05-0.20％。
在一个较佳的实施方案中，稳定剂为依地酸二钠，其在整个液体药物组合物中的质量百分数含量为0.05％-0.20％，优选0.05％-0.10％，更优选0.072％-0.088％。
本发明所述“缓冲液”是本领域技术人员所熟知的，并可以安全用于药学制剂中，包括但不限于：甘氨酸–盐酸缓冲液，邻苯二甲酸–盐酸缓冲液，磷酸氢二钠–柠檬酸缓冲液，柠檬酸–氢氧化钠-盐酸缓冲液，柠檬酸–柠檬酸钠缓冲液，乙酸–乙酸钠缓冲液，磷酸氢二钠–磷酸二氢钠缓冲液，磷酸氢二钠–磷酸二氢钾缓冲液，磷酸二氢钾–氢氧化钠缓冲液，巴比妥钠-盐酸缓冲液，Tris–盐酸缓冲液，硼酸–硼砂缓冲液，甘氨酸–氢氧化钠缓冲液，硼砂-氢氧化钠缓冲液，碳酸钠-碳酸氢钠缓冲液，PBS缓冲液(磷酸氢二钠–磷酸二氢钠–氯化钠缓冲液)等。本领域技术人员可以通过市售获得以上缓冲液，也可根据需要配制一定pH值的缓冲液。除非另有所述，本发明中所述的“pH值”都是在25℃条 件下所测的pH值。
在本发明的液体药物组合物中，优选使用的是pH 6.5～7.5的缓冲液。在一个较佳的实施方案中，所述pH6.5～7.5的缓冲液选自磷酸盐缓冲液，优选磷酸钠缓冲液、磷酸钾缓冲液或它们的组合，更优选磷酸氢二钠-磷酸二氢钾缓冲液，最优选pH 6.5、的磷酸氢二钠–磷酸二氢钾缓冲液、pH 6.9的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.0的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.4的磷酸氢二钠–磷酸二氢钾缓冲液或pH 7.5的磷酸氢二钠–磷酸二氢钾缓冲液。
术语“缓冲有效量”是指所述缓冲液的浓度足以使所述液体药物组合物的pH值维持在一个特定pH值(优选pH6.5～7.5)±0.5(更佳±0.3，还要佳±0.2，最佳±0.1)个pH单位内。例如但不限于，pH6.5±0.2(即pH6.3～6.7)，pH6.5±0.3(即pH6.2～6.8)等。具体所述缓冲液的浓度与缓冲液的种类、pH值、整个药物组合物的具体组成等因素有关，其可由本领域技术人员根据有限次的常规实验来方便地确定。一般，所述缓冲液的浓度为5mM～500mM(优选5mM～100mM，更优选5mM～50mM，还要优选5mM～20mM)。
在一个优选的实施方案中，所述液体药物组合物的缓冲体系为磷酸氢二钠-磷酸氢二钾，该组合物的pH约为7.0；其中，以该液体药物组合物总重计，所述液体药物组合物含有：0.006％-0.030％的苦丁皂苷A，约3.5％的乙醇，0.1％-0.5％的吐温80和0.072％-0.088％的依地酸二钠。
在一个较佳的实施方案中，所述液体药物组合物的特征在于，以液体药物组合物总重计，其含有：约0.006％的苦丁皂苷A，约3.5％的乙醇，约0.1％的吐温80，约0.072％的依地酸二钠和约96.2％的水；或含有约0.015％的苦丁皂苷A，约3.5％的乙醇，约0.3％的吐温80，约0.08％的依地酸二钠和约95.8％的水；或含有约0.03％的苦丁皂苷A，约3.5％的乙醇，约0.5％的吐温80，约0.088％的依地酸二钠和约95.2％的水。
根据CN106456657A公开的内容可知，本发明所述的液体药物组合物可扩张气管平滑肌，适用于治疗COPD和哮喘等疾病，吸入治疗是目前推荐治疗哮喘的最常用方法，吸入治疗采用的剂型包括吸入气雾剂，干粉吸入剂，雾化吸入剂，吸入溶液或混悬液等。
故，在一个较佳的实施方案中，所述液体药物组合物为溶液或混悬液。
在一个更佳的实施方案中，所述液体药物组合物的剂型为吸入用溶液或吸入用混悬液。在本发明的具体实施方案中，长期稳定性试验主要是对乙醇和苦丁皂苷类化合物的含量等指标作了考察。假设所述液体药物组合物中的乙醇含量为100％，在一定条件下经过一段时间，使用同样的检测手段，其乙醇含量改变为最初含量的70％以上(优选80％以上，更优选90％以上)；并且苦丁皂苷类化合物含量在一定条件下经过一段时间，其含量改变也为最初含量的90％-110％(优选95％-105％，更优选98％-102％)时；就认定该液体药物 组合物是“稳定”的，其用于哮喘、COPD或其他相关疾病的治疗也是可靠的。
在一些优选的实施方案中，本发明的液体药物组合物中的苦丁皂苷类化合物为苦丁皂苷A，所述液体药物组合物具有以下一项或多项特征：
(1)在温度为40℃±2℃、湿度≤25％的加速试验条件下测试9个月后，苦丁皂苷A的含量≥95％，作为杂质的苦丁皂苷D的含量≤0.30％，作为杂质的苦丁皂苷E的含量≤0.30％，且杂质总和不超过1.0％；
(2)在温度为30℃±2℃、湿度为35％±5％的长期试验条件下测试9个月后，苦丁皂苷A的含量≥100％，作为杂质的苦丁皂苷D的含量≤0.10％，作为杂质的苦丁皂苷E的含量≤0.10％，且杂质总和不超过0.50％；
(3)在温度为25℃±2℃、湿度为40％±5％的长期试验条件下测试9个月后，苦丁皂苷A的含量≥100％，作为杂质的苦丁皂苷D的含量≤0.10％，作为杂质的苦丁皂苷E的含量≤0.05％，且杂质总和不超过0.30％。
在一些优选的实施方案中，本发明的液体药物组合物中的苦丁皂苷类化合物为苦丁皂苷A，所述液体药物组合物具有以下一项或多项特征：
(1)在温度为40℃±2℃、湿度≤25％的加速试验条件下测试9个月期间，苦丁皂苷A的含量为98％-106％，作为杂质的苦丁皂苷D的含量≤0.30％，作为杂质的苦丁皂苷E的含量≤0.30％，且杂质总和不超过1.0％；
(2)在温度为30℃±2℃、湿度为35％±5％的长期试验条件下测试18个月期间，苦丁皂苷A的含量为99％-106％，作为杂质的苦丁皂苷D的含量≤0.20％，作为杂质的苦丁皂苷E的含量≤0.15％，且杂质总和不超过0.60％；
(3)在温度为25℃±2℃、湿度为40％±5％的长期试验条件下测试18个月期间，苦丁皂苷A的含量为99％-106％，作为杂质的苦丁皂苷D的含量≤0.15％，作为杂质的苦丁皂苷E的含量≤0.02％，且杂质总和不超过0.40％。
在一个优选的实施方案中，本发明所述液体药物组合物储存于密闭的药学上可接受的包装材料中。
术语“药学上可接受的包装材料”指容器密封材料和内容物之间没有严重的相互影响，没有导致产品活性和稳定性发生改变，或者产生毒性风险，且在正常贮存/使用条件下，包装材料成分与产品之间产生的任何影响均不会导致产品质量或包装发生不可接受变化的包装材料。所述药学上可接受的包装材料包括聚合物材料、玻璃瓶、铝箔材料或其组合。
在一个较佳的实施方案中，所述聚合物材料包括但不限于：低密度聚乙烯膜、低密度聚乙烯袋、低密度聚乙烯瓶、高密度聚乙烯膜、高密度聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、聚酯/铝/聚乙烯复合膜、聚酯/铝/聚乙烯复合袋、铝箔袋、玻璃瓶，或者它 们的组合；所述铝箔材料包括铝箔袋，优选药用铝箔袋。
本发明发现，在长期储存(如室温下储存180天甚至更长时间)中，若能将本发明液体药物组合物中乙醇的挥发量(即挥发的乙醇含量占其最初含量的比值)控制在30％以下、优选20％以下、更优选10％以下的范围内，则能提供稳定的液体药物组合物。
因此，在一个较佳的实施方案中，所述药学上可接受的包装材料是低密度聚乙烯瓶与铝箔袋的组合，其能更有效阻止乙醇的挥发。
在一个更佳的实施方案中，所述液体药物组合物采用低密度聚乙烯瓶包装，优选厚度为0.5-2.0mm的低密度聚乙烯瓶，更优选0.8-1.2mm的低密度聚乙烯瓶，最优选1.0-1.2mm的低密度聚乙烯瓶，再将其置于铝箔袋中。需要说明的是，为了减少溶解液体药物组合物的溶媒与空气之间接触后挥发，从而导致药物析出，所述低密度聚乙烯瓶与铝箔袋之间为真空或接近真空状态。本文所述的接近真空状态通常指压力≤50Kpa，优选压力≤20Kpa，更优选压力≤10Kpa，最优选压力≤1Kpa。
本发明制备液体药物组合物的方法包括：制备稳定剂(例如依地酸二钠)溶于其中的缓冲液(例如磷酸氢二钠-磷酸二氢钾缓冲液)，将全部溶媒(例如乙醇水溶液)和助溶剂(例如吐温80)溶于该缓冲液中，加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完成溶解；或先加入溶媒(例如乙醇水溶液)、稳定剂(例如依地酸二钠)和助溶剂(例如吐温80)与部分缓冲剂(例如磷酸氢二钠-磷酸二氢钾缓冲液)，使所得混合液中乙醇在整个液体药物组合物中的质量百分比含量小于100％(优选50％)，然后加入苦丁皂苷类化合物(例如苦丁皂苷A)，搅拌至完全溶解后，再加入余下的缓冲液(例如磷酸氢二钠-磷酸二氢钾缓冲液)；或者，所述方法包括，分别制备稳定剂(例如依地酸二钠)溶于其中的缓冲液(例如磷酸氢二钠-磷酸二氢钾缓冲液)，和苦丁皂苷类化合物(例如苦丁皂苷A)溶于溶媒(例如乙醇水溶液)和助溶剂(例如吐温80)的母液，混合缓冲液和母液，从而制备得到本发明的液体药物组合物。
下面将结合实施例进一步详细地描述本发明。然而应当理解，列举这些实施例只是为了起到说明作用，而并不是用来限制本发明的范围。
本发明实施例所采用的化合物为苦丁皂苷A，即3β-12α-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷(以下简称KA)，可以通过市售获得，其制备方法也为本领域技术人员所熟知，例如可以参考专利CN106456657A和文献“Triterpenes and triterpenoid saponins from the leaves of Ilex kudincha”。
实施例1：KA制剂的制备
(一)溶液配制
按照表1的制剂配方，称取配方量的注射用水，加入配方量的磷酸氢二钠、磷酸二氢钾、依地酸二钠，搅拌均匀，调节pH至7左右，制成缓冲液；同时称取配方量的乙醇与吐温80，取一部分制得的缓冲液加入其中，搅拌均匀，配制成乙醇浓度约为50％的溶液，向其中加入配方量的苦丁皂苷A，搅拌至完全溶解；最后加入剩余部分的缓冲液，搅拌均匀。获得3种配方制剂。
表1：制剂配方
Figure PCTCN2021139611-appb-000004
(二)灌装
采用吹灌封(blowing,filling and sealing,BFS)一体生产线灌装，分部灌装3种配方的3种不同厚度(0.6mm、1.0mm、1.2mm)的低密度聚乙烯(Low Density Polyethylene,LDPE)瓶，每瓶2ml。
(三)包装
包装1：灌装样品不进行任何处理。
包装2：灌装样品使用铝箔袋包装，并密封。
包装3：灌装样品使用铝箔袋包装，并在低密度聚乙烯瓶与铝箔袋之间抽真空至压力≤20Kpa。
制得以下9种样品，具体见表2样品1-样品9：
表2样品包装
Figure PCTCN2021139611-appb-000005
实施例2：KA制剂中乙醇含量稳定性的检测
吸入用制剂现采用吹灌封方法生产的低密度聚乙烯瓶(LDPE瓶)作为直接接触药物的包装材料，相比之前采用的玻璃安瓿瓶，LDPE瓶具有粒料纯净、添加物少、后期开瓶容易等优点。然而，LDPE瓶的半渗透性会导致储存在其中的某些溶剂(例如乙醇)的含量因挥发而下降。因乙醇含量的下降，活性化合物KA的溶解度随之减小，最终导致KA析出，因此，发明人需要防止乙醇挥发来增强制剂的稳定性，延长其储存时间。为此，发明人探究了表2中不同样品制剂中乙醇含量的稳定性。
取实施例1表2中得到的9种KA制剂样品进行乙醇含量的稳定性试验，探究在长期试验、加速试验和高温试验条件下(具体见表3)制剂中乙醇含量的变化。
表3：乙醇含量稳定性试验的条件
项目 试验条件
长期试验 温度:25℃±2℃；湿度:40％±5％
加速试验 温度:40℃±2℃；湿度:22％±5％
高温试验 温度:60℃±2℃
根据《2020年版药典(四部)》通用技术要求部分所记载的高效液相色谱法的定量分析法——外标法测定乙醇含量。其中，高效液相色谱法所用条件参数如下：
(1)气相条件：
仪器：气相色谱仪配置FID检测器，自动顶空进样器；
色谱柱：30m×0.53mm，膜厚3.0μm，以(6％)氰丙基苯基-(94％)二甲基聚硅氧烷为固定液的毛细管柱为色谱柱；
柱温：起始温度40℃，保持2分钟，然后以每分钟3℃的速率升温至65℃，再以每分钟25℃的速率升温至200℃，维持10分钟；
载气：氮气；分流比：1:1；
进样口温度：200℃；
FID检测器温度：220℃。
(2)顶空进样条件：
恒温炉温度：85℃；
样品瓶恒温时间：20分钟。
所测得乙醇的含量如下表4-6以及附图1A-1C、2A-2C、3A-3C所示：
表4：长期试验中乙醇含量检测结果
Figure PCTCN2021139611-appb-000006
表5：加速试验中乙醇含量检测结果
Figure PCTCN2021139611-appb-000007
Figure PCTCN2021139611-appb-000008
表6：高温试验中乙醇含量检测结果
Figure PCTCN2021139611-appb-000009
由表4-6以及附图1A-1C、2A-2C和3A-3C所示的结果可知：在长期试验、加速试验和高温试验条件下，样品1、4、7中的乙醇含量减少明显，这说明，若对储存样品的聚乙烯瓶不做任何包装处理，其储存样品中的乙醇含量会随着时间而不断减少；并且，不论在哪种稳定性试验条件下，样品6和样品9中乙醇的含量基本维持稳定，这说明，采用一定厚度(例如，0.6mm以上，优选1.0mm以上)的低密度聚乙烯材料，并且使用铝箔袋包装，在低密度聚乙烯瓶与其之间抽真空，对于维持乙醇的含量最有利。
另一方面，观察到：在长期试验条件下：样品1、4、7均在第180开始有沉淀析出；在加速试验条件下，样品1、4和7分别在第90、120、150天开始有沉淀析出；在高温试验条件下，样品1、4、7均在第30天开始有沉淀析出，样品2在第90天开始有沉淀析出，样品5在第120天开始有沉淀析出，样品3在第150天开始有沉淀析出，样品8在第180 开始有沉淀析出；而样品6和9始终未有沉淀析出。说明，随着乙醇含量的降低，有部分样品中，KA出现析出。
综上可知，采用一定厚度(例如，0.6mm以上，优选1.0mm以上)的低密度聚乙烯瓶和铝箔袋的复合包装，并且当两者之间为真空或接近真空状态时，所储存样品中的乙醇含量能基本维持稳定，并且不会有苦丁皂苷A的析出，此有利于样品的储藏。
实施例3：KA制剂的稳定性试验
选用实施例1中所示的样品6，按表7所示条件进行稳定性试验：
表7：稳定性试验条件
项目 试验条件
加速试验 温度:40℃±2℃；湿度:≤25％
长期试验一 温度:30℃±2℃；湿度:35％±5％
长期试验二 温度:25℃±2℃；湿度:40％±5％
根据《中国药典》(2020年版，四部)通则0512高效液相色谱法中外标法测定KA的含量。其中，高效液相色谱法所用色谱条件参数如下：
色谱柱：C18(2.1*100mm，1.8μm)；
流动相：乙腈：水(26：74)；
流速：0.6mL/min；
柱温：38℃；
检测波长：225nm；
进样量：5μL；
洗脱时间：28min。
根据《中国药典》(2020年版，四部)通则0512高效液相色谱法中加校正因子的主成分自身对照法测定制剂中有关物质的含量。其中，超高压液相色谱法色谱条件如下：
色谱柱：C18(2.1*100mm，1.8μm)；
流动相：A相为水，B相为乙腈；
柱温：50℃；
检测波长：225nm；
进样量5μl；
梯度洗脱条件如下表：
Figure PCTCN2021139611-appb-000010
所测得三种不同条件下的稳定性试验结果如下表8-10所示：
表8：加速试验
Figure PCTCN2021139611-appb-000011
注：ND为未检出。
表9：长期试验一
Figure PCTCN2021139611-appb-000012
Figure PCTCN2021139611-appb-000013
注：ND为未检出。
表10：长期试验二
Figure PCTCN2021139611-appb-000014
注：ND为未检出。
由表8-10所示的结果可知：选用实施例1中所配制的KA制剂——样品6，无论在哪种试验条件下，其都符合所规定的质量标准，说明其具有良好的稳定性。
尽管本发明描述了具体的例子，但是有一点对于本领域技术人员来说是明显的，即在不脱离本发明的精神和范围的前提下可对本发明作各种变化和改动。因此，所附权利要求覆盖了所有这些在本发明范围内的变动。

Claims (18)

  1. 一种稳定的液体药物组合物，其特征在于，该液体药物组合物包含治疗有效量的苦丁皂苷类化合物、缓冲有效量的pH 6.5～7.5的缓冲液以及药学上可接受的载体。
  2. 根据权利要求1所述的液体药物组合物，其特征在于，所述苦丁皂苷类化合物为通式(Ⅰ)所示化合物：
    Figure PCTCN2021139611-appb-100001
    其中：
    A环、B环、C环、D环或E环各自独自为完全饱和或部分饱和环；
    C2、C11、C12和C19位分别独自任选地被-OH取代；
    R 1为糖残基，优选单糖残基或寡糖残基；
    R 2a及R 2b共同形成-CO 2-；
    R 3a和R 3b共同形成CH 2＝，或分别独自选自-CH 3或-CH 2-OH。
  3. 如权利要求2所述的液体药物组合物，其特征在于，
    通式(I)中，A环、B环、C环和E环为完全饱和环，D环为部分饱和环，C12和C19位分别独自被-OH取代，R 1为单糖残基或寡糖残基，R 3a和R 3b分别为-CH 3；或
    通式(I)中，A环、B环、C环和E环为完全饱和环，D环为部分饱和环，C11和C19位分别独自地被-OH取代，R 3a和R 3b分别为-CH 3，R 1为单糖残基或寡糖残基；或
    通式(I)中，A环、B环和E环为完全饱和环，C环和D环为部分饱和环，C19位被-OH取代，R 3a和R 3b分别为-CH 3，R 1为单糖残基或寡糖残基；
    优选地，通式(I)所示化合物具有下式(II)、(III)或(IV)所示结构：
    Figure PCTCN2021139611-appb-100002
    式(II)、(III)和(IV)中，R 1为单糖残基或寡糖残基；优选地，单糖为阿拉伯糖、葡萄糖醛酸、2-脱氧-葡萄糖醛酸、葡萄糖或者鼠李糖；寡糖残基是二糖残基、三糖残基或四糖残基；优选地，寡糖残基包括葡萄糖、阿拉伯糖与鼠李糖的任意组合。
  4. 根据权利要求1所述的液体药物组合物，其特征在于，所述苦丁皂苷类化合物选自苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷D、苦丁皂苷E、苦丁皂苷F、苦丁皂苷I、苦丁皂苷J、苦丁茶冬青苷H、苦丁茶冬青苷I、苦丁茶冬青苷J；优选地，所述苦丁皂苷类化合物选自苦丁皂苷A、苦丁皂苷B、苦丁皂苷C、苦丁皂苷D、苦丁皂苷I、苦丁茶冬青苷I和苦丁茶冬青苷J；更优选地，所述苦丁皂苷类化合物为3β-12α-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷和/或3β-12β-19α-三羟基-乌苏烷-13(18)-烯-28,20β-内酯-3-O-[β-D-葡萄糖基-(1→3)-[α-L-鼠李糖基-(1→2)]-α-L-阿拉伯糖苷。
  5. 根据权利要求1所述的液体药物组合物，其特征在于，所述苦丁皂苷类化合物分离自冬青科冬青属植物；
    优选地，所述冬青科冬青属植物选自苦丁茶冬青、大叶冬青、枸骨、五棱苦丁茶、华中枸骨或霍山冬青。
  6. 根据权利要求1所述的液体药物组合物，其特征在于，所述液体药物组合物为溶液或混悬液，优选为吸入用溶液或吸入用混悬液的剂型。
  7. 根据权利要求1所述的液体药物组合物，其特征在于，所述苦丁皂苷类化合物在整个液体药物组合物中的质量百分比含量为0.001％-0.050％，优选0.006-0.030％，更优选0.010％-0.030％，还要优选0.015％。
  8. 根据权利要求1所述的液体药物组合物，其特征在于，所述pH 6.5～7.5的缓冲液为磷酸盐缓冲液，优选磷酸钠缓冲液、磷酸钾缓冲液或其组合，更优选磷酸氢二钠-磷酸二氢钾缓冲液，还要优选pH 6.5的磷酸氢二钠–磷酸二氢钾缓冲液、pH 6.9的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.0的磷酸氢二钠–磷酸二氢钾缓冲液、pH 7.4的磷酸氢二钠–磷酸二氢钾缓冲液或pH 7.5的磷酸氢二钠–磷酸二氢钾缓冲液。
  9. 根据权利要求1所述的液体药物组合物，其特征在于，所述药学上可接受的载体包括药学上可接受的溶媒、助溶剂、稳定剂或其组合。
  10. 根据权利要求9所述的液体药物组合物，其特征在于，所述药学上可接受的溶媒选自水、乙醇或其组合，优选乙醇水溶液；更优选地，所述药学上可接受的溶媒中，乙醇在整个液体药物组合物中的质量百分比含量为1.0％-5.0％；还要优选2.5-4.0％，最优选3.5％。
  11. 根据权利要求9所述的液体药物组合物，其特征在于，所述助溶剂选自丙二醇、丙三醇、聚乙二醇200、聚乙二醇400或吐温80，优选吐温80；优选地，所述助溶剂在整个液体药物组合物中的质量百分比含量为0.1％-0.8％，优选0.2％-0.5％；
    更优选地，所述助溶剂为吐温80，其在整个液体药物组合物中的质量百分比含量为0.1％-0.5％，还要优选0.3％。
  12. 根据权利要求9所述的液体药物组合物，其特征在于，所述稳定剂选自苯基乙醇或依地酸二钠，优选依地酸二钠；优选地，所述稳定剂在整个液体药物组合物中的质量百分比含量为0.05％-0.20％，优选0.05％-0.15％；
    更优选地，所述稳定剂为依地酸二钠，其在整个液体药物组合物的质量百分比含量为0.05％-0.20％；还要优选0.05％-0.10％，最优选0.072％-0.088％。
  13. 一种液体药物组合物，其特征在于，所述液体药物组合物的缓冲体系为磷酸氢二钠-磷酸二氢钾，该组合物的pH约为7.0；其中，以该液体药物组合物总重计，所述液体药物组合物含有：
    0.006％-0.030％的苦丁皂苷A；
    约3.5％的乙醇；
    0.1％-0.5％的吐温80；和
    0.072％-0.088％的依地酸二钠。
  14. 根据权利要求13所述的液体药物组合物，其特征在于，以液体药物组合物总重计，所述液体药物组合物含有：约0.006％的苦丁皂苷A，约3.5％的乙醇，约0.1％的吐温80，约0.072％的依地酸二钠和约96.2％的水；或含有约0.015％的苦丁皂苷A，约3.5％的乙醇，约0.3％的吐温80，约0.08％的依地酸二钠和约95.8％的水；或者含有约0.03％的苦丁皂苷A，约3.5％的乙醇，约0.5％的吐温80，约0.088％的依地酸二钠和约95.2％的水。
  15. 一种包装的药物产品，其特征在于，所述包装的药物产品包含由药学上可接受的包装材料形成的可密封容器，所述可密封容器内含有根据权利要求1-14任一项所述的液体药物组合物。
  16. 根据权利要求15所述的包装的药物产品，其特征在于，所述药学上可接受的包装材料选自聚合物材料和铝箔材料或其组合；
    其中，所述聚合物材料选自低密度聚乙烯膜、低密度聚乙烯袋、低密度聚乙烯瓶、高密度聚乙烯膜、高密度聚乙烯瓶、聚丙烯瓶、聚对苯二甲酸乙二醇酯瓶、玻璃瓶、聚酯/铝/聚乙烯复合膜、聚酯/铝/聚乙烯复合袋或其组合；
    所述铝箔材料包括铝箔袋，优选药用铝箔袋；
    优选地，所述药学上可接受的包装材料为低密度聚乙烯瓶与铝箔袋的组合。
  17. 根据权利要求16所述的包装的药物产品，其特征在于，所述液体药物组合物密封于由所述聚合物材料和铝箔材料形成的可密封容器内，且聚合物材料与所述铝箔材料之间为真空或接近真空状态。
  18. 根据权利要求16或17所述的液体药物组合物，其特征在于，所述低密度聚乙烯瓶厚度为0.5-2.0mm，优选0.8-1.2mm，更优选1.0-1.2mm。
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