WO2020147416A1 - 萜烯类药物组合物自乳化口服制剂及制备方法、应用 - Google Patents

萜烯类药物组合物自乳化口服制剂及制备方法、应用 Download PDF

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WO2020147416A1
WO2020147416A1 PCT/CN2019/119346 CN2019119346W WO2020147416A1 WO 2020147416 A1 WO2020147416 A1 WO 2020147416A1 CN 2019119346 W CN2019119346 W CN 2019119346W WO 2020147416 A1 WO2020147416 A1 WO 2020147416A1
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self
emulsifying
oral preparation
emulsifier
oil
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PCT/CN2019/119346
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English (en)
French (fr)
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沈芳玲
赵家欣
聂红梅
韩悦
石江林
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北京远大九和药业有限公司
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Priority to CN201980087982.3A priority Critical patent/CN113329736B/zh
Publication of WO2020147416A1 publication Critical patent/WO2020147416A1/zh

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    • 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
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • 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
    • A61K31/01—Hydrocarbons
    • A61K31/015—Hydrocarbons carbocyclic
    • 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
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • 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
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
    • 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
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics

Definitions

  • the invention relates to the technical field of pharmaceutical preparations, and relates to a self-emulsifying oral preparation of a terpene pharmaceutical composition and a preparation method and application thereof.
  • the pharmaceutical composition containing eucalyptol, limonene and ⁇ -pinene can be used to relieve cough, anti-inflammatory, expectorant and promote the discharge of contrast media in patients with respiratory diseases, and as aerosol inhaler for improving rhinitis and sinusitis caused
  • a pharmaceutical composition containing eucalyptol, limonene and ⁇ -pinene is disclosed in the prior art.
  • Fat emulsion injection and a preparation method thereof are disclosed.
  • the composition by weight of the injection includes eucalyptus.
  • This injection has multiple functions such as diluting sputum, accelerating the movement of trachea and bronchial cilia, and anti-inflammatory. It does not hurt the stomach, does not contain sugar, and is suitable for people with a history of stomach diseases.
  • the self-emulsifying drug delivery system is a uniform, clear, and homogeneous solution consisting of an oil solution and a surfactant, and sometimes also includes a co-solvent. After oral administration, the system spontaneously forms an oil-in-water emulsion in the water phase of gastric juice due to gastric motility and the presence of emulsifiers. Compared with emulsions, SEDDS is a thermodynamically stable system with simple process, stable properties and easy storage. In addition, the self-emulsifying preparation is convenient to administer, and can be made into capsules, tablets, pellets and other forms of administration. The dosage is accurate and convenient to take. It is suitable for large-scale production and has great development prospects and application value.
  • eucalyptol, limonene and ⁇ -pinene are three different substances with certain differences in properties.
  • the surfactants and/or cosolvents in the prior art are used to prepare eucalyptol, limonene and ⁇ -pinene.
  • the self-emulsifying liquid of the terpene-based pharmaceutical composition such as ene is unstable and is prone to stratification, and there are a large number of unemulsified oil droplets on the surface when dispersed in water, which makes it difficult to form a uniform liquid, resulting in the self-emulsification of the pharmaceutical composition.
  • the quality of emulsified preparations is unstable, which greatly limits its large-scale application.
  • the technical problem to be solved by the present invention is to overcome the defect of unstable preparation quality in the oral preparation of the pharmaceutical composition containing eucalyptol, limonene and ⁇ -pinene prepared by the existing method, thereby providing a terpene medicine
  • the composition is a self-emulsifying oral preparation.
  • the present invention also provides a preparation method and application of the self-emulsifying oral preparation of the terpene pharmaceutical composition.
  • the present invention provides a self-emulsifying oral preparation.
  • the self-emulsifying oral preparation contains: active ingredients including eucalyptol, lemon, and ⁇ -pinene; and a pharmaceutical carrier.
  • the self-emulsifying oral preparation according to the embodiment of the present invention has high stability, narrow particle size distribution range, fast drug absorption, high oral bioavailability, and small gastrointestinal adverse reactions.
  • the self-emulsifying oral preparation may further include at least one of the following additional technical features:
  • the self-emulsifying oral preparation contains: 40 to 65 parts by weight of the eucalyptol; 25 to 45 parts by weight of the limonene; and 5 to 20 parts by weight of the ⁇ -pinene .
  • the weight ratio of the active ingredient to the drug carrier is (1-15):10.
  • the weight ratio of the active ingredient to the drug carrier is (1-6):10.
  • the weight ratio of the active ingredient to the drug carrier is (1-5):10.
  • the weight ratio of the active ingredient to the drug carrier is (5-6):10.
  • the weight ratio of the active ingredient to the drug carrier is 5.4:10.
  • the drug carrier includes: an emulsifier; an optional fat; and an optional co-emulsifier.
  • the emulsifier includes at least one selected from the group consisting of Tween, polyoxyethylene castor oil, polyoxyethylene hydrogenated castor oil, phospholipids, caprylic acid capric acid polyethylene glycol glyceride.
  • the phospholipids include soybean phospholipids.
  • the oil includes at least one selected from soybean oil, medium chain triglycerides, ethyl oleate, corn oil, and olive oil.
  • the co-emulsifier includes at least one selected from ethanol, 1,2-propylene glycol, glycerin, polyethylene glycol, and diethylene glycol monoethyl ether.
  • the drug carrier includes: 10-50 parts by weight of the fat; 40-80 parts by weight of the emulsifier; and 5-30 parts by weight of the co-emulsifier.
  • the drug carrier includes: 10 to 35 parts by weight of the fat; 50 to 70 parts by weight of the emulsifier; and 10 to 25 parts by weight of the co-emulsifier.
  • the drug carrier includes: 25 to 35 parts by weight of the medium-chain triglyceride; 50 to 65 parts by weight of the caprylic acid capric acid polyethylene glycol glyceride; and 10 to 15 parts by weight Parts of diethylene glycol monoethyl ether.
  • the drug carrier contains: 0-5 parts by weight of the fat; 0-5 parts by weight of the co-emulsifier; and 90-100 parts by weight of the emulsifier.
  • the inventor found that the amount of the hydrophilic co-emulsifier is greatly reduced within the dosage range of the above-mentioned components, and the delamination phenomenon of the concentrate is greatly reduced. At the same time, the inventor also found that the concentrate is in water.
  • the dispersed particle size is greatly reduced, which is more conducive to promoting drug absorption and reducing adverse gastrointestinal reactions; in addition, the amount of oil is greatly reduced, and only oily active ingredients provide the oily ingredients of the preparation, which ensures the self-emulsification effect On the basis, the use of the oil phase is reduced, and the amount of auxiliary materials is reduced, which is conducive to compacting into a smaller preparation form.
  • the emulsifier is composed of at least two emulsifiers.
  • the emulsifier is composed of a first emulsifier and a second emulsifier. Based on the total mass of the self-emulsifying oral preparation, the mass fraction of the first emulsifier is 20 to 80%. The mass fraction of the second emulsifier is 10 to 70%.
  • the drug carrier is composed of the emulsifier.
  • the self-emulsifying oral preparation is in the form of a hard capsule, a soft capsule or a tablet.
  • the self-emulsifying oral preparation comprises: 18.2g eucalyptol, 16.4g limonene, 1.8g ⁇ -pinene, 181.8g soybean oil, 145.4g Tween 80, 36.4g propylene glycol; or
  • the present invention proposes a method for preparing the self-emulsifying oral preparation described above.
  • the method includes: mixing the active ingredient with the pharmaceutical carrier to obtain the self-emulsifying oral preparation.
  • the above method may further include at least one of the following additional technical features:
  • it further comprises encapsulating the mixture containing the active ingredient and the drug carrier to obtain a preparation.
  • the preparation is a soft capsule, a hard capsule or a tablet.
  • mixing the active ingredient with the pharmaceutical carrier further includes: subjecting the active ingredient and optionally the oil to a first mixing process to obtain an oil phase mixture; The mixture is subjected to a second mixing treatment with the emulsifier and optionally the co-emulsifier.
  • the first mixing treatment and the second mixing treatment are independently carried out under the following conditions: a temperature of 15-30 degrees Celsius; a stirring speed: 30-50 rpm; and/or mixing time For 1 to 2 hours.
  • the medicine is used to treat or prevent respiratory diseases.
  • the respiratory system diseases include: acute sinusitis, chronic sinusitis, sinusitis surgical inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, lung fungus At least one of infection, tuberculosis, and silicosis.
  • the present invention provides a method of treating or preventing respiratory diseases.
  • the method includes administering the aforementioned self-emulsifying oral preparation to patients with respiratory diseases.
  • the self-emulsifying oral preparation has faster absorption, higher oral bioavailability, weaker gastrointestinal reaction of the patient, and better therapeutic effect.
  • the above method may further include at least one of the following additional technical features:
  • the respiratory system diseases include: acute sinusitis, chronic sinusitis, sinusitis surgical inflammation, acute and chronic bronchitis, pneumonia, bronchiectasis, lung abscess, chronic obstructive pulmonary disease, lung fungus At least one of infection, tuberculosis, and silicosis.
  • the self-emulsifying oral preparation of terpene pharmaceutical composition includes a pharmaceutical composition of eucalyptol, limonene and ⁇ -pinene in a specific proportion, oil, emulsifier, and co-emulsifier.
  • a pharmaceutical composition of eucalyptol, limonene and ⁇ -pinene in a specific proportion, oil, emulsifier, and co-emulsifier.
  • the properties of the self-emulsifying liquid medicine of the terpene medicine composition are stable and uniform, and the quality stability of the self-emulsifying oral preparation of the terpene medicine composition is improved, and the therapeutic effect of the medicine is ensured, which is suitable for large clinical areas. Promote use.
  • the self-emulsifying oral preparation of terpene pharmaceutical composition provided by the present invention further limits the types and content of emulsifiers and co-emulsifiers, improves the uniformity of the self-emulsifying liquid of the terpene pharmaceutical composition, and is beneficial to Improve the quality of self-emulsifying oral preparations.
  • the self-emulsifying oral preparation of the terpene pharmaceutical composition provided by the present invention which forms an oil-in-water micro-organism spontaneously in the aqueous phase of the gastric juice after oral administration, under the action of gastric motility and emulsifiers and co-emulsifiers Milk can effectively mask the taste of eucalyptol, limonene and ⁇ -pinene, reduce the irritation of the drug on the gastrointestinal tract, and avoid nausea, vomiting and diarrhea. It is suitable for patients with a history of gastric diseases.
  • the self-emulsifying oral preparation of the terpene pharmaceutical composition provided by the present invention enters the gastric juice through oral administration, and contacts the moisture in the gastric juice to form a drug-loaded microemulsion.
  • the pharmaceutical composition is present in these fine oil droplets, rapidly Distributed throughout the stomach, relying on the huge specific surface area of the small oil droplets greatly improves the dissolution of water-insoluble drugs, makes it easier for the drug to pass through the hydration layer of the gastrointestinal wall, increases the permeability of the drug epithelial cell, and promotes the absorption of the drug It effectively solves the problem that terpene drugs are difficult to absorb in the human body.
  • the self-emulsifying oral preparation of terpene pharmaceutical composition provided by the present invention, said pharmaceutical composition including eucalyptol, limonene and ⁇ -pinene, all of which are derived from natural products, have wide sources, simple process and low cost , The chemical structure and composition are clear, with low toxicity and high safety.
  • the preparation method of the self-emulsifying oral preparation of the terpene pharmaceutical composition provided by the present invention has a simple process, and the self-emulsifying liquid can be made into soft capsules, hard capsules, tablets, granules, dropping pills or micro Oral dosage forms such as pills have low cost, good stability and controllable quality, and are suitable for large-scale mass production.
  • Figure 1 is a pseudo ternary phase diagram of a mixed oil phase-Tween 80-PEG-400 according to an embodiment of the present invention
  • Figure 2 is a pseudo ternary phase diagram of a mixed oil phase-Tween 80-Transcutol according to an embodiment of the present invention
  • Figure 3 is a pseudo ternary phase diagram of a mixed oil phase-Labrasol-PEG400 according to an embodiment of the present invention
  • Figure 4 is a pseudo ternary phase diagram of a mixed oil phase-Labrasol-Transcutol according to an embodiment of the present invention
  • Fig. 5 is a pseudo-ternary phase diagram of oil-free-emulsifier-less eucalyptus-emulsifier 1-emulsifier 2 according to an embodiment of the present invention
  • Figure 6 is a representative particle size distribution diagram of a self-emulsifying liquid medicine according to an embodiment of the present invention.
  • first and second are only used for descriptive purposes, and cannot be understood as indicating or implying relative importance or implicitly indicating the number of indicated technical features. Thus, the features defined as “first” and “second” may explicitly or implicitly include one or more of the features. Further, in the description of the present invention, unless otherwise specified, “plurality” means two or more.
  • the present invention mainly studies the prescription composition and preparation process of the self-emulsifying preparation from three parts: the preliminary screening of the prescription, the drawing of the pseudo-ternary phase diagram and the orthogonal experiment, and determines the optimal prescription of the self-emulsifying concentrate of the pharmaceutical composition.
  • the prescription ratio of the fixed self-emulsifying concentrate is unchanged, and the self-emulsifying concentrate is prepared with different oils, emulsifiers and co-emulsifiers, and suitable oils, emulsifiers and co-emulsifiers are selected through the self-emulsification effect.
  • the prescription for designing self-emulsifying preparations is:
  • the fats selected include soybean oil, corn oil, medium-chain triglycerides, ethyl oleate; the selected emulsifiers include Tween 80, polyoxyethylene castor oil (EL-35), polyoxyethylene hydrogenated castor oil (RH -40), caprylic acid capric acid polyethylene glycol glyceride (Labrasol); the selected co-emulsifiers include propylene glycol, glycerin, diethylene glycol monoethyl ether (Transcutol), PEG-400.
  • the fixed oil is soybean oil, and the results of screening the types of emulsifiers and co-emulsifiers are shown in Table 1.
  • the fixed emulsifier is Tween 80
  • the co-emulsifier is propylene glycol
  • Table 2 results of screening the types of fats are shown in Table 2.
  • soybean oil is selected as the oil, Tween 80, caprylic acid capric acid polyethylene glycol glyceride with better self-emulsifying effect as the emulsifier, and PEG-400 and diethylene glycol monoethyl ether as the auxiliary The emulsifier undergoes subsequent tests.
  • the inventor unexpectedly discovered in experiments that if the amount of oil and co-emulsifier is minimized, and the compound emulsifier is used, the emulsification rate will be greatly increased and the particle size of the emulsion droplets will be greatly reduced.
  • Table 3 shows the data on the appearance, emulsification rate, and droplet size of the concentrate after the inventor tried to reduce oil or co-emulsifier during the experiment.
  • the inventor draws a pseudo ternary phase diagram with no fat-no aid emulsifier-eucalyptus citrinum oil-emulsifier 1-emulsifier 2 to determine the effective self-emulsification area of each prescription, and the result is shown in FIG. 5.
  • the ratio of eucalyptus citrinine oil is 10-60%
  • the emulsifier 1 of the auxiliary material is 20-80%
  • the emulsifier 2 is 10-70%. Therefore, the ratio of drug to carrier is 1:9-6:4, that is, drug: carrier (1.1-15):10.
  • the pharmaceutical composition and soybean oil were used as the oil phase, Tween 80 was used as the emulsifier, and PEG-400 was used as the co-emulsifier.
  • the factor level table for designing the orthogonal test is shown in Table 4.
  • the optimal formula is 0.30g oil phase, 0.50g Tween 80, and 0.15g PEG-400.
  • the prepared self-emulsifying concentrate has a dispersion rate of 20-40s in water and a particle size of the emulsion droplets of 150-180nm.
  • the eucalyptol, limonene and ⁇ -pinene can be prepared by the following method: Eucalyptus oil (crude oil) obtained from Eucalyptus globulus, a plant of the Myrtaceae family, is rectified to obtain Eucalyptus The content of olein is 80-85%; the lemon oil (crude oil) obtained by steam distillation after squeezing the lemon peel of the orange citrus plant in the Rutaceae family is rectified to obtain limonene with a content of more than 93%; The oleoresin exuded from the Pinus massoniana is refined by steam distillation to obtain ⁇ -pinene with a content of more than 90%.
  • Eucalyptus oil obtained from Eucalyptus globulus, a plant of the Myrtaceae family, is rectified to obtain Eucalyptus
  • the content of olein is 80-85%
  • the prescription for self-emulsifying liquid is:
  • the preparation method is:
  • step (2) The self-emulsifying medicinal solution obtained in step (2) and the capsule skin obtained in step (3) are compressed in a soft capsule machine in a conventional manner, and set in a setting machine to form a self-emulsifying soft capsule of a terpene pharmaceutical composition.
  • the prescription for self-emulsifying liquid is:
  • the preparation method is:
  • step (2) The self-emulsifying medicinal solution obtained in step (2) and the capsule skin obtained in step (3) are compressed in a soft capsule machine in a conventional manner, and set in a setting machine to form a self-emulsifying soft capsule of a terpene pharmaceutical composition.
  • the prescription for self-emulsifying liquid is:
  • the preparation method is the same as in Example 2.
  • the prescription for self-emulsifying liquid is:
  • the preparation method is the same as in Example 2.
  • the prescription for self-emulsifying liquid is:
  • the preparation method is:
  • step (3) The self-emulsifying liquid obtained in step (2) is dropped into the micronized silica gel under stirring, magnesium stearate is added, and the mixture is divided into hard capsules to prepare the terpene-based pharmaceutical composition self-emulsifying hard capsules .
  • the prescription for self-emulsifying liquid is:
  • the preparation method is:
  • step (3) The self-emulsifying liquid obtained in step (2) is dripped into micronized silica gel under stirring conditions, and auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate, etc. are added, and terpenes are prepared by conventional direct compression method.
  • Self-emulsifying tablet of pharmaceutical composition is dripped into micronized silica gel under stirring conditions, and auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate, etc. are added, and terpenes are prepared by conventional direct compression method.
  • Self-emulsifying tablet of pharmaceutical composition is dripped into micronized silica gel under stirring conditions, and auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate, etc. are added, and terpenes are prepared by conventional direct compression method.
  • Self-emulsifying tablet of pharmaceutical composition is dripped into micronized silica gel under stirring conditions, and auxiliary materials such
  • the prescription for self-emulsifying liquid is:
  • step (2) The self-emulsifying concentrate obtained in step (2) and the capsule skin obtained in step (3) are made into soft capsules in a conventional manner.
  • the prescription for self-emulsifying liquid is:
  • step (2) The self-emulsifying concentrate obtained in step (2) and the capsule skin obtained in step (3) are made into soft capsules in a conventional manner.
  • the preparation process is the same as in Example 6.
  • the preparation process is the same as in Example 6.
  • step (3) The self-emulsifying concentrate obtained in step (2) is dropped into an appropriate amount of micronized silica gel under stirring, magnesium stearate is added, and the mixture is divided into hard capsules.
  • step (3) The self-emulsifying concentrate obtained in step (2) is dropped into an appropriate amount of micronized silica gel under stirring, and auxiliary materials such as microcrystalline cellulose, spray-dried lactose, magnesium stearate, etc. are added, and the self-emulsified tablet is prepared by the conventional direct compression method Agent.
  • step (2) The self-emulsifying concentrate obtained in step (2) and the capsule skin obtained in step (3) are made into soft capsules in a conventional manner.
  • step (2) The self-emulsifying concentrate obtained in step (2) and the capsule skin obtained in step (3) are made into soft capsules in a conventional manner.
  • the self-emulsifying concentrates of Examples 13 and 14 remove the hydrophilic co-emulsifier, reduce the delamination of the concentrate, facilitate the mixing of a large amount of drugs, and improve the uniformity of the drug content.
  • the prescription for designing a self-emulsifying liquid of terpene-based pharmaceutical composition is:
  • the published preparation method is:
  • step (3) The self-emulsifying medicinal solution obtained in step (3) and the capsule skin obtained in step (4) are compressed in a soft capsule machine in a conventional manner, and set in a setting machine to form a self-emulsifying soft capsule.
  • Comparative example 2 adopts the prescription of the existing self-emulsifying preparation and the preparation method of the present invention to prepare the self-emulsifying soft capsule of terpene pharmaceutical composition
  • the prescription for designing a self-emulsifying liquid of terpene-based pharmaceutical composition is:
  • the preparation method of the present invention is:
  • step (2) The self-emulsifying medicinal solution obtained in step (2) and the capsule skin obtained in step (3) are compressed in a soft capsule machine in a conventional manner, and the shape is set in the setting machine to form a self-emulsifying soft capsule.
  • the components are mixed thoroughly in different proportions, and allowed to stand for 2 hours. Visually observe whether a uniform, transparent and non-layered solution is formed. Take out 0.5 mL of the prescription that can form a uniform and transparent solution, and add it dropwise to 50 mL of purified water under stirring at 37° C. and 50 rpm to observe whether a clear and transparent emulsion is formed.
  • the self-emulsifying liquids in Comparative Examples 1 and 2 were separated after standing, and the self-emulsifying liquids of Comparative Example 1 were more serious.
  • the self-emulsifying liquids of Examples 1-11 of the present invention There is no stratification phenomenon after standing; 2.
  • the self-emulsifying liquid in Comparative Examples 1 and 2 cannot be quickly dispersed into a uniform emulsion in water. After dispersion, a large number of oil droplets float on the water surface, failing to achieve effective self-emulsification.
  • the self-emulsifying liquids of Examples 1-11 of the present invention can be quickly and uniformly dispersed in water, and the formed emulsion droplets have small particle size and uniform particle size distribution.
  • Example 1 Take 0.5 mL of the self-emulsifying liquid of Examples 1-11 and disperse it in 50 mL 37°C purified water. Take 2 mL of the dispersion to measure the particle size of the emulsion with a laser particle size analyzer. The results are shown in Table 6.
  • the value of the self-emulsified liquid in Example 1 See Figure 6 for a representative particle size distribution.
  • the self-emulsifying concentrate prepared by the formula of Example 1 can be quickly dispersed in water into a nano-sized emulsion with uniform particle size, the dispersion rate is 20-40s, the average particle size is (161.4 ⁇ 17.6) nm, and the polydispersity coefficient is 0.278 ⁇ 0.101.
  • Example 4 13.2 177.6 0.195
  • Example 5 29.6 164.6 0.274
  • Example 6 21.5 170.1 0.298
  • Example 7 18.9 160.6 0.230
  • Example 8 30.6 175.7 0.309
  • Example 9 44.9 161.7 0.265
  • Example 10 49.6 189.2 0.202
  • Example 11 56.5 157.8 0.257
  • Example 12 56.5 157.8 0.257
  • Example 13 64.3 106.25 0.271
  • Example 14 53.1 42.28 0.168
  • the self-emulsifying liquids of Examples 1-14 of the present invention can be quickly dispersed in water into nano-scale emulsions with uniform particle size, with a dispersion rate of 10-65s and an average particle size of 40-190nm ,
  • the polydispersity coefficient is 0.150 ⁇ 0.32.
  • the dispersed particle size of the self-emulsifying liquids of Examples 13 and 14 in water was significantly reduced.
  • the average particle size of Examples 1-12 was 140-190 nm, while the particle size of Example 13 was only 100-110 nm.
  • the diameter is 40-50nm.
  • Examples 13 and 14 have a significantly smaller particle size, which is beneficial to promote drug absorption and reduce gastrointestinal adverse reactions, and no oil phase is used, which effectively reduces the amount of excipients, saves costs, and can be suppressed It is made into a smaller soft capsule for easy swallowing.
  • the self-emulsifying medicinal liquid prepared by the invention can quickly disperse the eucalyptol, limonene and alpha-pinene medicinal composition into a nanoemulsion with a smaller particle size, which is beneficial for accelerating drug absorption and reducing gastrointestinal adverse reactions.

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Abstract

一种萜烯类药物组合物自乳化口服制剂及制备方法、应用，所述自乳化口服制剂包括特定比例的桉油精、柠檬烯和α-蒎烯的药物组合物及乳化剂、任选的油脂和助乳化剂，各成分之间相互配合，使制得的萜烯类药物组合物自乳化药液性质稳定、均一，提高了萜烯类药物组合物自乳化口服制剂的质量稳定性，确保了药物的治疗效果，适合临床大面积推广使用。

Description

萜烯类药物组合物自乳化口服制剂及制备方法、应用
优先权信息
本申请请求2019年1月15日向中国国家知识产权局提交的、专利申请号为201910036486.7的专利申请的优先权和权益，并且通过参照将其全文并入此处。
技术领域
本发明涉及药物制剂技术领域，涉及一种萜烯类药物组合物自乳化口服制剂及制备方法、应用。
背景技术
含桉油精、柠檬烯和α-蒎烯的药物组合物可以用于呼吸道疾病患者的止咳、消炎、祛痰和促进造影剂的排出，以及作为雾化吸入剂用于改善由鼻炎、鼻窦炎引起的粘液纤毛清除系统功能损害，如现有技术中公开了一种含桉油精、柠檬烯和α-蒎烯的药物组合物脂肪乳注射液及其制备方法，该注射液的重量％组成包括桉油精0.0128～0.032％、柠檬烯0.0084～0.0210％、α-蒎烯0.0028～0.0070％、注射用大豆油10～30％、注射用蛋黄卵磷脂1.0～1.5％或注射用大豆磷脂0.8～1.5％、注射用甘油2.0～2.5％、注射用水加至100mL，该注射剂具有稀释痰液、促进气管及支气管纤毛加速运动和抗炎等多种作用，并且不伤胃，不含糖，适合有胃病史和糖尿病史者使用，但作为注射剂，由于市场价格较贵，一般只适于临床急救用药，不适于恢复期的巩固治疗用药，病人在家中使用也很不方便。因此，有必要开发一种含桉油精、柠檬烯和α-蒎烯的药物组合物的口服制剂。
自乳化药物传递系统(self-emulsifying drug delivery system，简称SEDDS)是一种均一、澄清、各相同性的溶液，由油溶液和表面活性剂组成，有时也包括助溶剂。该体系口服后在胃液的水相中，由于胃蠕动和乳化剂的存在，自发形成水包油型乳剂。与乳剂相比，SEDDS属于热力学稳定体系，工艺简单，性质稳定，便于贮存。此外，自乳化制剂给药方便，可以做成胶囊、片剂、微丸等多种给药形式，剂量准确且服用方便，适合大规模生产，具有极大的发展前景和应用价值。
然而，桉油精、柠檬烯和α-蒎烯为性质具有一定差异的三种不同物质，用现有技术中的表面活性剂和/或助溶剂制备得到的含桉油精、柠檬烯和α-蒎烯等萜烯类药物组合物的自乳化药液不稳定，易产生分层现象，且分散在水中时表面存在大量未乳化的药 物油滴，难以形成均一药液，导致该药物组合物的自乳化制剂质量不稳定，极大限制了其大面积推广应用。
发明内容
因此，本发明要解决的技术问题在于克服现有的方法制备含桉油精、柠檬烯和α-蒎烯的药物组合物的口服制剂存在制剂质量不稳定的缺陷，从而提供一种萜烯类药物组合物自乳化口服制剂。同时，本发明还提供了所述萜烯类药物组合物自乳化口服制剂的制备方法及其应用。
为解决上述技术问题，本发明提供了一种自乳化口服制剂。根据本发明的实施例，所述自乳化口服制剂含有：活性成分，所述活性成分包括桉油精、柠檬和α-蒎烯；以及药物载体。根据本发明实施例的自乳化口服制剂稳定性高、粒径分布范围窄、药物吸收快、口服生物利用度高、胃肠道不良反应小。
根据本发明的实施例，上述自乳化口服制剂还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述自乳化口服制剂含有：40～65重量份的所述桉油精；25～45重量份的所述柠檬烯；以及5～20重量份的所述α-蒎烯。
根据本发明的实施例，所述活性成分与所述药物载体的重量比为(1～15):10。
根据本发明的实施例，所述活性成分与所述药物载体的重量比为(1～6):10。
根据本发明的实施例，所述活性成分与所述药物载体的重量比为(1～5):10。
根据本发明的实施例，所述活性成分与所述药物载体的重量比为(5～6):10。发明人发现，所述活性成分与所述药物载体的重量比在(5～6):10范围内，自乳化口服制剂的稳定性进一步提高、在水中的分散粒径进一步降低，药物吸收更好、胃肠道反应进一步降低。
根据本发明的实施例，所述活性成分与所述药物载体的重量比为5.4:10。
根据本发明的实施例，所述药物载体包括：乳化剂；可选的油脂；以及可选的助乳化剂。
根据本发明的实施例，所述乳化剂包括选自吐温、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、磷脂、辛酸癸酸聚乙二醇甘油酯的至少之一。
根据本发明的实施例，所述磷脂包括大豆磷脂。
根据本发明的实施例，所述油脂包括选自大豆油、中链甘油三酯、油酸乙酯、玉米油、橄榄油的至少之一。
根据本发明的实施例，所述助乳化剂包括选自乙醇、1,2-丙二醇、甘油、聚乙二醇、二乙二醇单乙基醚的至少之一。
根据本发明的实施例，所述药物载体包括：10～50重量份的所述油脂；40～80重量份的所述乳化剂；以及5～30重量份的所述助乳化剂。
根据本发明的实施例，所述药物载体包括：10～35重量份的所述油脂；50～70的所述乳化剂；以及10～25重量份的所述助乳化剂。
根据本发明的实施例，所述药物载体包括：25～35重量份的所述中链甘油三酯；50～65重量份的所述辛酸癸酸聚乙二醇甘油酯；以及10～15重量份的二乙二醇单乙基醚。
根据本发明的实施例，所述药物载体含有：0～5重量份的所述油脂；0～5重量份的所述助乳化剂；90～100重量份的所述乳化剂。发明人发现，所述药物载体在上述组分的用量范围内，亲水性的助乳化剂用量大幅降低，大大较少了浓缩液的分层现象，同时，发明人也发现，浓缩液在水中的分散粒径大幅降低，更有利于促进药物吸收、降低胃肠道的不良反应；再者，油脂的用量大幅降低，而仅由油性的活性成分提供制剂的油性成分，在保证自乳化效果的基础上减少了油相的使用，降低了辅料的用量，有利于压制成更小的制剂形式。
根据本发明的实施例，所述乳化剂由至少两种乳化剂组成。
根据本发明的实施例，所述乳化剂由第一乳化剂和第二乳化剂组成，基于自乳化口服制剂的总质量，所述第一乳化剂的质量分数为20～80％，所述第二乳化剂的质量分数为10～70％。
根据本发明的实施例，所述药物载体由所述乳化剂构成。
根据本发明的实施例，所述自乳化口服制剂呈硬胶囊、软胶囊或片剂的形式。
根据本发明的实施例，所述自乳化口服制剂包括：18.2g桉油精，16.4g柠檬烯，1.8gα-蒎烯，181.8g大豆油，145.4g吐温80，36.4g丙二醇；或
73.3g桉油精，33.3g柠檬烯，26.6gα-蒎烯，26.7g中链甘油三酯，213.4g辛酸癸酸聚乙二醇甘油酯，26.7g二乙二醇单乙基醚；或
14.6g桉油精，16.4g柠檬烯，5.4gα-蒎烯，90.9g中链甘油三酯，236.6g辛酸癸酸聚乙二醇甘油酯，36.4g二乙二醇单乙基醚；或
86.6g桉油精，40.0g柠檬烯，6.6gα-蒎烯，93.4g中链甘油三酯，133.4g辛酸癸酸聚乙二醇甘油酯，40g二乙二醇单乙基醚；或
53.3g桉油精，53.3g柠檬烯，26.6gα-蒎烯，26.7g油酸乙酯，160.1g聚氧乙烯蓖麻油，80.0g二乙二醇单乙基醚；或
78.0g桉油精，36.0g柠檬烯，6.0gα-蒎烯，126g玉米油，140g聚氧乙烯氢化蓖麻油，14.0g丙二醇；或
42.7g桉油精，28.0g柠檬烯，9.3gα-蒎烯，80g大豆油，180g吐温80，60g PEG-400；或
69.3g桉油精，45.5g柠檬烯，15.2gα-蒎烯，40g玉米油，170g聚氧乙烯蓖麻油，60g丙二醇；或
70.0g桉油精，45.5g柠檬烯，14.5gα-蒎烯，40g大豆油，180g聚氧乙烯氢化蓖麻油，50g丙二醇；或
70.0g桉油精，45.5g柠檬烯，14.5gα-蒎烯，50g油酸乙酯，160g辛酸癸酸聚乙二醇甘油酯，60g二乙二醇单乙基醚；或
69.3g桉油精，45.5g柠檬烯，15.2gα-蒎烯，40g大豆油，170g吐温80，60g丙二醇；或
69.3g桉油精，45.5g柠檬烯，15.2gα-蒎烯，40g大豆油，170g吐温80，60g丙二醇；或
75g桉油精，50g柠檬烯，16gα-蒎烯，79g吐温80，180g辛酸癸酸聚乙二醇甘油酯；或
75g桉油精，50g柠檬烯，16gα-蒎烯，165g辛酸癸酸聚乙二醇甘油酯，94g聚氧乙烯蓖麻油。
在本发明的第二方面，本发明提出了一种制备前面所述的自乳化口服制剂的方法。根据本发明的实施例，所述方法包括：将所述活性成分与所述药物载体混合以便获得所述自乳化口服制剂。
根据本发明的实施例，上述方法还可以进一步包括如下附加技术特征的至少之一：
根据本发明的实施例，进一步包括将含有所述活性成分与所述药物载体的混合物进行封装以便获得制剂。
根据本发明的实施例，所述制剂为软胶囊、硬胶囊或片剂。
根据本发明的实施例，将所述活性成分与所述药物载体混合进一步包括：将所述活性成分以及可选的所述油脂进行第一混合处理，以便获得油相混合物；将所述油相混合物与所述乳化剂以及可选的所述助乳化剂进行第二混合处理。
根据本发明的实施例，所述第一混合处理和所述第二混合处理分别独立地在下列条 件下进行的：温度为15～30摄氏度；搅拌速度为：30～50rpm；和/或混合时间为1～2小时。
根据本发明的实施例，所述药物用于治疗或者预防呼吸系统疾病。
根据本发明的实施例，所述呼吸系统疾病包括：急性鼻窦炎、慢性鼻窦炎、鼻窦炎手术炎症、急慢性支气管炎、肺炎、支气管扩张、肺脓肿、慢性阻塞性肺部疾病、肺部真菌感染、肺结核、矽肺中的至少一种。
在本发明的第三方面，本发明提出了一种治疗或者预防呼吸系统疾病的方法。根据本发明的实施例，所述方法包括为呼吸系统疾病患者给药前面所述的自乳化口服制剂。根据本发明实施例的方法，自乳化口服制剂的吸收更快、口服生物利用度更高、患者的胃肠道反应更弱，治疗效果更优。
根据本发明的实施例，上述方法还可以进一步包括如下附加技术特征至少之一：
根据本发明的实施例，所述呼吸系统疾病包括：急性鼻窦炎、慢性鼻窦炎、鼻窦炎手术炎症、急慢性支气管炎、肺炎、支气管扩张、肺脓肿、慢性阻塞性肺部疾病、肺部真菌感染、肺结核、矽肺中的至少一种。
本发明的技术方案，具有如下优点：
1、本发明提供的萜烯类药物组合物自乳化口服制剂，其包括特定比例的桉油精、柠檬烯和α-蒎烯的药物组合物及油脂、乳化剂、助乳化剂，各成分之间相互配合，使制得的萜烯类药物组合物自乳化药液性质稳定、均一，提高了萜烯类药物组合物自乳化口服制剂的质量稳定性，确保了药物的治疗效果，适合临床大面积推广使用。
2、本发明提供的萜烯类药物组合物自乳化口服制剂，进一步限定乳化剂、助乳化剂的种类及含量，提高了所述萜烯类药物组合物自乳化药液的均一性，有利于提高自乳化口服制剂的质量。
3、本发明提供的萜烯类药物组合物自乳化口服制剂，所述口服制剂口服后在胃液的水相中，在胃蠕动及乳化剂和助乳化剂的作用下自发形成水包油型微乳，有效掩盖桉油精、柠檬烯和α-蒎烯的味道，减少药物对胃肠道的刺激作用，避免恶心、呕吐和腹泻等不良反应的发生，适合有胃病史的患者使用。
4、本发明提供的萜烯类药物组合物自乳化口服制剂，通过口服进入胃液中，与胃液中的水分接触形成载药微乳，所述药物组合物存在于这些细小的油滴中，快速分布于整个胃部，依靠细小油滴的巨大比表面积大大提高了水不溶性药物的溶出，使药物更加容易通过胃肠壁的水化层，增加药物上皮细胞的通透性，促进了药物的吸收，有效解决了萜烯类药物在人体内难以吸收的难题。
5、本发明提供的萜烯类药物组合物自乳化口服制剂，所述药物组合物包括桉油精、柠檬烯和α-蒎烯，三者均来源于天然产物，来源广泛，工艺简单，成本低，化学结构和组成明确，毒性小，安全性高。
6、本发明提供的萜烯类药物组合物自乳化口服制剂的制备方法，所述方法工艺简单，可将自乳化药液制成软胶囊、硬胶囊、片剂、颗粒剂、滴丸或微丸等口服剂型，成本低廉，稳定性好，质量可控，适合大规模批量化生产。
本发明的附加方面和优点将在下面的描述中部分给出，部分将从下面的描述中变得明显，或通过本发明的实践了解到。
附图说明
本发明的上述和/或附加的方面和优点从结合下面附图对实施例的描述中将变得明显和容易理解，其中：
图1为根据本发明实施例的混合油相-吐温80-PEG-400的伪三元相图；
图2为根据本发明实施例的混合油相-吐温80-Transcutol的伪三元相图；
图3为根据本发明实施例的混合油相-Labrasol-PEG400的伪三元相图；
图4为根据本发明实施例的混合油相-Labrasol-Transcutol的伪三元相图；
图5为根据本发明实施例的无油脂-无助乳化剂-桉柠蒎油-乳化剂1-乳化剂2的伪三元相图；
图6为根据本发明实施例的自乳化药液的代表性粒径分布图。
发明详细描述
下面详细描述本发明的实施例，所述实施例的示例在附图中示出，其中自始至终相同或类似的标号表示相同或类似的元件或具有相同或类似功能的元件。下面通过参考附图描述的实施例是示例性的，仅用于解释本发明，而不能理解为对本发明的限制。
需要说明的是，术语“第一”、“第二”仅用于描述目的，而不能理解为指示或暗示相对重要性或者隐含指明所指示的技术特征的数量。由此，限定有“第一”、“第二”的特征可以明示或者隐含地包括一个或者更多个该特征。进一步地，在本发明的描述中，除非另有说明，“多个”的含义是两个或两个以上。
本发明主要从处方初步筛选、伪三元相图的绘制和正交试验三部分，对自乳化制剂的处方组成及制备工艺进行研究，确定药物组合物自乳化浓缩液的最优处方。
(1)处方初步筛选
固定自乳化浓缩液的处方比例不变，用不同油脂、乳化剂和助乳化剂分别制备自乳化浓缩液，通过自乳化效果筛选适宜的油脂、乳化剂和助乳化剂。
设计自乳化制剂的处方为：
Figure PCTCN2019119346-appb-000001
其中筛选的油脂包括大豆油、玉米油、中链甘油三酯、油酸乙酯；筛选的乳化剂包括吐温80、聚氧乙烯蓖麻油(EL-35)、聚氧乙烯氢化蓖麻油(RH-40)、辛酸癸酸聚乙二醇甘油酯(Labrasol)；筛选的助乳化剂包括丙二醇、甘油、二乙二醇单乙基醚(Transcutol)、PEG-400。
固定油脂为大豆油，筛选乳化剂和助乳化剂种类的结果见表1。
表1:乳化剂、助乳化剂的初步筛选结果
Figure PCTCN2019119346-appb-000002
固定乳化剂为吐温80，助乳化剂为丙二醇，筛选油脂种类的结果见表2。
表2:油脂种类筛选结果
Figure PCTCN2019119346-appb-000003
Figure PCTCN2019119346-appb-000004
综合以上试验结果，选择常用的大豆油作为油脂，自乳化效果较好的吐温80、辛酸癸酸聚乙二醇甘油酯作为乳化剂，PEG-400、二乙二醇单乙基醚作为助乳化剂进行后续试验。
另外，发明人在实验中意外的发现，如果尽量减少油脂和助乳化剂的用量，而采用复合乳化剂，乳化速率会大幅提高、乳滴粒径大幅降低。
表3为发明人在实验过程中尝试减少油脂或助乳化剂后的浓缩液外观、乳化速率和乳滴粒径数据。
表3：
Figure PCTCN2019119346-appb-000005
(2)伪三元相图的绘制
绘制各组合油相-乳化剂-助乳化剂的伪三元相图，确定各处方组成的有效自乳化区域。 结果如图1～4所示(图中标记出有效自乳化区域)，以油相-吐温80-PEG-400的伪三元相图为例(附图1)，可形成有效自乳化区域的质量比为油相0.1～0.4，吐温80 0.4～0.9，助PEG-4000.1～0.6。选取油相含量较高的处方比例进行后续试验。
另外，发明人以无油脂-无助乳化剂-桉柠蒎油-乳化剂1-乳化剂2绘制伪三元相图，确定各处方组成的有效自乳化区域，结果如图5所示。由图可见，可形成有效自乳化区域的范围中，桉柠蒎油的比例为10～60％，辅料乳化剂1为20～80％，乳化剂2为10～70％。因此药物与载体的比例为1:9～6:4，即药物：载体(1.1～15):10。
(3)正交试验
设计适宜的因素水平表及正交试验表，通过自乳化速率和乳滴粒径，筛选自乳化浓缩液最优处方。
以药物组合物与大豆油作为油相，吐温80为乳化剂，PEG-400为助乳化剂，设计正交试验的因素水平表见表4。
表4.正交试验因素水平表
Figure PCTCN2019119346-appb-000006
试验结果见表5。
表5.正交试验结果
Figure PCTCN2019119346-appb-000007
Figure PCTCN2019119346-appb-000008
通过直观分析法，得出最优处方为油相0.30g，吐温80 0.50g，PEG-400 0.15g。重复三次该处方，制备的自乳化浓缩液在水中的分散速率为20～40s，乳滴粒径为150～180nm。
提供下述实施例是为了更好地进一步理解本发明，并不局限于所述最佳实施方式，不对本发明的内容和保护范围构成限制，任何人在本发明的启示下或是将本发明与其他现有技术的特征进行组合而得出的任何与本发明相同或相近似的产品，均落在本发明的保护范围之内。
实施例中未注明具体实验步骤或条件者，按照本领域内的文献所描述的常规实验步骤的操作或条件即可进行。所用试剂或仪器未注明生产厂商者，均为可以通过市购获得的常规试剂产品。
以下实施例中，所述桉油精、柠檬烯和α-蒎烯可采用如下方法制备：将从桃金娘科桉属植物蓝桉中制得的桉树油(粗品油)经过精馏即得桉油精，含量为80～85％；将从芸香科桔属植物桔的柠檬皮压榨后用蒸汽蒸馏制得的柠檬油(粗品油)经过精馏即得柠檬烯，含量为93％以上；将松科松属植物马尾松渗出的油树脂用蒸汽蒸馏精制后即得α-蒎烯，含量为90％以上。
实施例1萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000009
制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和大豆油，15℃以50rpm的转速搅拌1小时，混匀，得到油相；
(2)取处方量的吐温80、丙二醇加入油相中，15℃以50rpm的转速搅拌1小时，混匀，形成均一自乳化药液；
(3)按重量比1：0.5：1.1称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化药液和步骤(3)所得胶囊皮，以常规方式上软胶囊机压制，置定型机中定型，制成萜烯类药物组合物自乳化软胶囊。
实施例2萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000010
制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和中链甘油三酯，30℃以30rpm的转速搅拌2小时，混匀，得到油相；
(2)取处方量Labrasol、Transcutol加入油相中，30℃以30rpm的转速搅拌2小时，混匀，形成均一自乳化药液；
(3)按重量比1:0.45:1.1称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化药液和步骤(3)所得胶囊皮，以常规方式上软胶囊机压制，置定型机中定型，制成萜烯类药物组合物自乳化软胶囊。
实施例3萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000011
制备方法同实施例2。
实施例4萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000012
制备方法同实施例2。
实施例5萜烯类药物组合物自乳化硬胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000013
制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和油酸乙酯，20℃搅拌2小时混匀，得到油相；
(2)取处方量的聚氧乙烯蓖麻油、二乙二醇单乙基醚加入油相中，20℃搅拌2小时混匀，形成均一自乳化药液；
(3)将步骤(2)所得形成自乳化药液于搅拌下条件下滴入微粉硅胶中，加入硬脂酸镁，分装于硬胶囊中，制得萜烯类药物组合物自乳化硬胶囊。
实施例6萜烯类药物组合物自乳化片剂的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000014
Figure PCTCN2019119346-appb-000015
制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和玉米油，20℃搅拌2小时混匀，得到油相；
(2)取处方量的聚氧乙烯氢化蓖麻油、丙二醇加入油相中，20℃搅拌2小时混匀，形成均一自乳化药液；
(3)将步骤(2)所得自乳化药液于搅拌条件下滴入微粉硅胶中，加入微晶纤维素、喷雾干燥乳糖、硬脂酸镁等辅料，采用常规直接压片法制得萜烯类药物组合物自乳化片剂。
实施例7萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000016
制备工艺：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和大豆油，20℃搅拌1小时混匀，得到油相；
(2)取处方量吐温80、PEG-400加入油相中，20℃搅拌2小时混匀，形成自乳化浓缩液；
(3)按重量比1:0.3～0.65:0.9～1.3称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化浓缩液和步骤(3)所得胶囊皮，以常规方式制成软胶囊。
实施例8萜烯类药物组合物自乳化软胶囊的制备
自乳化药液的处方为：
Figure PCTCN2019119346-appb-000017
Figure PCTCN2019119346-appb-000018
制备工艺：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和玉米油，20℃搅拌2小时混匀，得到油相；
(2)取处方量聚氧乙烯蓖麻油、丙二醇加入油相中，20℃搅拌2小时混匀，形成自乳化浓缩液；
(3)按重量比1:0.4～0.6:1.0～1.3称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化浓缩液和步骤(3)所得胶囊皮，以常规方式制成软胶囊。
实施例9药物组合物自乳化软胶囊的制备
内容物处方：
Figure PCTCN2019119346-appb-000019
制备工艺同实施例6。
实施例10药物组合物自乳化软胶囊的制备
内容物处方：
Figure PCTCN2019119346-appb-000020
Figure PCTCN2019119346-appb-000021
制备工艺同实施例6。
实施例11药物组合物自乳化硬胶囊的制备
内容物处方：
Figure PCTCN2019119346-appb-000022
制备工艺：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和大豆油，20℃搅拌2小时混匀，得到油相；
(2)取处方量吐温80、丙二醇加入油相中，20℃搅拌2小时混匀，形成自乳化浓缩液；
(3)将步骤(2)所得自乳化浓缩液于搅拌下滴入适量微粉硅胶中，加入硬脂酸镁，分装于硬胶囊中。
实施例12药物组合物自乳化片剂的制备
浓缩液处方：
Figure PCTCN2019119346-appb-000023
制备工艺：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和大豆油，20℃搅拌2小时混匀，得到油 相；
(2)取处方量吐温80、丙二醇加入油相中，20℃搅拌2小时混匀，形成自乳化浓缩液；
(3)将步骤(2)所得自乳化浓缩液于搅拌下滴入适量微粉硅胶中，加入微晶纤维素、喷雾干燥乳糖、硬脂酸镁等辅料，采用常规直接压片法制得自乳化片剂。
实施例13：药物组合物自乳化软胶囊的制备
内容物处方：
Figure PCTCN2019119346-appb-000024
制备工艺：
(1)取处方量中的桉油精、柠檬烯和α-蒎烯，20℃搅拌1小时混匀，得到油相；
(2)取处方量吐温80、辛酸癸酸聚乙二醇甘油酯加入油相中，20℃搅拌2小时混匀，形成自乳化浓缩液；
(3)按重量比1:0.3～0.65:0.9～1.3称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化浓缩液和步骤(3)所得胶囊皮，以常规方式制成软胶囊。
实施例14药物组合物自乳化软胶囊的制备
内容物处方：
Figure PCTCN2019119346-appb-000025
制备工艺：
(1)取处方量中的桉油精、柠檬烯和α-蒎烯，20℃搅拌1小时混匀，得到油相；
(2)取处方量辛酸癸酸聚乙二醇甘油酯、聚氧乙烯蓖麻油加入油相中，20℃搅拌2小 时混匀，形成自乳化浓缩液；
(3)按重量比1:0.3～0.65:0.9～1.3称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化浓缩液和步骤(3)所得胶囊皮，以常规方式制成软胶囊。
发明人发现，实施例13和14的自乳化浓缩液去除亲水性的助乳化剂，减少了浓缩液分层现象，便于混合大量药物，提高药物含量均匀度。
对比例1采用现有自乳化制剂处方工艺制备萜烯类药物组合物自乳化软胶囊
根据已公开自乳化制剂处方，设计萜烯类药物组合物自乳化药液的处方为：
Figure PCTCN2019119346-appb-000026
已公开的制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯，加入油酸乙酯混匀，得油相；
(2)取处方量吐温80、PEG-400混合，用磁力搅拌器混匀，得乳化相；
(3)将油相与乳化相混合，以搅拌、震荡、超声、或涡旋方式混匀，形成自乳化药液；
(4)按重量比1：0.45：1.1称取明胶、甘油、水配制胶囊皮；
(5)将步骤(3)所得自乳化药液和步骤(4)所得胶囊皮，以常规方式上软胶囊机压制，置定型机中定型，制成自乳化软胶囊。
对比例2采用现有自乳化制剂的处方及本发明的制备方法制备萜烯类药物组合物自乳化软胶囊
根据已公开自乳化制剂处方，设计萜烯类药物组合物自乳化药液的处方为：
Figure PCTCN2019119346-appb-000027
Figure PCTCN2019119346-appb-000028
本发明的制备方法为：
(1)取处方量中的桉油精、柠檬烯、α-蒎烯和油酸乙酯，15℃以50rpm的转速搅拌1小时，混匀，得到油相；
(2)取处方量的吐温80、PEG-400加入油相中，15℃以50rpm的转速搅拌1小时，得自乳化药液；
(3)按重量比1：0.5：1.1称取明胶、甘油、水配制胶囊皮；
(4)将步骤(2)所得自乳化药液和步骤(3)所得胶囊皮，以常规方式上软胶囊机压制，置定型机中定型，制成自乳化软胶囊。
实施例15不同自乳化制剂的性质观察
以油相、乳化剂和助乳化剂各为一相，各成分选择不同的比例充分混合，静置2h，目测观察是否形成均一、透明不分层的溶液。将可形成均一、透明溶液的处方取出0.5mL，在37℃、50rpm搅拌下滴加到50mL纯化水中，观察是否形成澄清透明的乳液。
结果显示：1、对比例1和2中的自乳化药液静置后分层，且对比例1的自乳化药液分层现象更为严重，本发明实施例1-11的自乳化药液静置后无任何分层现象；2、对比例1和2中的自乳化药液在水中不能快速分散成均匀的乳液，分散后有大量油滴漂浮于水表面，未能实现有效自乳化，而本发明实施例1-11的自乳化药液可在水中快速均匀分散，形成的乳滴粒径小且粒径分布均匀。
由此可知，现有已公开的自乳化制剂技术难以直接运用于本发明的萜烯类药物组合物，现有处方制备的萜烯类药物组合物自乳化制剂不能实现良好的自乳化效果。
实施例16自乳化分散液粒径测定
取实施例1～11的自乳化药液0.5mL，分散于50mL 37℃纯化水中，取2mL分散液用激光粒度仪测定乳滴粒径，结果见表6，实施例1中自乳化药液的代表性粒径分布图见图6。实施例1配方制备的自乳化浓缩液在水中可以快速分散成粒径均匀的纳米级乳剂，分散速率为20～40s，平均粒径为(161.4±17.6)nm，多分散系数为0.278±0.101。
表6：实施例1～14自乳化药液分散速率及乳滴粒径
实施例 分散速率(s) 粒径(nm) 多分散系数(PDI)
实施例1 30.7 142.5 0.257
实施例2 19.2 171.2 0.193
实施例3 13.5 161.9 0.219
实施例4 13.2 177.6 0.195
实施例5 29.6 164.6 0.274
实施例6 21.5 170.1 0.298
实施例7 18.9 160.6 0.230
实施例8 30.6 175.7 0.309
实施例9 44.9 161.7 0.265
实施例10 49.6 189.2 0.202
实施例11 56.5 157.8 0.257
实施例12 56.5 157.8 0.257
实施例13 64.3 106.25 0.271
实施例14 53.1 42.28 0.168
由表6和图6可以看出，本发明实施例1～14的自乳化药液在水中可以快速分散成粒径均匀的纳米级乳剂，分散速率为10～65s，平均粒径为40～190nm，多分散系数为0.150～0.32。实施例13和14的自乳化药液在水中的分散粒径显著降低，实施例1～12平均粒径为140～190nm，而实施例13的粒径仅为100～110nm、实施例14的粒径40～50nm，实施例13和14具有显著更小的粒径，有利于促进药物吸收，降低胃肠道不良反应，并且没有使用油相，有效降低了辅料用量，节约了成本，并可以压制成更小的软胶囊，便于吞咽。
本发明制备的自乳化药液可以将桉油精、柠檬烯和α-蒎烯药物组合物快速分散成纳米乳剂，粒径更小，有利于加快药物吸收，同时降低胃肠道不良反应。
尽管本发明的具体实施方式已经得到详细的描述，本领域技术人员将会理解。根据已经公开的所有教导，可以对那些细节进行各种修改和替换，这些改变均在本发明的保护范围之内。本发明的全部范围由所附权利要求及其任何等同物给出。
在本说明书的描述中，参考术语“一个实施例”、“一些实施例”、“示意性实施例”、“示例”、“具体示例”、或“一些示例”等的描述意指结合该实施例或示例描述的具体特征、结构、材料或者特点包含于本发明的至少一个实施例或示例中。在本说明书中，对上述术语的示意性表述不一定指的是相同的实施例或示例。而且，描述的具体特征、结构、材料或者特点可以在任何的一个或多个实施例或示例中以合适的方式结合。

Claims (29)

  1. 一种自乳化口服制剂，其特征在于，含有：
    活性成分，所述活性成分包括桉油精、柠檬和α-蒎烯；以及
    药物载体。
  2. 根据权利要求1所述的自乳化口服制剂，其中，所述自乳化口服制剂含有：
    40～65重量份的所述桉油精；
    25～45重量份的所述柠檬烯；以及
    5～20重量份的所述α-蒎烯。
  3. 根据权利要求1～2任一项所述的自乳化口服制剂，其特征在于，所述活性成分与所述药物载体的重量比为(1～15):10。
  4. 根据权利要求1～2任一项所述的自乳化口服制剂，其特征在于，所述活性成分与所述药物载体的重量比为(1～5):10。
  5. 根据权利要求1～2任一项所述的自乳化口服制剂，其特征在于，所述活性成分与所述药物载体的重量比为(5～6):10。
  6. 根据权利要求1～2任一项所述的自乳化口服制剂，其特征在于，所述活性成分与所述药物载体的重量比为5.4:10。
  7. 根据权利要求1～2任一项所述的自乳化口服制剂，其特征在于，所述药物载体包括：
    乳化剂；
    可选的油脂；以及
    可选的助乳化剂。
  8. 根据权利要求7所述的自乳化口服制剂，其特征在于，所述乳化剂包括选自吐温、聚氧乙烯蓖麻油、聚氧乙烯氢化蓖麻油、磷脂、辛酸癸酸聚乙二醇甘油酯的至少之一。
  9. 根据权利要求8所述的自乳化口服制剂，其特征在于，所述磷脂包括大豆磷脂。
  10. 根据权利要求7～9任一项所述的自乳化口服制剂，其特征在于，所述油脂包括选自大豆油、中链甘油三酯、油酸乙酯、玉米油、橄榄油的至少之一。
  11. 根据权利要求7～10任一项所述的自乳化口服制剂，其特征在于，所述助乳化剂包括选自乙醇、1,2-丙二醇、甘油、聚乙二醇、二乙二醇单乙基醚的至少之一。
  12. 根据权利要求7～11任一项所述的自乳化口服制剂，其特征在于，所述药物载体包括：
    10～50重量份的所述油脂；
    40～80重量份的所述乳化剂；以及
    5～30重量份的所述助乳化剂。
  13. 根据权利要求7～12任一项所述的自乳化口服制剂，其特征在于，所述药物载体包括：
    10～35重量份的所述油脂；
    50～70的所述乳化剂；以及
    10～25重量份的所述助乳化剂。
  14. 根据权利要求7～13任一项所述的自乳化口服制剂，其特征在于，所述药物载体包括：
    25～35重量份的所述中链甘油三酯；
    50～65重量份的所述辛酸癸酸聚乙二醇甘油酯；以及
    10～15重量份的二乙二醇单乙基醚。
  15. 根据权利要求7～11任一项所述的自乳化口服制剂，其特征在于，所述药物载体含有：
    0～5重量份的所述油脂；
    0～5重量份的所述助乳化剂；
    90～100重量份的所述乳化剂。
  16. 根据权利要求15所述的自乳化口服制剂，其特征在于，所述乳化剂由至少两种乳化剂组成。
  17. 根据权利要求15所述的自乳化口服制剂，其特征在于，所述乳化剂由第一乳化剂和第二乳化剂组成，基于自乳化口服制剂的总质量，所述第一乳化剂的质量分数为20～80％，所述第二乳化剂的质量分数为10～70％。
  18. 根据权利要求7～11、15～17任一项所述的自乳化口服制剂，其特征在于，所述药物载体由所述乳化剂构成。
  19. 根据前述任一项所述的自乳化口服制剂，其特征在于，所述自乳化口服制剂呈硬胶囊、软胶囊或片剂的形式。
  20. 根据权利要求1～19任一项所述的自乳化口服制剂，其特征在于，包括：
    18.2g桉油精，
    16.4g柠檬烯，
    1.8gα-蒎烯，
    181.8g大豆油，
    145.4g吐温80，
    36.4g丙二醇；或
    73.3g桉油精，
    33.3g柠檬烯，
    26.6gα-蒎烯，
    26.7g中链甘油三酯，
    213.4g辛酸癸酸聚乙二醇甘油酯，
    26.7g二乙二醇单乙基醚；或
    14.6g桉油精，
    16.4g柠檬烯，
    5.4gα-蒎烯，
    90.9g中链甘油三酯，
    236.6g辛酸癸酸聚乙二醇甘油酯，
    36.4g二乙二醇单乙基醚；或
    86.6g桉油精，
    40.0g柠檬烯，
    6.6gα-蒎烯，
    93.4g中链甘油三酯，
    133.4g辛酸癸酸聚乙二醇甘油酯，
    40g二乙二醇单乙基醚；或
    53.3g桉油精，
    53.3g柠檬烯，
    26.6gα-蒎烯，
    26.7g油酸乙酯，
    160.1g聚氧乙烯蓖麻油，
    80.0g二乙二醇单乙基醚；或
    78.0g桉油精，
    36.0g柠檬烯，
    6.0gα-蒎烯，
    126g玉米油，
    140g聚氧乙烯氢化蓖麻油，
    14.0g丙二醇；或
    42.7g桉油精，
    28.0g柠檬烯，
    9.3gα-蒎烯，
    80g大豆油，
    180g吐温80，
    60gPEG-400；或
    69.3g桉油精，
    45.5g柠檬烯，
    15.2gα-蒎烯，
    40g玉米油，
    170g聚氧乙烯蓖麻油，
    60g丙二醇；或
    70.0g桉油精，
    45.5g柠檬烯，
    14.5gα-蒎烯，
    40g大豆油，
    180g聚氧乙烯氢化蓖麻油，
    50g丙二醇；或
    70.0g桉油精，
    45.5g柠檬烯，
    14.5gα-蒎烯，
    50g油酸乙酯，
    160g辛酸癸酸聚乙二醇甘油酯，
    60g二乙二醇单乙基醚；或
    69.3g桉油精，
    45.5g柠檬烯，
    15.2gα-蒎烯，
    40g大豆油，
    170g吐温80，
    60g丙二醇；或
    69.3g桉油精，
    45.5g柠檬烯，
    15.2gα-蒎烯，
    40g大豆油，
    170g吐温80，
    60g丙二醇；或
    75g桉油精，
    50g柠檬烯，
    16gα-蒎烯，
    79g吐温80，
    180g辛酸癸酸聚乙二醇甘油酯；或
    75g桉油精，
    50g柠檬烯，
    16gα-蒎烯，
    165g辛酸癸酸聚乙二醇甘油酯，
    94g聚氧乙烯蓖麻油。
  21. 一种制备前述权利要求任一项所述的自乳化口服制剂的方法，其特征在于，包括：
    将所述活性成分与所述药物载体混合以便获得所述自乳化口服制剂。
  22. 根据权利要求21所述的方法，其特征在于，进一步包括将含有所述活性成分与所述药物载体的混合物进行封装以便获得制剂。
  23. 根据权利要求22所述的方法，其特征在于，所述制剂为软胶囊、硬胶囊或片剂。
  24. 根据权利要求21所述的方法，其特征在于，将所述活性成分与所述药物载体混合进一步包括：
    将所述活性成分以及可选的所述油脂进行第一混合处理，以便获得油相混合物；
    将所述油相混合物与所述乳化剂以及可选的所述助乳化剂进行第二混合处理。
  25. 根据权利要求24所述的方法，其特征在于，所述第一混合处理和所述第二混合处理分别独立地在下列条件下进行的：
    温度为15～30摄氏度；
    搅拌速度为：30～50rpm；和/或
    混合时间为1～2小时。
  26. 权利要求1～20任一项所述的自乳化口服制剂在制备药物中的用途，所述药物用于治疗或者预防呼吸系统疾病。
  27. 根据权利要求26所述的用途，其特征在于，所述呼吸系统疾病包括：急性鼻窦炎、慢性鼻窦炎、鼻窦炎手术炎症、急慢性支气管炎、肺炎、支气管扩张、肺脓肿、慢性阻塞性肺部疾病、肺部真菌感染、肺结核、矽肺中的至少一种。
  28. 一种治疗或者预防呼吸系统疾病的方法，其特征在于，为呼吸系统疾病患者给药 权利要求1～20任一项所述的自乳化口服制剂。
  29. 根据权利要求28所述的方法，其特征在于，所述呼吸系统疾病包括：急性鼻窦炎、慢性鼻窦炎、鼻窦炎手术炎症、急慢性支气管炎、肺炎、支气管扩张、肺脓肿、慢性阻塞性肺部疾病、肺部真菌感染、肺结核、矽肺中的至少一种。
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