WO2021184639A1 - 一种小儿消积止咳微囊制剂及其制备方法 - Google Patents

一种小儿消积止咳微囊制剂及其制备方法 Download PDF

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WO2021184639A1
WO2021184639A1 PCT/CN2020/105725 CN2020105725W WO2021184639A1 WO 2021184639 A1 WO2021184639 A1 WO 2021184639A1 CN 2020105725 W CN2020105725 W CN 2020105725W WO 2021184639 A1 WO2021184639 A1 WO 2021184639A1
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cough
extract
weight
preparation
fine powder
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PCT/CN2020/105725
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English (en)
French (fr)
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张贵民
李蔚群
王海祥
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山东新时代药业有限公司
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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5052—Proteins, e.g. albumin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/56—Materials from animals other than mammals
    • A61K35/63—Arthropods
    • A61K35/64—Insects, e.g. bees, wasps or fleas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/31—Brassicaceae or Cruciferae (Mustard family), e.g. broccoli, cabbage or kohlrabi
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/34—Campanulaceae (Bellflower family)
    • A61K36/346—Platycodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/42—Cucurbitaceae (Cucumber family)
    • A61K36/428—Trichosanthes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/63—Oleaceae (Olive family), e.g. jasmine, lilac or ash tree
    • A61K36/634—Forsythia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/73—Rosaceae (Rose family), e.g. strawberry, chokeberry, blackberry, pear or firethorn
    • A61K36/734—Crataegus (hawthorn)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/75—Rutaceae (Rue family)
    • A61K36/752—Citrus, e.g. lime, orange or lemon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/889—Arecaceae, Palmae or Palmaceae (Palm family), e.g. date or coconut palm or palmetto
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/14—Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
    • 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
    • A61P11/14—Antitussive agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/331—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using water, e.g. cold water, infusion, tea, steam distillation, decoction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/39—Complex extraction schemes, e.g. fractionation or repeated extraction steps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/51—Concentration or drying of the extract, e.g. Lyophilisation, freeze-drying or spray-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/50—Methods involving additional extraction steps
    • A61K2236/55—Liquid-liquid separation; Phase separation

Definitions

  • the invention relates to a microcapsule preparation for Xiaoerxiaoji cough relieving and a preparation method thereof, and belongs to the field of traditional Chinese medicine preparations.
  • Chinese patent CN1201786C discloses a Chinese medicinal composition with the dual effects of eliminating food, leading to stagnation, resolving phlegm and relieving cough, and a preparation method. ®”.
  • Microencapsulation technology uses natural or synthetic polymer encapsulation materials (collectively referred to as capsule materials) as the shell of the capsule membrane to pack solid or liquid drugs (collectively referred to as core materials) in tiny, semi-permeable or sealed capsules.
  • capsule materials natural or synthetic polymer encapsulation materials
  • core materials solid or liquid drugs
  • microcapsule a drug storage type microcapsule because its particle size is 1 ⁇ 250 ⁇ m, which belongs to the micron level.
  • the existing researches on Chinese medicine microcapsules mainly focus on Chinese medicine monomer compounds, and there are few studies on the active ingredient extracts of single Chinese medicines and Chinese medicine compound prescriptions with more complex compositions.
  • microcapsule preparation for Xiaoerxiaoji cough-reducing microcapsules includes the following components in terms of weight percentage:
  • the capsule material is one or more of gum arabic, maltodextrin, octenyl succinate starch, ⁇ -lactoglobulin, soy protein isolate, and xanthan gum by weight;
  • the anti-sticking agent It is one or more of glyceryl monostearate, stearyl alcohol, and titanium dioxide;
  • the plasticizer is one or more of polyethylene glycol 6000, propylene glycol, and citric acid.
  • the fine powder of Xiaoerxiaoji cough extract is made of the following raw materials:
  • Tinglizi 80-150 parts by weight Platycodon 80-150 parts by weight Forsythia 80-150 parts by weight
  • the fine powder of Xiaoerxiaoji cough extract is made of the following raw materials:
  • Tinglizi 100 parts by weight of Tinglizi 100 parts by weight of Platycodon grandiflorum Forsythia 100 parts by weight The cicada shed 66 parts by weight.
  • the formulation formulation contains the following ingredients:
  • Another object of the present invention is to provide a preparation method of the Xiaoerxiaoji Antitussive Microcapsule Preparation, which mainly includes the preparation of the fine powder of the Xiaoerxiaoji Antitussive extract, the preparation of the emulsion and the spray drying.
  • a preparation method of Xiaoerxiaoji cough-reducing microcapsule preparation includes the following steps:
  • Step A The filtrate is concentrated under reduced pressure to an extract with a density of 1.15-1.20 at 60°C-65°C. Add 5-7 times the amount of water to dissolve and extract, refrigerate for 24-48 hours, filter, and concentrate the filtrate under reduced pressure to 60 A thick paste with a relative density of 1.20-1.25 at °C-65°C, dried, crushed into a fine powder, and sieved to obtain a fine powder of Xiaoerxiaoji Cough Extract, which is ready for use;
  • Step B Weigh the amount of the formula in Step B.
  • the fine powder, capsule material, anti-sticking agent and plasticizer of step B Xiaoer Xiaoji cough extract, add the capsule material, anti-sticking agent and plasticizer to purified water at 47°C-60°C Under heating and stirring to dissolve, configure into a capsule material solution with a mass fraction of 24%-36%, cool to room temperature, add the fine powder of Xiaoerxiaoji cough extract and emulsifier under stirring, and homogenize and emulsify to obtain an emulsion for use. ;
  • Step C The emulsion is spray-dried under the conditions of air inlet temperature of 163°C-172°C, spray pressure of 0.34MPa-0.41MPa, and feed rate of 13ml/min-22ml/min.
  • the microcapsules are collected and cooled to obtain.
  • step 1) the extraction and purification process includes the following steps:
  • Step A The filtrate is concentrated under reduced pressure to a density of 1.18 at 65°C. Add 6 times the amount of water to dissolve and extract, refrigerate for 48 hours, and filter. The filtrate is concentrated under reduced pressure to a thick paste with a relative density of 1.23 at 65°C. , Belt vacuum drying, pulverized into fine powder, sieved to obtain the fine powder of Xiaoer Xiaoji Cough Extract, for use;
  • the conditions of the belt vacuum drying in step 1) B are vacuum degree -0.08MPa-0.10Mpa, and drying temperature 52°C-59°C.
  • the step 2) preparation process includes the following steps:
  • Step B Xiaoerxiaoji cough extract powder, capsule material, anti-sticking agent and plasticizer, add capsule material, anti-sticking agent and plasticizer to purified water, heat and stir at 54°C Dissolve it and prepare it into a 33% mass fraction of the capsule material solution, cool it to room temperature, add the fine powder of Xiaoerxiaoji Cough Extract and emulsifier under stirring, homogenize and emulsify to obtain an emulsion for use;
  • Step C The emulsion is spray-dried under the conditions of an inlet air temperature of 168°C, a spray pressure of 0.40 MPa, and a feed rate of 21.5 ml/min, collects the microcapsules, and cools them to obtain.
  • the emulsifier in step C is one or more of Tween 80, soybean phospholipid, lecithin, poloxamer, and sucrose fatty acid ester, and the amount is 0.5%-1.1 of the total formulation formula by mass fraction. %;
  • microcapsules of the present invention can be used as ordinary powders or granules, and can be further used as intermediates to be filled into capsules and compressed into tablets, etc., thereby obtaining Xiaoerxiaoji Anti-cough Microcapsule Capsules and Xiaoer Xiaoji Anti-cough Microcapsule Tablets.
  • the Xiaoer Xiaoji Anti-cough Microcapsule Preparation is a drug storage type microcapsule, which is spherical or quasi-spherical, has good fluidity, low moisture absorption, good stability, and is not easy to agglomerate. It can improve the easy precipitation of the Xiaoer Xiaoji Anti-cough product oral liquid. Problems such as unstable preparations;
  • Xiaoer Xiaoji Anti-cough is a medicine for treating children's food product cough, which requires mild and long-lasting effect.
  • the Xiaoer Xiaoji anti-cough microcapsule preparation of the present invention has obvious slow-release effect, high bioavailability, and is not affected by gastrointestinal rhythms. Play the best cough treatment effect;
  • the fine powder of Xiaoerxiaoji Anti-cough Extract powder can cover the inherent bad smell and taste of Xiaoerxiaoji Anti-cough Oral Liquid through the encapsulation and concealment of the capsule material, and the pediatric patients have good medication compliance.
  • the microcapsule preparation for Xiaoerxiaoji cough-reducing microcapsules of the present invention is off-white or off-white powder, is loose, has no bad smell, has good fluidity, and has good dispersibility and stability. Except for individual dents on the surface of the microcapsule particles, the particles are relatively round and close to spherical, and the surface is compact and non-porous, basically non-adhesive.
  • the particle size distribution of the capsules is relatively uniform, and the particle size distribution is relatively narrow, mostly concentrated around 25 ⁇ m, and Approximately normal distribution.
  • the measurement results of the encapsulation rate show that the encapsulation rate of the Xiaoerxiaoji cough-reducing microcapsule preparation obtained by the formulation and preparation process of the present invention is above 80%, up to 94.1%, and the microencapsulation effect is good.
  • the cumulative dissolution test in vitro shows that the cumulative dissolution percentage of the Xiaoerxiaoji Antitussive Microcapsules and Xiaoerxiaoji Antitussive Microcapsule Tablets of the present invention is less than 53% within 1 hour, reaches more than 84% within 2 hours, and is basically completely released within 3 hours.
  • the Xiaoerxiaoji Antitussive Microcapsule Preparation of the invention has a certain slow-release effect.
  • Figure 1 is a graph showing the cumulative dissolution percentage curve of Example 4 Xiaoer Xiaoji Anti-cough Microcapsule Capsules and Example 7 Xiaoer Xiaoji Anti-cough Microcapsule Tablets.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.19 at 60°C-65°C , Add 7 times the amount of water to dissolve and extract, refrigerate for 36 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.24 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 58 °C, crushed into fine powder, sieved to obtain 112g of fine powder of Xiaoer Xiaoji Cough Extract, ready for use;
  • Titanium dioxide 11g
  • Polyethylene glycol 6000 42g
  • capsule material, anti-sticking agent and plasticizer of the above formula into purified water, heat and stir at 55°C to dissolve, configure into a capsule material solution with a mass fraction of 28%, cool to room temperature, and add the formula under stirring
  • the fine powder of Xiaoerxiaoji cough extract and 8g of sucrose fatty acid lipid were homogenized and emulsified to obtain an emulsified liquid.
  • the microcapsules were collected by spray drying at an inlet air temperature of 170°C, a spray pressure of 0.37MPa, and a feed rate of 18ml/min. , Cool, get 787g microcapsules.
  • step 2 microcapsules, add 213g starch, fill, polish in a grinder, remove damaged capsules, and get ready.
  • the above 10 flavors add water to decoc 2 times, the first time add 8 times the amount of water to decocate for 1.5 hours, the second time add 9 times the amount of water to decocate for 1.5 hours, combine the decocting liquid, filter, and concentrate under reduced pressure to 60°C- An extract with a density of 1.15 at 65°C, add 95% ethanol and alcohol precipitation to make the ethanol content reach 70%, refrigerate for 48 hours, and filter to obtain the filtrate.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.17 at 60°C-65°C , Add 5 times the amount of water to dissolve and extract, refrigerate for 48 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.2 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 52°C, crushed into fine powder, sieved to obtain 97g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • step 2 microcapsules, add 177g of sucrose powder, mix well, make coarse granules, dry, pulverize, sieving, granulate, dry at low temperature, whole granules, add 10g magnesium stearate and 8g talcum powder, mix well , Press the tablet and get it.
  • the above 10 flavors add water to decoc 2 times, the first time add 9 times the amount of water to decoc for 2 hours, the second time add 8 times the amount of water to decoc for 2 hours, combine the decocting liquid, filter, and concentrate under reduced pressure to 60°C-
  • the extract with a density of 1.12 at 65°C add 95% ethanol and alcohol precipitation to make the ethanol content reach 80%, refrigerate for 12 hours, and filter to obtain the filtrate.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.15 at 60°C-65°C , Add 6 times the amount of water to dissolve and extract, refrigerate for 24 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.21 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 53°C, crushed into fine powder, sieved to obtain 107g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • capsule material, anti-sticking agent and plasticizer of the above formula into purified water, heat and stir at 60°C to dissolve, configure into a capsule material solution with a mass fraction of 23%, cool to room temperature, and add the formula under stirring Xiaoerxiaoji cough extract powder and Tween80 5g, homogenized and emulsified to obtain an emulsified liquid, spray dried under the conditions of air inlet temperature of 163°C, spray pressure of 0.34MPa, and feed rate of 19ml/min, collect microcapsules, and cool , Get 815g of microcapsules.
  • step 2 microcapsules, add 185g lactose, fill, polish in a grinder, remove damaged capsules, and get ready.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.18 at 60°C-65°C , Add 6 times the amount of water to dissolve and extract, refrigerate for 48 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.23 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 56°C, crushed into fine powder, sieved to obtain 1755g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • step 2 microcapsules, add 128g of micro-powder silica gel, fill, polish in a grinder, and remove damaged capsules to get it.
  • the above 10 flavors add water to decoc 2 times, the first time add 8 times the amount of water to decoc 2 hours, the second time add 9 times the amount of water to decoc for 1.5 hours, combine the decoction, filter, and concentrate under reduced pressure to 60 °C- An extract with a density of 1.15 at 65°C, add 95% ethanol and alcohol precipitation to make the ethanol content reach 70%, refrigerate for 24 hours, and filter to obtain a filtrate.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.16 at 60°C-65°C , Add 7 times the amount of water to dissolve and extract, refrigerate for 36 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.25 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 57°C, crushed into fine powder, sieved to obtain 153g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • step 2 microcapsules, add 135g of dextrin, mix well, make coarse particles, dry, pulverize, sieving, make granules, dry at low temperature, sizing, add 7g magnesium stearate and 12g talcum powder, mix well , Press the tablet and get it.
  • the above 10 flavors add water to decoc 2 times, the first time add 9 times the amount of water to decoc for 2.5 hours, the second time add 10 times the amount of water to decoc for 2 hours, combine the decoction, filter, and concentrate under reduced pressure to 60 °C- An extract with a density of 1.14 at 65°C, add 95% ethanol and alcohol precipitation to make the ethanol content reach 80%, refrigerate for 48 hours, and filter to obtain the filtrate.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.19 at 60°C-65°C , Add 5 times the amount of water to dissolve and extract, refrigerate for 24 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.22 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 54°C, crushed into fine powder, sieved to obtain 185g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • capsule material, anti-adhesive agent and plasticizer of the above formula into purified water, heat and stir at 58°C to dissolve, configure into a capsule material solution with a mass fraction of 25%, cool to room temperature, and add the formula under stirring Xiaoerxiaoji cough extract powder, 6g of sucrose fatty acid ester, 5g of lecithin, homogenized and emulsified to obtain an emulsified liquid, sprayed under the conditions of air inlet temperature of 167°C, spray pressure of 0.40MPa, and feed rate of 17ml/min Dry, collect the microcapsules, and cool to obtain 833g microcapsules.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • step 2 microcapsules, add 125g of microcrystalline cellulose, mix well, make coarse particles, dry, pulverize, sieving, granulate, dry at low temperature, and size, add 6g magnesium stearate and 11g talc, Mix well, press tablets, and get ready.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.2 at 60°C-65°C , Add 7 times the amount of water to dissolve and extract, refrigerate for 48 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.25 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 56 °C, crushed into fine powder, sieved to obtain 122g of fine powder of Xiaoer Xiaoji Cough Extract, ready for use;
  • capsule material, anti-adhesive agent and plasticizer of the above formula into purified water, heat and stir at 47°C to dissolve, configure into a capsule material solution with a mass fraction of 30%, cool to room temperature, and add the formula under stirring 7g of Xiaoerxiaoji cough extract powder and Tween80, homogenized and emulsified to obtain an emulsified liquid, spray-dried under the conditions of inlet air temperature 172°C, spray pressure 0.41MPa, and feed rate 14ml/min, collect microcapsules, and cool , 820g microcapsules are obtained.
  • step 2 microcapsules, add 160g sucrose powder, mix, make coarse granules, dry, pulverize, sieving, granulate, low-temperature drying, whole granules, add 8g magnesium stearate and 12g talcum powder, mix well , Press the tablet and get it.
  • the filtrate is concentrated under reduced pressure to an extract with a density of 1.18 at 60°C-65°C , Add 6 times the amount of water to dissolve and extract, refrigerate for 36 hours, filter, and concentrate the filtrate under reduced pressure to a thick paste with a relative density of 1.23 at 60°C-65°C, belt vacuum drying, vacuum degree -0.08MPa--0.10Mpa , Drying temperature 58°C, crushed into fine powder, sieved to obtain 165g of fine powder of Xiaoerxiaoji Cough Extract, ready for use;
  • step 2 microcapsules, add 201g of dextrin, fill, polish in a polishing machine, remove damaged capsules, and get ready.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A, Xiaoerxiaoji cough extract fine powder: 117g B, maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g glyceryl monostearate: 6g D, polyethylene glycol 6000: 45g
  • capsule material, anti-adhesive agent and plasticizer of the above formula into purified water, heat and stir at 54°C to dissolve, configure into a capsule material solution with a mass fraction of 33%, cool to room temperature, and add the formula under stirring Xiaoerxiaoji cough extract powder, 2g of soy lecithin, 5g of sucrose fatty acid, homogenized and emulsified to obtain an emulsified liquid, under the conditions of inlet air temperature of 168°C, spray pressure of 0.40MPa, and feed rate of 21.5ml/min After spray drying, the microcapsules were collected and cooled to obtain 803 g of microcapsules.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A. Fine powder of Xiaoerxiaoji cough extract: 117g B. Maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g glyceryl monostearate: 6g D. Citric acid: 45g
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A, Xiaoerxiaoji cough extract fine powder: 117g B, maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g glyceryl monostearate: 6g D, polyethylene glycol 6000: 22.5 Citric acid: 22.5g
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A. Fine powder of Xiaoerxiaoji cough extract: 117g B. Maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g glyceryl monostearate: 6g D. Polyethylene glycol 6000: 33.75g Citric acid: 11.25g
  • capsule material, anti-adhesive agent and plasticizer of the above formula into purified water, heat and stir at 54°C to dissolve, configure into a capsule material solution with a mass fraction of 33%, cool to room temperature, and add the formula under stirring Xiaoerxiaoji cough extract powder, 2g of soy lecithin, 5g of sucrose fatty acid, homogenized and emulsified to obtain an emulsified liquid, under the conditions of inlet air temperature of 168°C, spray pressure of 0.40MPa, and feed rate of 21.5ml/min After spray drying, the microcapsules were collected and cooled to obtain 829 g of microcapsules.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A. Xiaoerxiaoji cough extract fine powder: 117g B. Maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g glyceryl monostearate: 6g D. Polyethylene glycol 6000: 36g Citric acid: 9g
  • capsule material, anti-adhesive agent and plasticizer of the above formula into purified water, heat and stir at 54°C to dissolve, configure into a capsule material solution with a mass fraction of 33%, cool to room temperature, and add the formula under stirring Xiaoerxiaoji cough extract powder, 2g of soy lecithin, 5g of sucrose fatty acid, homogenized and emulsified to obtain an emulsified liquid, under the conditions of inlet air temperature of 168°C, spray pressure of 0.40MPa, and feed rate of 21.5ml/min After spray drying, the microcapsules are collected and cooled to obtain 825 g of microcapsules.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • Preparation process A. Fine powder of Xiaoerxiaoji cough extract: 117g B. Maltodextrin: 578g ⁇ -lactoglobulin: 248g C. Titanium dioxide: 6g Glyceryl monostearate: 6g D. Polyethylene glycol 6000: 37.5g Citric acid: 7.5g
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • the microcapsule preparation method used refers to the best effect example 5 of the Chinese patent "A compound vinegar microcapsule and its preparation method and application (authorization announcement number CN106036829B)" to investigate the application of the prior art microcapsule preparation method to Xiaoerxiao The preparation effect achieved when the fine powder of antitussive extract is accumulated.
  • microcapsules prepared above are sent to a spray dryer for spray drying with a pump, the air inlet temperature is controlled to be 185°C, and the spray pressure is 0.185MPa, and finally the microcapsules are drained to obtain 384g of finished microcapsules.
  • the fine powder of Xiaoerxiaoji cough extract used in this example is the fine powder of Xiaoerxiaoji cough extract obtained in step 1) of the extraction and purification process in Example 4.
  • the microcapsule preparation method used refers to "Hu Rui, Zhou Guangping, Song Weichun. Preparation and in vitro controlled release analysis of Chinese medicine prebiotic microcapsules by spray drying method[J]. Anhui Agricultural Sciences, 2016, 44(29): 89-94.”
  • Example 4 and Example 7 Take an appropriate amount of the microcapsule samples of Example 4 and Example 7, and place them in an evaporating dish, and observe their color and shape under natural light or in a room equivalent to natural light.
  • the microcapsule sample was observed to be white or off-white powder, loose, no bad smell, good fluidity, good dispersibility and stability.
  • Example 4 and Example 7 Take about 0.03g of the microcapsule samples of Example 4 and Example 7, use 50% ethanol as the dispersion medium, and set the Winner2005B intelligent laser particle size analyzer (Jinan Micronano Particle Instrument Co., Ltd.) to determine the particle size (D).
  • the result See Table 1 (D10, D50, D90 in the table respectively represent the equivalent diameter of the largest particle when the cumulative distribution in the distribution curve is 10%, 50%, and 90%, and Dav represents the average particle diameter).
  • the particle size distribution of the microcapsules of Xiaoerxiaoji Antitussive and Antitussive Microcapsules is relatively uniform, mostly concentrated in the vicinity of 25 ⁇ m.
  • the average particle size of the microcapsules of Example 4 is 25.84 ⁇ m
  • the average particle size of the microcapsules of Example 7 is 25.42. ⁇ m
  • the particle size distribution of the microcapsules of the two samples is narrow, and the distribution is approximately normal, and the microencapsulation effect is better.
  • Encapsulation rate refers to the percentage of the actual drug content in the microcapsule to the total drug content (ie, drug loading) in the microcapsule sample, that is, the percentage of the drug content of the prepared microcapsule to the total drug content of the system. The higher the encapsulation rate, the better the degree of drug encapsulation.
  • the specific method for determining the encapsulation rate of Xiaoerxiaoji Antitussive Microencapsulation is as follows.
  • Chromatographic conditions and system suitability test Use octadecylsilane-bonded silica gel as filler; use acetonitrile-methanol-potassium dihydrogen phosphate solution (take 0.6g potassium dihydrogen phosphate, 1.0g sodium dodecyl sulfonate, 1ml glacial acetic acid, dissolve and dilute with water To 1000ml) (15:30:55) is the mobile phase; the detection wavelength is 224nm. The number of theoretical plates should not be less than 2000 calculated by Synephrine.
  • Preparation of reference solution Take an appropriate amount of synephrine reference substance, accurately weigh it, and add 50% methanol to make a solution containing 20 ⁇ g per lml, and it is ready.
  • test solution Accurately weigh an appropriate amount of Pediatric Xiaoji Antitussive Microcapsule sample, place it in a 100mL volumetric flask, dilute to 100mL with 75% ethanol, and shake it up so that all the Pediatric Xiaoji Antitussive Extract on the outer surface of the microcapsule is dissolved in the ethanol solution.
  • Assay Take the standard solution and the test solution, respectively inject 20ul samples, use the external standard two-point logarithmic equation to calculate the content of synephrine in the sample, and calculate the amount of fine powder extract from the outer surface of the microcapsule based on the content of synephrine ( m) and the amount of fine powder of the total extract of the microcapsules (M).
  • Encapsulation rate (total amount of drug in the microcapsule sample M ⁇ the amount of extra-microcapsule drug m) ⁇ 100%/total amount of drug in the microcapsule sample M.
  • Comparative Example 7 and Comparative Example 8 for preparing microcapsules by the preparation process of traditional Chinese medicine compound microcapsules described in the prior art patents and literatures have poor microencapsulation rates of 36.4% and 45.7%, respectively; the yields are relatively high. Low, 38.4% and 41.7% respectively. It can be seen that the encapsulation rate and product yield cannot meet the corresponding requirements for preparing the Xiaoerxiaoji cough-reducing oral liquid with the microcapsule preparation formula and the microcapsule preparation method of the prior art, and industrial production cannot be realized.
  • Example 4 of the present invention Xiaoer Xiaoji Anti-cough Microcapsule Capsule, Example 7 Xiaoer Xiaoji Anti-cough Microcapsule Tablets Reference Dissolution Test Method ("Chinese Pharmacopoeia" 2015 Edition Si Bu General Principle 0931 Sustained or Controlled Release Preparation) in 250ml phosphate buffer
  • the in vitro dissolution test was carried out under the conditions of liquid (pH6.8) as the dissolution medium, the temperature of the water bath was 37°C ⁇ 0.5°C, and the rotation speed was 100r ⁇ min -1, and synephrine was used as an indicator to investigate.
  • Chromatographic conditions and system suitability test Use octadecylsilane-bonded silica gel as filler; use acetonitrile-methanol-potassium dihydrogen phosphate solution (take 0.6g potassium dihydrogen phosphate, 1.0g sodium dodecyl sulfonate, 1ml glacial acetic acid, dissolve and dilute with water To 1000ml) (15:30:55) is the mobile phase; the detection wavelength is 224nm. The number of theoretical plates should not be less than 2000 calculated by Synephrine.
  • Preparation of reference solution Take an appropriate amount of synephrine reference substance, accurately weigh it, and add 50% methanol to make a solution containing 20 ⁇ g per lml, and it is ready.
  • Preparation of test solution Take 10ml samples at each time point and add 10ml of distilled water at the same temperature at the same time. The samples are filtered through 0.45 ⁇ m microporous membrane. 5ml of continuous filtrate is taken and passed through a polyamide column (30-60 mesh, 2.5g, inner diameter 12.5mm) Elute with 30ml of water, collect the eluate and place it in a 50ml measuring flask, add water to the mark, shake well, filter, and take the additional filtrate to get it.
  • Example 4 Xiaoerxiaoji Antitussive Microcapsule Capsules and Example 7 Xiaoer Xiaoji Antitussive Microcapsule Tablets.
  • the selected samples of the Xiaoerxiaoji cough-reducing microcapsule preparation used in this experiment are samples obtained from the representative formula and preparation process of the present invention, and the other formulas and preparation methods included in the present invention involve the tests involved in the samples And the results, due to space limitations, will not be exhaustive here.
  • Example 4 microcapsules Two batches of samples of the present invention (Example 4 microcapsules, Example 7 microcapsule tablets) are stored in an aluminum-plastic package (6 tablets/plate) in an accelerated test box (40 ⁇ 2°C, RH75% ⁇ 5). Month, samples were taken at 0 months, 1 month, 2 months, 3 months, and 6 months respectively) for accelerated stability testing.
  • the method for determining the content of synephrine is the same as that of Experimental Example 2, and the testing methods for other indicators refer to "Chinese Pharmacopoeia" 2015 edition four.
  • the accelerated stability test data of the two batches of products are shown in Table 4 and Table 5.

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Abstract

本发明属于中药制剂领域，公开了一种小儿消积止咳微囊制剂及其制备方法，所述微囊制剂由小儿消积止咳提取物细粉、囊材、抗粘剂和增塑剂制成，所述小儿消积止咳微囊制剂的制备方法包括小儿消积止咳提取物细粉的制备及微囊的制备。本发明小儿消积止咳微囊呈球形或类球形，引湿性小，流动性好，不易结块；所得的微囊制剂具有明显缓释作用，生物利用度高，且不受胃肠节律的影响，可发挥最佳的治疗咳嗽的效果；同时通过囊材的包埋，可掩盖小儿消积止咳制剂固有的不良气味，改善口感，提升了患儿用药的依从性性。

Description

一种小儿消积止咳微囊制剂及其制备方法 技术领域
本发明涉及一种小儿消积止咳微囊制剂及其制备方法，属于中药制剂领域。
 背景技术
中国专利CN1201786C公开了一种具有消食导滞、化痰止咳双重功效的中药组合物及制备方法，产品为治疗小儿食积咳嗽的中药复方制剂“小儿消积止咳口服液”，商品名为“宁宝®”。
微囊化技术系利用天然或合成的高分子包囊材料（统称囊材）作为囊膜壁壳，将固态药物或液态药物（统称芯材）包在微小、半透性或密封的囊内，从而形成药库型微型胶囊，因其粒径在1～250μm，属微米级，故名微囊。现有中药微囊的研究主要集中在中药单体化合物，对成分比较复杂的单味中药有效成分提取物及中药复方的研究很少。
 技术解决方案
针对现有小儿消积止咳口服液存在的不足和产品升级换代的需要，以期增加小儿消积止咳产品的剂型序列，充分发挥产品的临床治疗价值，有必要发明一种不同于普通口服液剂特性和释药机制的微囊化产品。
一种小儿消积止咳微囊制剂，按重量百分比计，微囊制剂配方包括以下组分：
A、小儿消积止咳提取物细粉9.7%-18.5%   B、囊材74.8% -85.2%  C、抗粘剂0.7%-2.3%     D、增塑剂3.9%-4.7%
所述囊材按重量计为阿拉伯胶、麦芽糊精、辛烯基琥珀酸酯化淀粉、β-乳球蛋白、大豆分离蛋白、黄原胶中的一种或几种；所述抗粘剂为单硬脂酸甘油酯、十八醇、二氧化钛中的一种或几种；所述增塑剂为聚乙二醇6000、丙二醇、柠檬酸中的一种或几种。
其中，所述小儿消积止咳提取物细粉由下列原料制成：
山楂50-200重量份      槟榔50-200重量份       枇杷叶50-200重量份 
枳实50-200重量份      莱菔子80-150重量份     瓜蒌67-268重量份 
葶苈子80-150重量份    桔梗80-150重量份       连翘80-150重量份 
蝉蜕50-100重量份；
优选地，所述小儿消积止咳提取物细粉由下列原料制成：
山楂100重量份    槟榔100重量份      枇杷叶100重量份
枳实100重量份    莱菔子100重量份    全瓜蒌134重量份
葶苈子100重量份  桔梗100重量份      连翘100重量份  蝉蜕66重量份。
优选地，按重量百分比计，制剂配方包含以下成分：
A、小儿消积止咳提取物细粉11.2%-16.5%     B、囊材78.1% -83.5%  C、抗粘剂1.2%-1.7%        D、增塑剂4.1%-4.5%
所述囊材按重量计为麦芽糊精：β-乳球蛋白=7：3、阿拉伯胶：麦芽糊精=8：5、大豆分离蛋白：麦芽糊精：黄原胶=9：4：1 、辛烯基琥珀酸酯化淀粉：β-乳球蛋白=5：2中的一种；所述抗粘剂按重量计为十八醇：二氧化钛=5：3或单硬脂酸甘油酯；所述增塑剂按重量计为聚乙二醇6000：柠檬酸=1-4：1或丙二醇。
本发明的另一个目的是提供所述小儿消积止咳微囊制剂的制备方法，主要包括小儿消积止咳提取物细粉的制备、乳化液的制备以及喷雾干燥。
一种小儿消积止咳微囊制剂的制备方法，包括下列步骤：
1）提取、纯化工艺
A、将炒山楂、槟榔、蜜炙枇杷叶、枳实、炒莱菔子、瓜蒌、炒葶苈子、桔梗、连翘、蝉蜕加8-10倍量水煎煮2次，每次1.5-2.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.10-1.15的浸膏，加95%乙醇醇沉，使乙醇含量达到60%-80%，冷藏12-48小时，过滤，得滤液，备用；
B、步骤A滤液减压浓缩至60℃-65℃时密度为1.15-1.20的浸膏，加5-7倍量水转溶精提，冷藏24-48小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.20-1.25的稠膏，干燥，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉，备用；
2）制剂工艺
C、按配方量称取步骤B小儿消积止咳提取物细粉、囊材、抗粘剂和增塑剂，将囊材、抗粘剂和增塑剂加入纯化水，47℃-60℃条件下加热搅拌使溶解，配置成质量分数为24%-36%的囊材溶液，冷却至室温，搅拌状态下加入小儿消积止咳提取物细粉和乳化剂，均质乳化，得乳化液，备用；
D、步骤C乳化液在进风温度163℃-172℃、喷雾压力0.34MPa-0.41MPa、进料速度13ml/min-22ml/min条件下进行喷雾干燥，收集微囊，冷却，即得。
优选地，步骤1）提取、纯化工艺包括下列步骤：
A、将炒山楂、槟榔、蜜炙枇杷叶、枳实、炒莱菔子、瓜蒌、炒葶苈子、桔梗、连翘、蝉蜕加水煎煮2次，第一次加10倍量水煎煮2.5小时，第二次加8倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至65℃时密度为1.12的浸膏，加95%乙醇醇沉，使乙醇含量达到70%，冷藏24小时，过滤，得滤液，备用；
B、步骤A滤液减压浓缩至65℃时密度为1.18的浸膏，加6倍量水转溶精提，冷藏48小时，过滤，滤液减压浓缩至65℃时相对密度为1.23的稠膏，带式真空干燥，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉，备用；
优选地，步骤1）B中带式真空干燥的条件为真空度-0.08MPa--0.10Mpa，干燥温度52℃-59℃。
优选地，所述步骤2）制剂工艺包括下列步骤：
C、按配方量称取步骤B小儿消积止咳提取物细粉、囊材、抗粘剂和增塑剂，将囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入小儿消积止咳提取物细粉和乳化剂，均质乳化，得乳化液，备用；
D、步骤C乳化液在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，即得。
优选地，步骤C所述乳化剂为Tween80、大豆磷脂、卵磷脂、泊洛沙姆、蔗糖脂肪酸酯中的一种或几种，用量按质量分数计为制剂配方总量的0.5%-1.1%；
优选地，步骤C所述乳化剂按重量计为大豆磷脂：蔗糖脂肪酸酯=2∶5的复合乳化剂，用量按质量分数计为制剂配方总量的1.0%。
本发明微囊除了可作为普通散剂或颗粒剂使用外，还可进一步作为中间体灌装成胶囊，压制成片剂等，从而得到小儿消积止咳微囊胶囊和小儿消积止咳微囊片。
本发明小儿消积止咳微囊制剂，具有以下的特点和有益效果：
1）小儿消积止咳微囊制剂为药库型微型胶囊，呈球形或类球形，流动性好，引湿性小，稳定性好，不易结块，可改善小儿消积止咳成品口服液易沉淀、制剂不稳定等问题；
2）小儿消积止咳为治疗小儿食积咳嗽的药物，要求起效温和持久，本发明小儿消积止咳微囊制剂具有明显缓释作用，生物利用度高，且不受胃肠节律的影响，可发挥最佳的治疗咳嗽的效果；
3）小儿消积止咳提取物细粉通过囊材的包埋和掩盖，可掩盖小儿消积止咳口服液固有的的不良气味及口感，小儿患者用药依从性好。
 有益效果
本发明小儿消积止咳微囊制剂呈类白色或灰白色粉末，呈疏松状，无不良气味，流动性较好，分散性和稳定性均佳。微囊颗粒表面除有个别存在凹痕外，颗粒较圆整并接近球形，表面致密无孔隙，基本无黏连，囊粒径分布相对均匀，粒径分布较窄，多数集中在25μm附近，且呈近似的正态分布。包封率测定结果表明，本发明制剂配方及制备工艺所得的小儿消积止咳微囊制剂，其包封率均在80%以上，最高达94.1%，微囊化效果较好。
体外累积溶出度试验表明，本发明小儿消积止咳微囊胶囊、小儿消积止咳微囊片在1h内累积溶出百分率小于53%，2h内均达到84%以上的溶出，3h内基本释放完全。与传统口服液相比，本发明小儿消积止咳微囊制剂具有一定的缓释作用。
加速稳定性试验结果表明，在加速试验条件（40±2℃、RH 75％±5）下放置6个月，小儿消积止咳微囊片及微囊胶囊性状无变化，含量无明显变化，水分、溶散时限及卫生学各项考察指标均符合要求。由上述实验数据可知，本发明所制备的小儿消积止咳微囊制剂稳定性好，质量可控。
 附图说明
图1为实施例4小儿消积止咳微囊胶囊、实施例7小儿消积止咳微囊片累积溶出度百分率曲线图。
 本发明的实施方式
以下通过具体实施例进一步描述本发明，但本发明并不仅仅限于以下实施例，任何形式的等同替换对本领域普通技术人员来说都是显而易见且包含在本发明之中的。
实施例 1  小儿消积止咳微囊胶囊
1）提取、纯化工艺：山楂200g     槟榔50g       枇杷叶200g枳实50g      莱菔子150g    全瓜蒌67g  葶苈子150g   桔梗80g       连翘150g  蝉蜕50g
以上10味，加水煎煮2次，第一次加10倍量水煎煮2小时，第二次加10倍量水煎煮2.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.13的浸膏，加95%乙醇醇沉，使乙醇含量达到60%，冷藏24小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.19的浸膏，加7倍量水转溶精提，冷藏36小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.24的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度58℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉112g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：112g   B、阿拉伯胶：835g
C、二氧化钛：11g    D、聚乙二醇6000：42g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，55℃条件下加热搅拌使溶解，配置成质量分数为28%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和蔗糖脂肪酸脂8g，均质乳化，得乳化液，在进风温度170℃、喷雾压力0.37MPa、进料速度18ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊787g。
取步骤2）微囊，加入淀粉213g，灌装，磨光机中抛光，剔除破损胶囊，即得。
实施例 2  小儿消积止咳微囊片
1）提取、纯化工艺：山楂70g     槟榔180g    枇杷叶70g  枳实70g      莱菔子140g    全瓜蒌75g  葶苈子140g   桔梗90g       连翘140g  蝉蜕60g
以上10味，加水煎煮2次，第一次加8倍量水煎煮1.5小时，第二次加9倍量水煎煮1.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.15的浸膏，加95%乙醇醇沉，使乙醇含量达到70%，冷藏48小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.17的浸膏，加5倍量水转溶精提，冷藏48小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.2的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度52℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉97g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：97g  B、麦芽糊精：568g  β-乳球蛋白：284g  C、十八醇：11g  D、丙二醇：30g  柠檬酸：10g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，48℃条件下加热搅拌使溶解，配置成质量分数为31%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和泊洛沙姆6g，均质乳化，得乳化液，在进风温度169℃、喷雾压力0.4MPa、进料速度13ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊805g。
取步骤2）微囊，加入蔗糖粉177g，混匀，制成粗颗粒，干燥，粉碎，过筛，制颗粒，低温干燥，整粒，加入10g硬脂酸镁和8g的滑石粉，混匀，压片，即得。
实施例 3  小儿消积止咳微囊胶囊
1）提取、纯化工艺：山楂170g     槟榔80g    枇杷叶170g  枳实80g    莱菔子130g    全瓜蒌90g   葶苈子130g    桔梗100g    连翘130g    蝉蜕80g
以上10味，加水煎煮2次，第一次加9倍量水煎煮2小时，第二次加8倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.12的浸膏，加95%乙醇醇沉，使乙醇含量达到80%，冷藏12小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.15的浸膏，加6倍量水转溶精提，冷藏24小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.21的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度53℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉107g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：107g   B、阿拉伯胶：494g   大豆分离蛋白：329g   C、十八醇：8g    二氧化钛：15    D、丙二醇：47g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，60℃条件下加热搅拌使溶解，配置成质量分数为23%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和Tween80 5g，均质乳化，得乳化液，在进风温度163℃、喷雾压力0.34MPa、进料速度19ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊815g。
取步骤2）微囊，加入乳糖185g，灌装，磨光机中抛光，剔除破损胶囊，即得。
实施例 4  小儿消积止咳微囊胶囊
1）提取、纯化工艺（15倍处方量）：山楂1500g    槟榔1500g    枇杷叶1500g  枳实1500g    莱菔子1500g   全瓜蒌2010g  葶苈子1500g   桔梗1500g     连翘1500g   蝉蜕990g。
以上10味，加水煎煮2次，第一次加10倍量水煎煮2.5小时，第二次加8倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.12的浸膏，加95%乙醇醇沉，使乙醇含量达到70%，冷藏24小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.18的浸膏，加6倍量水转溶精提，冷藏48小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.23的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度56℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉1755g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：117g   B、麦芽糊精：578g  β-乳球蛋白：248g  C、二氧化钛：6g   单硬脂酸甘油酯：6g   D、聚乙二醇6000：30g  柠檬酸：15g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊872g。
取步骤2）微囊，加入微粉硅胶128g，灌装，磨光机中抛光，剔除破损胶囊，即得。
实施例 5  小儿消积止咳微囊片
1）提取、纯化工艺：山楂135g     槟榔125g      枇杷叶125g  枳实115g     莱菔子110g    全瓜蒌185g  葶苈子125g   桔梗125g      连翘125g   蝉蜕75
以上10味，加水煎煮2次，第一次加8倍量水煎煮2小时，第二次加9倍量水煎煮1.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.15的浸膏，加95%乙醇醇沉，使乙醇含量达到70%，冷藏24小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.16的浸膏，加7倍量水转溶精提，冷藏36小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.25的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度57℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉153g，备用；
2）制剂工艺
A、小儿消积止咳提取物细粉：153g   B、阿拉伯胶：495g  麦芽糊精：309g   C、十八醇：22g    D、聚乙二醇6000：24g   丙二醇：20g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，50℃条件下加热搅拌使溶解，配置成质量分数为36%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和泊洛沙姆9g，均质乳化，得乳化液，在进风温度165℃、喷雾压力0.35MPa、进料速度22ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊846g。
取步骤2）微囊，加入糊精135g，混匀，制成粗颗粒，干燥，粉碎，过筛，制颗粒，低温干燥，整粒，加入7g硬脂酸镁和12g的滑石粉，混匀，压片，即得。
实施例 6  小儿消积止咳微囊
1）提取、纯化工艺：山楂50g     槟榔200g     枇杷叶50g  枳实200g    莱菔子80g    全瓜蒌268g   葶苈子80g   桔梗150g     连翘80g   蝉蜕100g
以上10味，加水煎煮2次，第一次加9倍量水煎煮2.5小时，第二次加10倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.14的浸膏，加95%乙醇醇沉，使乙醇含量达到80%，冷藏48小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.19的浸膏，加5倍量水转溶精提，冷藏24小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.22的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度54℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉185g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：185g   B、黄原胶：374g  麦芽糊精：374g   C、二氧化钛：22g   D、柠檬酸 45g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，58℃条件下加热搅拌使溶解，配置成质量分数为25%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和蔗糖脂肪酸酯6g、卵磷脂5g，均质乳化，得乳化液，在进风温度167℃、喷雾压力0.40MPa、进料速度17ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊833g。
实施例 7  小儿消积止咳微囊片
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g   B、大豆分离蛋白：530g   麦芽糊精：236g  C、单硬脂酸甘油酯：17g   D、丙二醇：41g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，52℃条件下加热搅拌使溶解，配置成质量分数为35%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和卵磷脂9g，均质乳化，得乳化液，在进风温度166℃、喷雾压力0.39MPa、进料速度20ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊858g。
取步骤2）微囊，加入微晶纤维素125g，混匀，制成粗颗粒，干燥，粉碎，过筛，制颗粒，低温干燥，整粒，加入6g硬脂酸镁和11g的滑石粉，混匀，压片，即得。
实施例 8  小儿消积止咳微囊片
1）提取、纯化工艺：山楂190g     槟榔60g       枇杷叶190g   枳实60g      莱菔子140g    全瓜蒌77g   葶苈子140g   桔梗90g       连翘140g  蝉蜕60g
以上10味，加水煎煮2次，第一次加10倍量水煎煮1.5小时，第二次加8倍量水煎煮2.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.13的浸膏，加95%乙醇醇沉，使乙醇含量达到60%，冷藏24小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.2的浸膏，加7倍量水转溶精提，冷藏48小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.25的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度56℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉122g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：122g   B、辛烯基琥珀酸酯化淀粉：596g  β-乳球蛋白：239g  C、十八醇：7g   D、聚乙二6000：36g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，47℃条件下加热搅拌使溶解，配置成质量分数为30%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和Tween80 7g，均质乳化，得乳化液，在进风温度172℃、喷雾压力0.41MPa、进料速度14ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊820g。
取步骤2）微囊，加入蔗糖粉160g，混匀，制成粗颗粒，干燥，粉碎，过筛，制颗粒，低温干燥，整粒，加入8g硬脂酸镁和12g的滑石粉，混匀，压片，即得。
实施例 9  小儿消积止咳微囊胶囊
1）提取、纯化工艺：山楂100g     槟榔150g       枇杷叶100g   枳实150g     莱菔子110g     全瓜蒌228g  葶苈子110g   桔梗130g       连翘100g   蝉蜕80g
以上10味，加水煎煮2次，第一次加10倍量水煎煮2小时，第二次加9倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.12的浸膏，加95%乙醇醇沉，使乙醇含量达到80%，冷藏48小时，过滤，得滤液，滤液减压浓缩至60℃-65℃时密度为1.18的浸膏，加6倍量水转溶精提，冷藏36小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.23的稠膏，带式真空干燥，真空度-0.08MPa--0.10Mpa，干燥温度58℃，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉165g，备用；
2）制剂工艺：A、小儿消积止咳提取物细粉：165g   B、辛烯基琥珀酸酯化淀粉：776g   C、单硬脂酸甘油酯：10g    二氧化钛：10g  D、丙二醇：39g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，56℃条件下加热搅拌使溶解，配置成质量分数为32%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂10g，均质乳化，得乳化液，在进风温度171℃、喷雾压力0.38MPa、进料速度20ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊799g。
取步骤2）微囊，加入糊精201g，灌装，磨光机中抛光，剔除破损胶囊，即得。
对比实施例 1  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g   B、麦芽糊精：578gβ-乳球蛋白：248g   C、二氧化钛：6g   单硬脂酸甘油酯：6g   D、聚乙二醇6000：45g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊803g。
对比实施例 2  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g   B、麦芽糊精：578g  β-乳球蛋白：248g   C、二氧化钛：6g   单硬脂酸甘油酯：6g    D、柠檬酸：45g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊808g。
对比实施例 3  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g  B、麦芽糊精：578gβ-乳球蛋白：248g   C、二氧化钛：6g  单硬脂酸甘油酯：6g   D、聚乙二醇6000：22.5   柠檬酸：22.5g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊833g。
对比实施例 4  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g   B、麦芽糊精：578gβ-乳球蛋白：248g  C、二氧化钛：6g   单硬脂酸甘油酯：6g  D、聚乙二醇6000：33.75g   柠檬酸：11.25g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊829g。
对比实施例 5  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g  B、麦芽糊精：578g β-乳球蛋白：248g  C、二氧化钛：6g  单硬脂酸甘油酯：6g  D、聚乙二醇6000：36g  柠檬酸：9g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊825g。
对比实施例 6  小儿消积止咳微囊
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。
制剂工艺：A、小儿消积止咳提取物细粉：117g    B、麦芽糊精：578gβ-乳球蛋白：248g   C、二氧化钛：6g   单硬脂酸甘油酯：6g   D、聚乙二醇6000：37.5g   柠檬酸：7.5g
将以上配方量的囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入配方量的小儿消积止咳提取物细粉和大豆卵磷脂2g、蔗糖脂肪酸脂5g，均质乳化，得乳化液，在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊819g。
对比实施例 7  小儿消积止咳颗微囊的制备
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。所用微囊制备方法参照中国专利“一种复方陈醋微囊及其制备方法与应用（授权公告号CN106036829B）”的最佳效果实施例5，以此考察现有技术微囊制备方法应用于小儿消积止咳提取物细粉时所达到的制剂效果。
制剂工艺：A、小儿消积止咳提取物细粉：222g   B、3%海藻酸钠溶液：778g
将上述配方量的小儿消积止咳提取物细粉加入到质量分数为3%的海藻酸钠溶液，制得微囊囊芯混合液，其中海藻酸钠与小儿消积止咳提取物细粉的重量比为3.5：1；
将上述囊芯混合液混合均匀，在搅拌状态下滴入1.5%的壳聚糖与3.5%的氯化钙混合液体系中进行微囊化包埋；
用泵将上述制得的微囊送到喷雾干燥机进行喷雾干燥，控制进风口温度为185℃，喷雾压力0.185MPa，最终微囊沥出得到微囊成品384g。
对比实施例 8  小儿消积止咳微囊的制备
本实施例所用小儿消积止咳提取物细粉为实施例4步骤1）提取、纯化工艺所得的小儿消积止咳提取物细粉。所用微囊制备方法参照“胡锐，周广萍，宋维春.喷雾干燥法中药益生元微囊的制备及体外控释分析[J].安徽农业科学，2016，44（29）：89-94.”中最佳的微囊制备工艺，即囊材为明胶：海藻酸钠=1：3，芯材质量分数为20%，进风口温度187℃、出风口温度60℃、进料速度为32mL/min。
制剂工艺：A、小儿消积止咳提取物细粉：200g   B、明胶：200g  海藻酸钠：600g
将以上配方量的明胶、海藻酸钠加入纯化水，50℃条件下加热搅拌使溶解，配制成质量分数为4%的囊材溶液，冷却至室温，搅拌状态下加入小儿消积止咳提取物细粉，均质乳化，得乳化液，在进风温度187℃、出风口温度60℃、喷雾压力0.39MPa、进料速度32ml/min条件下进行喷雾干燥，收集微囊，冷却，得微囊417g。
 工业实用性
实验例 1  微囊形态及粒径分布
一、形态
取实施例4、实施例7微囊样品适量，置蒸发皿中，于自然光处或相当于自然光的室内，观察其色泽、形状。肉眼观测到微囊样品呈白色或灰白色粉末，呈疏松状，无不良气味，流动性较好，分散性和稳定性均佳。
将上述样品分别加入少量丙酮，超声2min（使重叠粘连的微囊分散），蘸取并滴加在玻片上，加盖玻片，置于Winner99C型静态颗粒图像仪（济南微纳颗粒仪器股份有限公司）放大1000倍观察，微囊颗粒表面除有个别存在凹痕外，颗粒较圆整并接近球形，表面致密无孔隙，基本无黏连，符合微囊要求。
二、粒径分布
取实施例4、实施例7微囊样品约0.03g，以50％乙醇作为分散介质，置Winner2005B智能型激光粒度分析仪（济南微纳颗粒仪器股份有限公司）中测定粒径（D），结果见表1（表中D10、D50、D90分别表示分布曲线中累积分布为10％、50％、90％时最大颗粒的等效直径，Dav表示平均粒径）。
表1  小儿消积止咳微囊粒径检测结果
样品 D10，μm D50，μm D90，μm Dav，μm
实施例4 6.712 22.646 49.208 25.843
实施例7 6.645 22.596 48.823 25.422
从表1可以看出，小儿消积止咳微囊粒径分布相对均匀，多数集中在25μm附近，其中实施例4微囊的平均粒径为25.84μm，实施例7微囊的平均粒径为25.42μm，两份样品的微囊粒径分布较窄，且呈近似的正态分布，微囊化效果较好。
实验例 2  小儿消积止咳微囊包封率测定
包封率指微囊中的实际含药量占微囊样品中总药量（即载药量）的百分比，即制得的微囊含药量占系统总含药量的百分比。包封率越高，表明药物被包埋的程度越好，小儿消积止咳微囊包封率测定的具体方法如下。
色谱条件与系统适用性试验   以十八烷基硅烷键合硅胶为填充剂；以乙腈-甲醇-磷酸二氢钾溶液（取磷酸二氢钾0.6g，十二烷基磺酸钠1.0g，冰醋酸1ml，加水溶解并稀释至1000ml)(15：30：55)为流动相；检测波长为224nm。理论板数按辛弗林峰计算应不低于2000。
对照品溶液的制备   取辛弗林对照品适量，精密称定，加50%甲醇制成每lml含20μg的溶液，即得。
供试品溶液的制备   精密称取适量小儿消积止咳微囊样品，置100mL容量瓶中，以75%的乙醇定容至100mL，摇匀，使微囊外表面小儿消积止咳提取物全部溶解在乙醇溶液中，精密移取10ml上述溶液置另一25mL容量瓶中，并以75%的乙醇溶液定容至刻度，取5ml样品溶液，通过聚酰胺柱(30〜60目，2.5g，内径为12.5mm)，用水30ml洗脱，收集洗脱液置50ml量瓶中，加水至刻度，摇匀，滤过，取续滤液，即得微囊外辛弗林供试品溶液。
另精密称取适量小儿消积止咳微囊样品，置100mL容量瓶中，以pH=7.6的磷酸二氢钾-氢氧化钠缓冲液溶解并定容至100mL，摇匀，使微囊外表面及微囊内小儿消积止咳提取物全部溶解于缓冲液中，其余操作同上，即得微囊辛弗林供试品溶液。
测定法   取标准溶液及供试品溶液，分别进样20ul，采用外标两点法对数方程计算样品中辛弗林的含量，通过辛弗林的含量计算微囊外表面提取物细粉的量（m）及微囊总提取物细粉的量（M）。包封率=（微囊样品中总药量M−微囊外药量m）×100%/微囊样品中总药量M。
表2  小儿消积止咳微囊包封率及收率
序号 实施例 包封率，% 收率，%
1 实施例4  94.1 86.3
2 实施例7  92.8 87.7
3 对比实施例1 79.5 80.3
4 对比实施例2 77.2 80.8
5 对比实施例3 83.8 83.3
6 对比实施例4   82.5 82.9
7 对比实施例5   81.9 82.5
8 对比实施例6   81.1 81..9
9 对比实施例7   36.4 38.4
10 对比实施例8   45.7 41.7
由表2可得，在增塑剂为聚乙二醇6000和柠檬酸复合物，且用量固定为制剂配方总量4.5%时，随着聚乙二醇6000与柠檬酸用量比例的变化，小儿消积止咳微囊的包封率和合格微囊的收率也随之变化，从实验结果来看，聚乙二醇6000：柠檬酸=2：1时，其包封率最好，成品收率最高，并明显高于增塑剂为单味聚乙二醇6000的对比实施例1以及增塑剂为单味柠檬酸的对比实施例2。
以现有技术专利及文献所述中药复方微囊制备工艺进行微囊制备的对比实施例7和对比实施例8所得微囊包封率较差，分别为36.4%和45.7%；其收率较低，分别为38.4%和41.7%。可见，以现有技术微囊制剂配方及微囊制备方法进行小儿消积止咳口服液的制备，其包封率及产品收率无法达到相应的要求，无法实现工业化生产。
实验例 3  体外累积溶出度试验
本发明实施例4小儿消积止咳微囊胶囊、实施例7小儿消积止咳微囊片参照溶出度测定法（《中国药典》2015年版四部通则0931缓释或控释制剂）于250ml磷酸盐缓冲液(pH6.8)为溶出介质、水浴温度为37℃±0.5℃、转速100r˙min -1的条件下进行体外溶出试验，以辛弗林为指标进行考察。
色谱条件与系统适用性试验   以十八烷基硅烷键合硅胶为填充剂；以乙腈-甲醇-磷酸二氢钾溶液（取磷酸二氢钾0.6g，十二烷基磺酸钠1.0g，冰醋酸1ml，加水溶解并稀释至1000ml)(15：30：55)为流动相；检测波长为224nm。理论板数按辛弗林峰计算应不低于2000。
对照品溶液的制备   取辛弗林对照品适量，精密称定，加50%甲醇制成每lml含20μg的溶液，即得。
供试品溶液的制备   取各时间点样品10ml，同时补加10ml的同温蒸馏水，样品经0.45μm微孔滤膜滤过，取5ml续滤液，通过聚酰胺柱(30〜60目，2.5g，内径为12.5mm)，用水30ml洗脱，收集洗脱液置50ml量瓶中，加水至刻度，摇匀，滤过，取续滤液，即得。
测定法   取标准溶液，样品溶液，分别进样20ul，采用外标两点法对数方程计算样品中辛弗林的含量，计算各时间点辛弗林的累积溶出百分率，结果见表3。
表3  不同样品累积溶出百分率
Figure 708495dest_path_image001
以溶出时间（min）为横坐标，累积溶出百分率（%）为纵坐标，绘制溶出曲线，见附图1。由附图1可以看出，小儿消积止咳微囊胶囊和小儿消积止咳微囊片在1h内累积溶出百分率小于56%，2h内均达到了84%以上的溶出，3h内基本释放完全，小儿消积止咳微囊制剂具有一定的缓释效果。
实验例 4  加速稳定性考察
为验证本发明小儿消积止咳微囊制剂的稳定性，发明人对实施例4小儿消积止咳微囊胶囊和实施例7小儿消积止咳微囊片进行加速稳定性试验研究。需要说明的是，本试验所用的小儿消积止咳微囊制剂所选取样品为本发明具有代表性的配方及其制备工艺所得的样品，本发明所包含的其它配方及制备方法所得样品涉及的试验及其结果，由于篇幅限制，在此不一一穷举。
本发明两批样品(实施例4微囊胶囊、实施例7微囊片)在铝塑包装下（6粒/版），采用加速试验箱（40±2℃、RH75％±5）保存6个月，分别按0个月，1个月，2个月，3个月，6个月取样)进行加速稳定性考查，其中辛弗林含量测定方法与实验例2同，其它指标的检测方法参照《中国药典》2015年版四部。两批产品加速稳定性试验数据见表4、表5。
Figure 155395dest_path_image002
Figure 857772dest_path_image003
表4、表5加速稳定性试验结果表明，在加速试验条件（40±2℃、RH75％±5）下放置6个月，小儿消积止咳微囊胶囊及微囊片性状无变化，含量无明显变化，水分、崩解（溶散）时限及卫生学各项考察指标均符合要求。由上述加速稳定性试验结果可知，本发明所制备的小儿消积止咳微囊制剂稳定性好，质量可控。

Claims (9)

  1. 一种小儿消积止咳微囊制剂，其特征在于，按重量百分比计，微囊制剂配方包括以下组分：A、小儿消积止咳提取物细粉9.7%-18.5%  B、囊材74.8% -85.2%  C、抗粘剂0.7%-2.3%       D、增塑剂3.9%-4.7%
    所述囊材为阿拉伯胶、麦芽糊精、辛烯基琥珀酸酯化淀粉、β-乳球蛋白、大豆分离蛋白、黄原胶中的一种或几种；所述抗粘剂为单硬脂酸甘油酯、十八醇、二氧化钛中的一种或几种；所述增塑剂为聚乙二醇6000、丙二醇、柠檬酸中的一种或几种。
  2. 如权利要求1所述的微囊制剂，其特征在于，所述小儿消积止咳提取物细粉由下列原料制成：山楂50-200重量份      槟榔50-200重量份       枇杷叶50-200重量份 
    枳实50-200重量份      莱菔子80-150重量份     瓜蒌67-268重量份 
    葶苈子80-150重量份    桔梗80-150重量份       连翘80-150重量份 
    蝉蜕50-100重量份；
    优选之一，所述小儿消积止咳提取物细粉由下列原料制成：
    山楂100重量份    槟榔100重量份      枇杷叶100重量份
    枳实100重量份    莱菔子100重量份    全瓜蒌134重量份
    葶苈子100重量份  桔梗100重量份      连翘100重量份
    蝉蜕66重量份。
  3. 如权利要求1或2所述的微囊制剂，其特征在于，按重量百分比计，制剂配方包含以下成分：A、小儿消积止咳提取物细粉11.2%-16.5%   B、囊材78.1% -83.5%
    C、抗粘剂1.2%-1.7%                     D、增塑剂4.1%-4.5%
    所述囊材按重量计为麦芽糊精：β-乳球蛋白=7：3、阿拉伯胶：麦芽糊精=8：5、大豆分离蛋白：麦芽糊精：黄原胶=9：4：1 、辛烯基琥珀酸酯化淀粉：β-乳球蛋白=5：2中的一种；所述抗粘剂按重量计为十八醇：二氧化钛=5：3或单硬脂酸甘油酯；所述增塑剂按重量计为聚乙二醇6000：柠檬酸=1-5：1或丙二醇。
  4. 如权利要求1-3中任一项所述小儿消积止咳微囊制剂的制备方法，其特征在于，包括下列步骤：1）提取、纯化工艺
    A、将炒山楂、槟榔、蜜炙枇杷叶、枳实、炒莱菔子、瓜蒌、炒葶苈子、桔梗、连翘、蝉蜕加8-10倍量水煎煮2次，每次1.5-2.5小时，合并煎煮液，过滤，减压浓缩至60℃-65℃时密度为1.10-1.15的浸膏，加95%乙醇醇沉，使乙醇含量达到60%-80%，冷藏12-48小时，过滤，得滤液，备用；
    B、步骤A滤液减压浓缩至60℃-65℃时密度为1.15-1.20的浸膏，加5-7倍量水转溶精提，冷藏24-48小时，过滤，滤液减压浓缩至60℃-65℃时相对密度为1.20-1.25的稠膏，干燥，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉，备用；
    2）制剂工艺
    C、按配方量称取步骤B小儿消积止咳提取物细粉、囊材、抗粘剂和增塑剂，将囊材、抗粘剂和增塑剂加入纯化水，47℃-60℃条件下加热搅拌使溶解，配置成质量分数为24%-36%的囊材溶液，冷却至室温，搅拌状态下加入小儿消积止咳提取物细粉和乳化剂，均质乳化，得乳化液，备用；
    D、步骤C乳化液在进风温度163℃-172℃、喷雾压力0.34MPa-0.41MPa、进料速度13ml/min-22ml/min条件下进行喷雾干燥，收集微囊，冷却，即得。
  5. 根据权利要求4所述的方法，其特征在于，步骤1）所述提取、纯化工艺包括下列步骤：
    A、将炒山楂、槟榔、蜜炙枇杷叶、枳实、炒莱菔子、瓜蒌、炒葶苈子、桔梗、连翘、蝉蜕加水煎煮2次，第一次加10倍量水煎煮2.5小时，第二次加8倍量水煎煮2小时，合并煎煮液，过滤，减压浓缩至65℃时密度为1.12的浸膏，加95%乙醇醇沉，使乙醇含量达到70%，冷藏24小时，过滤，得滤液，备用；
    B、步骤A滤液减压浓缩至65℃时密度为1.18的浸膏，加6倍量水转溶精提，冷藏48小时，过滤，滤液减压浓缩至65℃时相对密度为1.23的稠膏，带式真空干燥，粉碎成细粉，过筛，即得小儿消积止咳提取物细粉，备用。
  6. 根据权利要求5所述的方法，其特征在于，步骤1）B中带式真空干燥的条件为真空度-0.08MPa--0.10Mpa，干燥温度52℃-59℃。
  7. 根据权利要求4-6中任一项所述的方法，其特征在于，步骤2）所述制剂工艺包括下列步骤：C、按配方量称取步骤B小儿消积止咳提取物细粉、囊材、抗粘剂和增塑剂，将囊材、抗粘剂和增塑剂加入纯化水，54℃条件下加热搅拌使溶解，配置成质量分数为33%的囊材溶液，冷却至室温，搅拌状态下加入小儿消积止咳提取物细粉和乳化剂，均质乳化，得乳化液，备用；
    D、步骤C乳化液在进风温度168℃、喷雾压力0.40MPa、进料速度21.5ml/min条件下进行喷雾干燥，收集微囊，冷却，即得。
  8. 如权利要求7所述的方法，其特征在于，步骤C所述乳化剂为Tween80、大豆磷脂、卵磷脂、泊洛沙姆、蔗糖脂肪酸酯中的一种或几种，用量按质量分数计为制剂配方总量的0.5%-1.1%。
  9. 如权利要求8所述的方法，其特征在于，步骤C所述乳化剂按重量计为大豆磷脂：蔗糖脂肪酸酯=2∶5的复合乳化剂，用量按质量分数计为制剂配方总量的1.0%。
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