WO2015032319A1 - 一种冻干赋型制剂的包装和递送系统及其制备方法 - Google Patents

一种冻干赋型制剂的包装和递送系统及其制备方法 Download PDF

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Publication number
WO2015032319A1
WO2015032319A1 PCT/CN2014/085822 CN2014085822W WO2015032319A1 WO 2015032319 A1 WO2015032319 A1 WO 2015032319A1 CN 2014085822 W CN2014085822 W CN 2014085822W WO 2015032319 A1 WO2015032319 A1 WO 2015032319A1
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Prior art keywords
chamber
packaging
delivery system
cavity
piston
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PCT/CN2014/085822
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English (en)
French (fr)
Inventor
李和伟
Original Assignee
Li Hewei
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Publication of WO2015032319A1 publication Critical patent/WO2015032319A1/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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L3/00—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs
    • A23L3/40—Preservation of foods or foodstuffs, in general, e.g. pasteurising, sterilising, specially adapted for foods or foodstuffs by drying or kilning; Subsequent reconstitution
    • A23L3/44—Freeze-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9789—Magnoliopsida [dicotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K8/00—Cosmetics or similar toiletry preparations
    • A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
    • A61K8/96—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution
    • A61K8/97—Cosmetics or similar toiletry preparations characterised by the composition containing materials, or derivatives thereof of undetermined constitution from algae, fungi, lichens or plants; from derivatives thereof
    • A61K8/9783—Angiosperms [Magnoliophyta]
    • A61K8/9794—Liliopsida [monocotyledons]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
    • A61Q19/00—Preparations for care of the skin
    • B—PERFORMING OPERATIONS; TRANSPORTING
    • B65—CONVEYING; PACKING; STORING; HANDLING THIN OR FILAMENTARY MATERIAL
    • B65D—CONTAINERS FOR STORAGE OR TRANSPORT OF ARTICLES OR MATERIALS, e.g. BAGS, BARRELS, BOTTLES, BOXES, CANS, CARTONS, CRATES, DRUMS, JARS, TANKS, HOPPERS, FORWARDING CONTAINERS; ACCESSORIES, CLOSURES, OR FITTINGS THEREFOR; PACKAGING ELEMENTS; PACKAGES
    • B65D81/00—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents
    • B65D81/32—Containers, packaging elements, or packages, for contents presenting particular transport or storage problems, or adapted to be used for non-packaging purposes after removal of contents for packaging two or more different materials which must be maintained separate prior to use in admixture
    • B65D81/3255—Containers provided with a piston or a movable bottom, and permitting admixture within the container
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J1/00—Containers specially adapted for medical or pharmaceutical purposes
    • A61J1/14—Details; Accessories therefor
    • A61J1/20—Arrangements for transferring or mixing fluids, e.g. from vial to syringe
    • A61J1/2093—Containers having several compartments for products to be mixed
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61J—CONTAINERS SPECIALLY ADAPTED FOR MEDICAL OR PHARMACEUTICAL PURPOSES; DEVICES OR METHODS SPECIALLY ADAPTED FOR BRINGING PHARMACEUTICAL PRODUCTS INTO PARTICULAR PHYSICAL OR ADMINISTERING FORMS; DEVICES FOR ADMINISTERING FOOD OR MEDICINES ORALLY; BABY COMFORTERS; DEVICES FOR RECEIVING SPITTLE
    • A61J7/00—Devices for administering medicines orally, e.g. spoons; Pill counting devices; Arrangements for time indication or reminder for taking medicine
    • A61J7/0015—Devices specially adapted for taking medicines
    • A61J7/0053—Syringes, pipettes or oral dispensers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/84—Products or compounds obtained by lyophilisation, freeze-drying
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2800/00—Properties of cosmetic compositions or active ingredients thereof or formulation aids used therein and process related aspects
    • A61K2800/80—Process related aspects concerning the preparation of the cosmetic composition or the storage or application thereof
    • A61K2800/88—Two- or multipart kits
    • A61K2800/882—Mixing prior to application

Definitions

  • the invention relates to a packaging and delivery system for a freeze-dried preparation and a preparation method thereof, in particular to a lyophilized preparation for food, health food, oral medicine, external medicine and cosmetics, which is combined with a solvent.
  • a dual chamber mixing device and delivery system that are separately stored in the same package, ready to use, and their corresponding preparation methods.
  • the freeze-dried shaped preparation is a preparation form prepared by using a freeze-drying forming technique, which is formed by injecting a raw material of a preparation into a molding die and then performing a freeze-drying process. Since the preparation adopts a freeze-drying process, the heat-sensitive component can be protected from being destroyed, and the preparation itself has a large number of micropores and pores, so that it can be quickly disintegrated and dissolved, and thus is widely used for orally disintegrating tablets and speed. Release tablets, chewable tablets, special cosmetics and other pharmaceuticals, food, health food and cosmetics.
  • the freeze-dried preparations Due to the large number of micropores and pores in the process of freeze-drying the preparation, the freeze-dried preparations have defects such as low strength, easy brittleness and high moisture absorption. Therefore, most of the packaging devices selected for the preparation prepared by the freeze-drying technique are double-aluminum packaging to ensure moisture resistance, oxygen barrier property and the like.
  • the double aluminum packaging often does not have good supportability by itself, and needs to be protected by other auxiliary packagings with certain hardness; it is cumbersome to open and use, and brings a certain sense of experience for the use of the product. influences.
  • double When the aluminum package is used it needs to be opened and packaged, and it can be used after mixing with the solvent. During the mixing process, the process of opening the package, mixing and exporting the mixed liquid is complicated, and it is easy to mix bacteria and the secondary pollution after the package is opened. .
  • the traditional pre-filled double-cavity syringe is mainly used for injection purposes.
  • it is necessary to complete the packaging process in the 100-level clean area after lyophilization in the syringe.
  • Increased production costs because traditional freeze-drying is based on small molecule sugars, sugar alcohols and amino acids, the lyophilized powder system is very sensitive to physical and mechanical forces, if not used in situ freeze-drying It is very easy to break, resulting in inaccurate dosage.
  • the freeze-dried comminuted piece which is broken or peeled off also brings great problems to the assembly and use of the pre-filled double-chamber syringe.
  • the inventors are determined to innovate, carry out a lot of in-depth research and experimental work, and develop a non-injection use.
  • the packaged and delivered system of the freeze-dried preparation and the preparation of the corresponding freeze-dried preparation can be separately stored in the same package as the solvent, and the lyophilized preparation can be separately stored in the same package. And the assembly method, thereby completing the present invention.
  • a packaging and delivery system for a lyophilized formulation comprising a lyophilized formulation, a solvent, and a packaging and delivery device for the lyophilized formulation and solvent.
  • the lyophilized formulation and solvent packaging and delivery device comprises a dual chamber mixing device.
  • the packaging and delivery device itself is a two-chamber mixing device in which the solvent and the lyophilized formulation are separately stored in different chambers of the dual chamber mixing chamber in the dual chamber mixing device.
  • the interaction of the various components of the dual chamber mixing device allows the solvent and lyophilized formulation to be mixed and exported immediately upon use.
  • the dual chamber mixing chamber for the preservation of the solvent and the lyophilized formulation is separable from other components for replacement.
  • the binder is a water-soluble polymer material which is edible, cosmetic or pharmaceutically acceptable, and may be, for example, a polysaccharide, a polypeptide, or a protein; It may be an artificially polymerized polymer or a modified natural polymer material or a mixture thereof.
  • Binders used in the present invention include, but are not limited to, gelatins (e.g., gelatin, hydrolyzed gelatin, etc.), cellulose ethers (e.g., carboxymethylcellulose, hydroxyethylmethylcellulose, etc.), modified starches ( For example, pullulan, hydroxypropyl starch, etc.), PVP, PVA, hyaluronic acid, albumin, chitosan and their different molecular weight products or any combination thereof.
  • gelatins e.g., gelatin, hydrolyzed gelatin, etc.
  • cellulose ethers e.g., carboxymethylcellulose, hydroxyethylmethylcellulose, etc.
  • modified starches For example, pullulan, hydroxypropyl starch, etc.
  • PVP polyvinyl
  • PVA hyaluronic acid
  • albumin chitosan and their different molecular weight products or any combination thereof.
  • the active ingredient may be water-soluble or water-insoluble, and may be a chemical, a biopharmaceutical, a Chinese herbal extract, a vitamin, a mineral, a cosmetic benefit component, and One or more of the other active ingredients that are beneficial to the human body.
  • the active ingredient in the present invention may be selected from one of the following ingredients or any combination thereof:
  • Antipyretic analgesic anti-inflammatory drugs such as aspirin, diflunisal, salicylate, acetamino group Phenol, indomethacin, ibuprofen, naproxen, ketoprofen, piroxine, sulprofen, flurbiprofen, piroxicam, meloxicam, nimesulide, benzbromarone, etc.;
  • Central stimulants such as pimoline, aprefini, piracetam, etc.
  • migraine drugs such as sumatriptan succinate
  • Analgesics such as rotundin, buprenorphine, pentazocine, naloxone, etc.;
  • Anti-Parkinson's disease and treatment of Alzheimer's disease drugs such as levodopa, compound carbidopa, compound benserazide, amantadine hydrochloride, piracetil, prolamine, donepezil, huperzine A, etc.;
  • Antipsychotic drugs such as chlorpromazine, promethazine, pethidine, thioridazine, cloprofen, clozapine, sulpiride, tiapride, penfluridol, risperidone, etc.;
  • Antiepileptic and anticonvulsant drugs such as phenytoin, carbamazepine, primidone, gabapentin, lamotrigine, sodium valproate, clonazepam, and the like.
  • Sedative hypnotics such as diazepam, nitrazepam, oxazepam, lorazepam, phenobarbital, etc.;
  • a cholinesterase inhibitor such as scopolamine
  • Antiarrhythmic drugs such as propionate, tonicani, mexiletine, ethyl thiazide, phenytoin, propafenone, amiodarone, etc.;
  • Anti-angina and anti-atherosclerotic drugs such as propranolol, nifedipine, gemfibrozil, bezafibrate, lovastatin, simvastatin, pravastatin, etc.;
  • Antihypertensive drugs such as enalapril, captopril, hydrochlorothiazide, amlodipine;
  • Adrenal receptor blockers such as acebutolol, aprol, etc.
  • Corticosteroids such as betamethasone, cortisone acetate, etc.
  • Antidiabetic drugs such as repaglinide
  • Antithyroid drugs such as propylthiouracil, carbimabazole, methimazole, etc.;
  • Antihistamines such as cetirizine hydrochloride, loratadine, etc.;
  • Digestive system medications such as butyl bromide, granisetron hydrochloride, etc.;
  • Blood system drugs such as EPO, adenosine cobalamin, etc.
  • Urinary system drugs such as azosemide, furosemide, etc.
  • Reproductive system drugs such as estrogen, Nandrolone phenylpropionate, etc.
  • Antiparasitic drugs such as albendazole, canbendazole, etc.
  • Antineoplastic agents such as ammonia, ampicillin, etc.
  • Antimicrobial agents such as ampicillin, sulphacillin sodium, etc.
  • Antibiotics such as amoxicillin, cephalexin, cefprozil, cefuroxime axetil, roxithromycin, erythromycin ethylsuccinate, josamycin, etc.;
  • Chinese herbal medicine active ingredient monomers such as: breviscapine, artemisinin, etc.;
  • Single-flavored Chinese herbal medicine extract and compound Chinese medicine extract such as: tanshinone extract, salvia miltiorrhiza phenolic acid extract, compound Danshen dripping pill extract, Niuhuang Shangqing pill compound extract, ginseng stem and leaf total saponin, and northern bean root extract , ginseng total saponins, breviscapine, notoginsenoside saponins, swollen wind extract, panax notoginseng saponins, capillaris extract, rhubarb extract, andrographolide, hawthorn leaf extract, centella asiatica ;
  • Natural plant extracts such as aloe extract, yam extract, bilberry extract, bitter gourd extract, green tea extract, fucoidan, licorice, paeoniflorin, etc.;
  • Biological active ingredients EGF, bFGF, aFGF, KGF, IGF, PDGF, VEGF, placental hydrolysate, milk extract, etc.;
  • the lyophilized formulation in addition to the active ingredient and the binder, may or may not contain a skeleton support agent, a thickening suspension, or an antioxidant according to the formulation process.
  • a skeleton support agent e.g., aluminosilicate, aluminosilicate, aluminosilicate, or aluminosilicate, or aluminosilicate.
  • a thickening suspension e.g., a thickening suspension, or an antioxidant according to the formulation process.
  • an antioxidant e.g., a skeleton support agent, a thickening suspension, or an antioxidant according to the formulation process.
  • the backbone support agent includes, but is not limited to, sugars (such as maltose, trehalose, etc.), sugar alcohols (such as mannitol, sorbitol), amino acids of 2 to 12 carbon atoms (such as glycine, Alanine, glutamic acid, etc.) and inorganic salts (such as sodium phosphate, aluminum silicate, etc.).
  • sugars such as maltose, trehalose, etc.
  • sugar alcohols such as mannitol, sorbitol
  • amino acids of 2 to 12 carbon atoms such as glycine, Alanine, glutamic acid, etc.
  • inorganic salts such as sodium phosphate, aluminum silicate, etc.
  • the other excipients include, but are not limited to, thickening suspensions, antioxidants, flavorings and flavors, transdermal absorption enhancers, pH adjusters, etc.; wherein the thickening suspension may be selected from the group consisting of dextran, gum arabic, yellow Raw rubber, carrageenan, pectin, konjac gum, agar, carbomer, carrageenan, and the like, and a synthetic polymer compound and one of other polypeptides or polysaccharides, or any combination thereof;
  • Antioxidants include, but are not limited to, one of vitamin C and its derivatives, anthocyanins, resveratrol, plant-derived polyphenolic compounds, or any combination thereof;
  • the flavoring agents and flavors include, but are not limited to, One or a combination of a flavor of mint, chocolate, vanilla, coffee, tea, corn, lemon, milk, etc.;
  • the transdermal absorption enhancer includes, but is not limited to, lecithin, saponin, One
  • the lyophilized formulation and solvent packaging and delivery device provided by the present invention may be any device capable of achieving the objects of the present invention, preferably a dual chamber mixing device.
  • the dual chamber mixing device comprises a pusher (1) and a dual chamber mixing chamber (9).
  • the pushing device (1) is composed of a pushing chamber (12), a receiving chamber (15), and a push rod piston device (7, 8, 11); while providing a driving force, it can also mix double chambers inside thereof.
  • the cavity plays a very good role in protection.
  • the double chamber mixing chamber (9) is composed of a double chamber (No. N1, No. N2), two pistons (2, 4), a bypass (6), a discharge port (17), and an discharge cover ( 10) Composition; used to store the lyophilized excipient and solvent separately before use, and the lyophilized excipient can be mixed with the solvent under the driving of power under use.
  • the pushing chamber (12) of the pushing device (1) is a two-end opening device; the size thereof is adapted to the shape and volume of the push rod piston device; the lower end of the pushing chamber (12) has a locking device (14);
  • the receiving compartment (15) of the pushing device (1) is a two-end opening device; the size thereof is adapted to the shape and volume of the double-chamber mixing cavity; and the upper end of the receiving compartment (15) has another locking device ( 13), the receiving compartment (15) has a detachable protective cover (16), and the double-chamber mixing cavity can be placed by opening the protective cover (16), and the protective cover (16) can be closed to fix and protect the double a cavity mixing chamber, the lower end of the protective cover (16) has a bayonet or a screw mouth, and the bayonet or screw mouth is matched with the lower end of the double chamber mixing chamber (9), and the double chamber can be mixed a cavity (9) is fixed in the receiving compartment (15);
  • the locking device (14) of the push chamber (12) is matched with the locking device (13) of the receiving compartment (15), and the pushing chamber (12) and the receiving chamber (15) are passed through the locking device (13, 14)
  • the locking can form a firm whole;
  • the locking form of the locking device (13, 14) can be various, as long as the above purpose can be achieved, such as snap-on, threaded, etc.;
  • the push chamber (12) and the storage chamber (15) may be made of blank or printed plastic, metal, glass, ceramics, etc., intended to be fixed, protected and marked;
  • the push rod piston device (7, 8, 11) comprises a pusher (11), a push rod (7) and a piston (8); the push rod (7) and the piston (8) are driven by pushing the push head (11) Moving toward the discharge port, the air between the piston (8) and the piston (2) is squeezed to drive the piston (2) and the liquid in the liquid preparation chamber moves toward the discharge port, and the liquid drives the piston (4) upward. The direction of the nozzle moves.
  • the bottom of the piston (4) moves below the bypass (6), the liquid in the liquid preparation chamber is driven by the piston (2), bypassing the piston (4) directly through the bypass (6). Enter the solid formulation cavity and mix with the lyophilized formulation.
  • the power source for pushing the push head (11) may be any manner that can drive the movement of the manual, electric or mechanical movement, and the pushing distance and the force are fixed or adjustable, and the push rod (7) may be a spring rod or the like. a corresponding device that changes the length;
  • the double cavity (number N1, number N2) of the double chamber mixing chamber (9) is an integral cavity, open at both ends, and fixed in the housing compartment (15); double cavity (number N1, number N2)
  • the piston (2, 4) and the discharge cover (10) constitute two chambers of a solid preparation chamber (No. N1) and a liquid preparation chamber (No.
  • the discharge port 17 can be any shape, such as a suction tube, a drop tube, a ball shape, a spray head, etc.; the solid preparation chamber is close to the discharge port 17, the liquid preparation chamber is away from the discharge port 17; the freeze-drying in the solid preparation chamber
  • the preparation (5) may be a lyophilized preparation of various formulations and forms, and is a preparation which is divided into a solid preparation cavity after being lyophilized in a molding die; the solvent in the liquid preparation cavity may be water and has a certain The nutrient solution and essence of the functional ingredients and various solvents which can be directly used in combination with the freeze-drying type; the double cavity can be used as needed Made of Italian material, the scale can be marked on the double cavity for quantitative purposes.
  • the bypass (6) is located on the side of the solid preparation chamber and has a width slightly larger than the thickness of the piston (4), so that the solvent in the liquid preparation chamber can be opened by the piston to the bypass (6) to form an opening and the solid preparation.
  • the lyophilized formulation (5) in the chamber is mixed.
  • the discharge cover (10) is a device capable of sealing the mouth of the discharge device to isolate the material in the cavity from the external environment.
  • the double-chamber mixing chamber (9) contains a single-use metered freeze-dried preparation product, which can be used to disassemble and replace the double-chamber mixing chamber (9), and the pushing device (1) can be used repeatedly. .
  • the lyophilized formulation is packaged in a solid preparation cavity which is lyophilized in a molding die, demolded and assembled into a two-cavity mixer, and the preparation method comprises the following steps:
  • the injection molding volume in the step (a) is 0.01-5.0 ml; wherein the injection molding can be adopted Accurate quantitative pipetting, pipetting, electronic pipetting and other pipetting devices, plunger pump, gear pump, peristaltic pump, etc., can be used to inject the configured solution or suspension into the quantitative forming mold;
  • the degassing method may adopt a centrifugal degassing method, a vacuum degassing method, an ultrasonic degassing method, etc., wherein the freezing may be performed by liquid nitrogen or liquid, solid carbon dioxide spray cooling, turboexpander cooling mode or cascade cooling mode. , rapidly freezing the solution or suspension to a solid at a temperature of -20 ° C to 196 ° C;
  • the lyophilization is carried out using a vacuum of 0.01-20 mbar, and the temperature is lyophilized between -70 ° C and 50 ° C.
  • the packaging and delivery system is a single-dose package, the amount of liquid is in line with the requirements of the aircraft, easy to carry;
  • the packaging and delivery system does not need to unpack the package, put it into the palm, add liquid, and use the fingers to mix the complicated use of the hands. Push or press to start the push rod piston device. After fully mixing, open the discharge port to use two actions, which is very convenient;
  • Figure 1 is a schematic exploded view of the components of the packaging and delivery system device of the freeze-dried formulation
  • 2 to 3 are schematic diagrams showing combinations of components of a packaging and delivery system device of a freeze-dried formulation
  • Figures 4-9 are graphical representations of the steps of use of the packaging and delivery system for a lyophilized formulation.
  • the bottom of the cavity referred to in the following embodiments refers to the distal end of the cavity away from the discharge port; the upper side of the bypass (6) refers to the end near the discharge port, and the bottom of the bypass (6) means the distance away from the outlet.
  • a push rod piston device 7, 8, 11 is loaded into the push chamber 12, the push chamber 12 is locked with the receiving compartment 15, and the double chamber mixing chamber 9 is loaded into the housing chamber 15, and the push is pushed.
  • the head 11 drives the push rod 7 and the piston 8 to move toward the discharge port, and the air between the piston 8 and the piston 2 is compressed to drive the piston 2 and the liquid in the liquid preparation chamber to move toward the discharge port, and the liquid drives the piston 4 to the outlet.
  • the bottom of the piston 4 moves beyond the bypass 6, the liquid in the liquid preparation chamber is driven by the piston 2, bypasses the piston 4 directly through the bypass 6, enters the solid preparation chamber, and freezes with the liquid therein.
  • the formulation is mixed, and the pusher is pushed forward until the top of the piston 2 is in contact with the bottom of the piston 4.
  • the 2 ml of deionized water in the liquid preparation chamber is completely mixed with the freeze-dried preparation to form a solution containing 2.5% vitamin C;
  • the discharge cover 10 continues to push the push rod piston devices 7, 8, 11 to drive the piston 2 against the piston 4, and the aforementioned mixed solution is extruded from the discharge port 17 and directly applied to the face to become a modern cosmetic.
  • the used double-chamber mixing chamber can be taken out and discarded, and the new dual-chamber mixing chamber can be used again next time.
  • EGF stock solution after thawing, add gelatin and hydrolyzed gelatin, prepare EGF (weight ratio) containing 5% of 100,000 parts, contain 5% gelatin + hydrolyzed gelatin solution, fill into 0.1 ml molding die, freeze-dry molding and then load Double-cavity solid preparation chamber with scaled transparent glass
  • the rubber material piston 4 is assembled into the bottom of the solid preparation chamber, below the bypass 6; then 2 ml of 3% hyaluronic acid solution is filled into the liquid preparation chamber separated by the rubber piston 2;
  • the rubber-made piston 2 allows the liquid to be completely stored in the liquid preparation chamber without oozing out between the rubber-made piston 4 and the rubber-made piston 2, thereby obtaining a double-chamber compound containing the freeze-dried preparation and the solvent.
  • the cavity is combined with a transparent plastic material containment chamber, a push chamber and a manual push rod piston to form a dual chamber mixer device.
  • a push rod piston device 7, 8, 11 is loaded into the push chamber 12, the push chamber 12 is locked with the receiving compartment 15, and the double chamber mixing chamber is loaded into the receiving compartment 15 to push the push head.
  • 11 driving push rod 7 and piston 8 move toward the discharge port, the air between the piston 8 and the piston 2 is compressed to drive the piston 2 and the liquid in the liquid preparation chamber to move to the discharge port, and the liquid drives the piston 4 to discharge.
  • the used double-chamber mixing chamber can be taken out and discarded, and the new dual-chamber mixing chamber can be used again next time.
  • the cabin, the push chamber and the electric push rod piston together form a dual chamber mixer device.
  • the electric push rod piston device 7, 8, 11 is loaded into the push chamber 12, the push chamber 12 is locked with the receiving compartment 15, and the double chamber mixing chamber is loaded into the containing compartment 15, and the electric motor is held down. Button, the electric device pushes the pusher 11 to drive the push rod 7 and the piston 8 to move toward the discharge port, and the air between the piston 8 and the piston 2 is compressed to drive the piston 2 and the liquid in the liquid preparation chamber to move to the discharge port, the liquid The piston 4 is driven to move toward the discharge port. When the bottom of the piston 4 moves beyond the bypass 6, the liquid in the liquid preparation chamber is driven by the piston 2, bypassing the piston 4 directly through the bypass 6, and entering the solid preparation chamber.
  • the used double-chamber mixing chamber can be taken out and discarded, and the new dual-chamber mixing chamber can be used again next time.
  • the cabin, the push chamber and the fully automatic mixing metering push rod piston together form a dual chamber mixer device.
  • the fully automatic mixing and metering push rod piston devices 7, 8, 11 are loaded into the push chamber 12, the push chamber 12 is locked with the receiving compartment 15, and the double chamber mixing chamber is loaded into the containing compartment 15, Pressing the electric button, the electric device pushes the pusher 11 to drive the push rod 7 and the piston 8 to move toward the discharge port, and the air between the piston 8 and the piston 2 is compressed to drive the piston 2 and the liquid in the liquid preparation chamber to the discharge port. Movement, the liquid drives the piston 4 to move toward the discharge port. When the bottom of the piston 4 moves beyond the bypass 6, the liquid in the liquid preparation chamber is driven by the piston 2, bypassing the piston 4 directly through the bypass 6, and entering.
  • the solid preparation chamber is mixed with the freeze-dried preparation, and when the top of the piston 2 is in contact with the bottom of the piston 4, 20 ml of deionized water containing the natural pigment in the liquid preparation chamber is completely mixed with the freeze-dried preparation to form 0.5. % solution of cranberry extract; open the discharge cap 10, adjust the required metering, press the electric button again, push the rod 7 to drive the piston 2 to press the piston 4, and squeeze the quantitative mixture solution out of the discharge port 17 Direct oral administration to form a solid drink Food.
  • the used double-chamber mixing chamber can be taken out and discarded, and the new dual-chamber mixing chamber can be used again next time.
  • the package structure of the present invention is not limited to the form exemplified in the embodiment, and the embodiment is only The preferred embodiments of the present invention are not intended to limit the scope of the invention. Simple or equivalent variations and modifications within the scope of the claims of the invention are within the scope of the invention.

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Abstract

一种冻干赋型制剂（5）的包装和递送系统及其制备方法，冻干赋型制剂（5）应用于食品、保健食品、口服药品、外用药品以及化妆品。该冻干赋型制剂（5）的包装和递送系统包括冻干赋型制剂（5）、溶剂以及所述冻干赋型制剂（5）和溶剂的包装和递送装置，所述包装和递送装置中包含一个双腔混料装置，其中溶剂以及冻干赋型制剂（5）分别保存于双腔混料装置中的双腔混料腔体（9）的不同腔体（N1、N2）中，通过双腔混料装置各部件的相互作用使溶剂和冻干赋型制剂（5）在使用时可以即时混合并导出。该冻干赋型制剂（5）的包装和递送系统可以保护活性成分的稳定性、提高使用效果、降低潜在的副反应、延长货架期、避免污染、使用方便以及降低成本。

Description

一种冻干赋型制剂的包装和递送系统及其制备方法 技术领域
本发明涉及一种冻干赋型制剂的包装和递送系统及其制备方法，特别是一种应用于食品、保健食品、口服药品、外用药品以及化妆品的冻干赋型制剂，将其与溶剂在同一包装内分别保存、使用时即配即用的双腔混料装置和递送系统，以及其相应的制备方法。
背景技术
冻干赋型制剂是利用冻干赋型技术制备的一种制剂形态，其通过将制剂原辅料灌注到成型模具中再经过冷冻干燥的工艺过程成型而成。由于该类制剂采用冷冻干燥工艺，可以保护热敏感成分不被破坏，同时制剂本身具有大量微孔和孔道，使其可以很快的崩解和溶解，因此被广泛应用到口腔崩解片、速释片、咀嚼片、特殊化妆品等药品、食品、保健食品及化妆品领域中。
由于冻干赋型制剂的工艺过程产生大量微孔和孔道的特性，使冻干赋型制剂均具有制剂强度不高、容易脆碎以及极易吸潮等缺陷。因此冻干赋型技术制备的制剂所选用的包装装置大多为双铝包装，以保证其隔潮性、隔氧性等。但双铝包装往往本身不具有很好的支撑性，需要借助其他具有一定硬度的辅助包装增强对制剂的保护性；其在开启与使用时均较为繁琐，为其产品使用的体验感带来一定影响。且双 铝包装在使用时需要开启其包装，与其溶剂进行混合后方可使用，在混合过程中，开启包装、混合以及将混合液导出的过程比较复杂，并容易混入细菌等造成包装开启后的二次污染。
传统的预灌装式双腔注射器主要用于注射使用用途，为避免生产和使用过程中的微生物和其它污染，必须在注射器内完成原位冻干后于百级洁净区内完成包装过程，大大提高了生产成本；同时，由于传统的冷冻干燥是基于小分子糖类、糖醇和氨基酸为主的冻干保护剂体系，其冻干粉形态对物理机械力非常敏感，如果不使用原位冻干，非常容易破碎，造成剂量的不准确，同时破碎或脱落的冻干粉碎片也会给预灌装式双腔注射器的装配和使用带来很大的问题。
发明内容
为了解决冻干赋型制剂的包装和使用方式，同时为了开拓非注射式冻干制剂的包装和使用方式，发明人锐意创新，进行了大量深入的研究和试验工作，开发了一种非注射使用的、可以在使用时即配即用、冻干赋型制剂与其溶剂在同一包装内分开保存，使用时直接混合导出的冻干赋型制剂的包装和递送系统以及相应冻干赋型制剂的制备和装配方法，由此完成了本发明。
根据本发明的一个方面，提供了一种冻干赋型制剂的包装和递送系统，其包括冻干赋型制剂、溶剂以及所述冻干赋型制剂和溶剂的包装和递送装置。
在本发明的一个实施方案中，所述冻干赋型制剂和溶剂的包装和递送装置中包含一个双腔混料装置。
优选的，所述包装和递送装置本身即为一个双腔混料装置，其中溶剂以及冻干赋型制剂分别保存于双腔混料装置中的双腔混料腔体的不同腔体中，通过双腔混料装置各部件的相互作用使溶剂和冻干赋型制剂在使用时可以即时混合并导出。保存溶剂及冻干赋型制剂的双腔混料腔体与其它部件可分离以便于更换。
根据本发明的另一方面，提供了在上述包装和递送系统中使用的冻干赋型制剂，其主要由活性成分和粘结剂组成，且粘结剂：活性成分(重量比)＝1:10至10:1。
在本发明的一个实施方案中，所述粘结剂是可食用、可做化妆品用或者可药用的一种水溶性高分子材料，例如可以是多糖、多肽、蛋白质；所述粘结剂也可能是人工聚合高分子，或者是经过改性的天然高分子材料或其混合物。本发明所用的粘结剂包括但不限于：明胶类(例如明胶、水解明胶等)、纤维素醚类(例如羧甲基纤维素，羟乙基甲基纤维素等)、改性淀粉类(例如普鲁兰糖、羟丙基淀粉等)、PVP、PVA、透明质酸类、白蛋白、壳聚糖及其不同分子量产物或它们的任意组合等。
在本发明的另一个实施方案中，所述的活性成分可以是溶于水也可以是不溶于水的物质，可以为化学药物、生物药物、中药提取物、维生素、矿物质、化妆有益成分和其它对人体有益的活性成分中的一种或一种以上。
在一个优选的实施方案中，本发明中的活性成分可以选自下列成分中一种或它们的任意组合：
化学药物(药物活性成分)：
解热镇痛抗炎药，例如阿司匹林、二氟尼柳、双水杨酯、对乙酰氨基 酚、吲哚美辛、布洛芬、萘普生、酮洛芬、吡洛芬、舒洛芬、氟比洛芬、吡罗昔康、美洛昔康、尼美舒利、苯溴马隆等；
中枢兴奋药，例如匹莫林、阿屈非尼、吡拉西坦等；
治疗偏头痛药，例如琥珀酸舒马普坦；
镇痛药，例如罗通定、丁丙诺啡、喷他佐辛、纳洛酮等；
抗帕金森病和治疗老年痴呆药，例如左旋多巴、复方卡比多巴、复方苄丝肼、盐酸金刚烷胺、吡贝地尔、普罗酚胺、多奈哌齐、石杉碱甲等；
抗精神失常药，例如氯丙嗪、异丙嗪、哌替啶、硫利达嗪、氯普噻吨、氯氮平、舒必利、泰必利、五氟利多、利培酮等；
抗癫痫病和抗惊厥药，例如苯妥英钠、卡马西平、扑米酮、加巴喷丁、拉莫三嗪、丙戊酸钠、氯硝西泮等。
镇静催眠药，例如地西泮、硝西泮、奥沙西泮、劳拉西泮、苯巴比妥等；
胆碱酯酶抑制药，例如东莨菪碱等；
抗心律失常药，例如丙吡啶、妥卡尼、美西律、乙吗噻嗪、苯妥英钠、普罗帕酮、胺碘酮等；
抗心绞痛与抗动脉粥样硬化药，例如普萘洛尔、硝苯地平、吉非贝齐、苯扎贝特、洛伐他汀、辛伐他汀、普伐他汀等；
抗高血压药，例如依拉普利、卡托普利、氢氯噻嗪、氨氯地平等；
肾上腺受体阻断剂，例如醋丁洛尔、阿普洛尔等；
皮质甾类药，例如倍他米松、醋酸可的松等；
抗糖尿病药，例如瑞格列奈等；
抗甲状腺药，例如丙硫氧嘧啶、卡比马唑、甲巯咪唑等；
抗组织胺药，例如盐酸西替利嗪、氯雷他定等；
自体活性物质，例如地诺前列酮、前列地尔、倍他司汀等；
消化系统用药，例如丁溴东莨菪碱、盐酸格拉司琼等；
血液系统药，例如EPO、腺苷钴胺等；
泌尿系统药，例如阿佐塞米、呋塞米等；
生殖系统药，例如雌激素、苯丙酸诺龙等；
抗寄生虫药，例如阿苯达唑、坎苯达唑等；
抗肿瘤药，例如氨鲁米特、安吖啶等；
抗微生物药，例如氨苄西林、磺苄西林钠等；
抗生素类药，例如阿莫西林、头孢氨苄、头孢丙烯、头孢呋辛酯、罗红霉素、琥乙红霉素、交沙霉素等；
中药成分：
中药有效成分单体，如：灯盏花素、青蒿素等；
单味中药材提取物及复方中药提取物，如：丹参酮提取物、丹参总酚酸提取物、复方丹参滴丸提取物、牛黄上清丸复方提取物、人参茎叶总皂苷、北豆根提取物、人参总皂苷、灯盏花素、三七三醇皂苷、肿节风浸膏、三七总皂苷、茵陈提取物、大黄浸膏、穿心莲内酯、山楂叶提取物、积雪草总苷等；
天然植物提取物：如芦荟提取物、山药提取物、越橘提取物、苦瓜提取物、绿茶提取物、岩藻多糖、光甘草定、芍药苷等；
生物活性成分：EGF、bFGF、aFGF、KGF、IGF、PDGF、VEGF、胎盘水解液、牛奶提取物等；
化妆有益成分：胶原蛋白、透明质酸、海藻酸钠、芦荟提取物、人参总皂苷、三七总皂苷、大黄提取物、竹莲水百合提取物、芍药提取物、 EGF、bFGF、aFGF、KGF、IGF、PDGF、VEGF、胎盘水解液、牛奶提取物、各类表面活性剂、藻类提取物、各种维生素、各种有益矿物质、SOD、金属硫蛋白、其他原料见于《国际化妆品原料标准中文名称目录(2010年版)》。
在本发明的另一个实施方案中，所述冻干赋型制剂中除了活性成分、粘结剂之外，还可根据制剂工艺需要添加或不添加骨架支持剂、增稠混悬剂、抗氧化剂、矫味剂和香精、透皮吸收促进剂、pH调节剂等其它辅料中的一种或它们的任意组合。
在一个优选的实施方案中，所述骨架支持剂包含但不限于糖(如麦芽糖、海藻糖等)、糖醇(如甘露醇、山梨醇)、2-12个碳原子的氨基酸(如甘氨酸、丙氨酸、谷氨酸等)以及无机盐(如磷酸钠、硅酸铝等)等物质。
所述的其它辅料包含但不限于增稠混悬剂、抗氧化剂、矫味剂及香精、透皮吸收促进剂、pH调节剂等；其中增稠混悬剂可选自右旋糖酐、阿拉伯胶、黄原胶、卡拉胶、果胶、魔芋胶、琼脂、卡波姆、角叉菜胶等天然来源胶类和合成高分子化合物以及其他多肽或多糖中的一种或它们的任意组合等；所述抗氧化剂包括但不限于维生素C及其衍生物、花青素、白藜芦醇、植物来源的多元酚类化合物中的一种或它们的任意组合；所述矫味剂和香精包括但不限于薄荷味、巧克力味、香草味、咖啡味、茶味、玉米味、柠檬味、牛奶味等香精中的一种或它们的任意组合；所述透皮吸收促进剂包括但不限于卵磷脂、皂苷、月桂醇酸呐、氮酮、吐温、司盘中的一种或它们的任意组合；所述pH调节剂包括但不限于柠檬酸、酒石酸、碳酸盐、碳酸钠、磷酸盐中的一种或它们的任意组合。
在本发明的另一个实施方案中，本发明所提供的冻干赋型制剂和溶剂的包装和递送装置可以是能够实现本发明目的的任何一种装置，优选为一种双腔混料装置。
在一个优选的实施方案中，所述双腔混料装置，包括推动装置(1)及双腔混料腔体(9)两部分。
所述推动装置(1)由推动舱(12)、容纳舱(15)、推杆活塞装置(7、8、11)组成；在提供推动力的同时，还能对其内部的双腔混料腔体起到很好的保护作用。
所述双腔混料腔体(9)由双腔体(编号N1、编号N2)、二活塞(2、4)、一旁路(6)、一出料口(17)、一出料盖(10)组成；使用前用于分别存放冻干赋型剂及溶剂，使用时在动力的驱动下能够将冻干赋型剂与溶剂混合。
所述推动装置(1)的推动舱(12)为一两端开口装置；其尺寸大小与推杆活塞装置外形及体积相适应；推动舱(12)的下端具有一锁合装置(14)；
所述推动装置(1)的容纳舱(15)为一两端开口装置；其尺寸大小与双腔混料腔体外形及体积相适应；容纳舱(15)的上端具有另一锁合装置(13)，容纳舱(15)具有可掀开的保护盖(16)，打开保护盖(16)就能够将双腔混料腔体放入，合上保护盖(16)就能够固定并保护双腔混料腔体，所述保护盖(16)的下端具有卡口或螺旋口，所述卡口或螺旋口与双腔混料腔体(9)的下端相吻合，能够将双腔混料腔体(9)固定于所述容纳舱(15)内；
所述推动舱(12)的锁合装置(14)与容纳舱(15)的锁合装置(13)相匹配，推动舱(12)及容纳舱(15)通过锁合装置(13、14) 的锁合能够形成一个牢固的整体；锁合装置(13、14)的锁合形式可以是多钟多样的，只要能实现上述目的即可，如卡扣式、螺纹式等等；
所述推动舱(12)、容纳舱(15)可以由空白或有印刷的塑料、金属、玻璃、陶瓷等材质制成，意在起到固定、保护及标识的作用；
所述推杆活塞装置(7、8、11)，包括推头(11)、推杆(7)和活塞(8)；通过推动推头(11)驱动推杆(7)及活塞(8)向出料口方向运动，活塞(8)与活塞(2)之间的空气受到挤压驱动活塞(2)及液体制剂腔内的液体向出料口运动，液体又驱动活塞(4)向出料口方向运动，当活塞(4)底部运动超过旁路(6)下方时，液体制剂腔内的液体在活塞(2)的驱动下，通过旁路(6)直接绕开活塞(4)，进入固体制剂腔，与其中的冻干赋型制剂混合。推动推头(11)的动力来源可以是手动、电动或机械运动等任何可以驱动其运动的方式，其推动距离与力度为固定或可调等方式，推杆(7)可以是弹簧杆等可改变长度的相应装置；
所述双腔混料腔体(9)的双腔体(编号N1、编号N2)为一整体腔体，两端开口，固定于容纳舱(15)内；双腔体(编号N1、编号N2)通过活塞(2、4)及出料盖(10)组成固体制剂腔(编号N1)和液体制剂腔(编号N2)两个腔室，有出料盖(10)的一端为出料口17；出料口17可以是任何形状的，如吸管状、滴管状、滚珠状、喷雾头等；固体制剂腔靠近出料口17，液体制剂腔远离出料口17；固体制剂腔中的冻干赋型制剂(5)可以是各种配方、形态的冻干赋型制剂，为在成型模具中进行冻干后分装入固体制剂腔中的制剂；液体制剂腔中的溶剂可以为水、具有一定功效成分的营养液、精华液及可与冻干赋型直接配合使用的各种溶剂；双腔体可以根据需要采用任 意材质制成，同时双腔体上可标示刻度，达到定量使用的目的。
所述一旁路(6)，位于固体制剂腔侧面，其宽度略大于活塞(4)的厚度，可使液体制剂腔中的溶剂通过活塞运动至旁路(6)处时形成开口从而与固体制剂腔中的冻干赋型制剂(5)进行混合。
所述一出料盖(10)，为可密封出料器口的装置，使腔体内物质与外界环境隔离。
在使用时，双腔混料腔体(9)内含单次使用计量的冻干赋型制剂产品，使用后可拆卸更换双腔混料腔体(9)，推动装置(1)可反复使用。
根据本发明的又一方面，还提供了一种上述冻干赋型制剂的制备方法。
所述冻干赋型制剂是在成型模具中冻干后脱模并装配入双腔混料器中的固体制剂腔体中进行包装，其制备方法包括如下步骤：
(a)将活性成分、粘结剂及其它辅料配制成溶液、乳浊液或者悬浮液注模；或将固体活性成分注模，再加入粘结剂及其它辅料配成溶液、乳浊液或悬浮液；
(b)将(a)得到的溶液或悬浮液在定量成型模具中进行脱气；
(c)将(b)得到的脱气后的溶液、乳浊液或悬浮液或直接将(a)得到的溶液乳浊液或悬浮液、在低温下冷冻；
(d)将(c)得到的制剂在定量成型模具中冷冻干燥、除去溶剂，得到冻干赋型制剂；
(e)将(d)得到的冻干赋型制剂脱离成型模具并装入包装装置或其成型模具就是其中一个腔体，以此直接进行装配。
其中步骤(a)所述注模体积为0.01-5.0ml；其中注模可以采用 精确定量移液管、移液枪、电子移液枪等移液装置，也可采用柱塞泵、齿轮泵、蠕动泵等，将配置好的溶液或悬浮液注入定量成型模具；
其中脱气方法可以采用离心脱气法、真空脱气法以及超声脱气法等；其中冷冻可以采用液氮或液体、固体二氧化碳喷淋制冷的方式，透平膨胀机制冷方式或复叠制冷方式，在-20℃-196℃温度下，迅速将溶液或悬浮液冷冻成为固体；
其中冻干采用0.01-20毫巴的真空度，温度在-70℃-50℃范围之间冻干。
本发明至少可以产生一种下述的有益效果：
保护活性成分的稳定性：通过这种包装和递送系统，实现了固体和液体分开，高活性物质稳定性往往不好，以固体形态保存，其稳定性大大提高，会提高使用效果、降低潜在的副反应、延长货架期；
单剂量包装：与常规的多计量产品相比，该包装和递送系统是单剂量包装，其液体量符合飞机随身携带要求，便于携带；
避免污染：与传统的冻干赋形双铝包装和传统双瓶装冻干粉形态相比，该包装和递送系统所有组装过程在洁净生产区内完成，没有暴露部件只从出料口挤出，不会造成配制过程中的微生物污染；
使用方便：与传统的冻干赋形双铝包装相比，该包装和递送系统，无需揭开包装，放入掌中，再加入液体，以手指混匀的双手配合的复杂使用方式，只需一推或一按启动推杆活塞装置，待完全混合后打开出料口进行使用两个动作即可，非常方便；
降低成本：与冻干粉相比，没有复杂的双瓶和瓶盖系统；与传统的冻干赋形双铝包装相比，没有复杂的支撑和结构设计，完全自动化包装，大幅降低生产成本。
附图说明
图1为冻干赋型制剂的包装和递送系统装置各部件分解结构示意图；
图2-图3为冻干赋型制剂的包装和递送系统装置各部件组合示意图；
图4-图9为冻干赋型制剂的包装和递送系统的使用步骤图解。
具体实施方式
以下通过实施例进一步说明本发明，但本发明并不仅仅限于此。
以下实施例所指的腔体的底部，是指腔体远离出料口的远端；旁路(6)的上方是指靠近出料口的一端，旁路(6)的下方是指远离出料口的另一端；活塞的顶部是指活塞靠近出料口的一端，活塞的底部是指活塞远离出料口的另一端。
实施例1：
维生素C：普鲁兰＝5：1，混合后的粉末60mg,其中50mg以固体形式灌装进入0.4毫升成型模具，然后将剩余的10mg以0.4毫升水溶解后，灌装进含有粉末的成型模具，冻干后将获得的冻干赋型制剂装入带有旁路6的塑料材质的双腔混料腔体的固体制剂腔中，然后将硅胶材质的活塞4装配入塑料材质的固体制剂腔的底部、旁路6下方； 将去离子水2毫升灌装入硅胶材质的活塞2隔离出的塑料材质的液体制剂腔中；之后加入硅胶材质的活塞2，使液体完整保存于液体制剂腔内，不会从硅胶材质的活塞4和硅胶材质的活塞2之间渗出，即得到包含冻干赋型制剂和溶剂的双腔混料腔体，与透明塑料材质的容纳舱、推动舱及手动推杆活塞一起组成双腔混料器装置。
使用时将一推杆活塞装置7、8、11装入推动舱12中，将推动舱12与容纳舱15锁合好，再将双腔混料腔体9装入容纳舱15中，推动推头11驱动推杆7及活塞8向出料口方向运动，活塞8与活塞2之间的空气受到压缩驱动活塞2及液体制剂腔内的液体向出料口运动，液体又驱动活塞4向出料口方向运动，当活塞4底部运动超过旁路6下方时，液体制剂腔内的液体在活塞2的驱动下，通过旁路6直接绕开活塞4，进入固体制剂腔，与其中的冻干赋型制剂混合，继续向前推动推杆至活塞2顶部与活塞4底部接触，液体制剂腔内的2毫升去离子水完全与冻干赋型制剂混合，形成含有2.5％维生素C的溶液；打开出料盖10继续推动推杆活塞装置7、8、11，带动活塞2紧压活塞4，将前述的混合溶液从出料口17挤出，直接涂于脸部，成为现代化妆品。
使用后可将已用完的双腔混料腔体取出丢弃，下次再用时装上新的双腔混料腔体即可。
实施例2：
EGF原液，解冻后加入明胶、水解明胶，配制成含十万分之五的EGF(重量比)、含5％的明胶+水解明胶溶液，灌装进入0.1毫升成型模具，冻干成型后装入带刻度的透明玻璃材质的双腔体的固体制剂腔 中，然后将橡胶材质的活塞4装配入固体制剂腔的底部、旁路6下方；再将3％的透明质酸溶液2毫升灌装入橡胶材质的活塞2隔离出的液体制剂腔；之后加入橡胶材质的活塞2，使液体完整保存于液体制剂腔内，不会从橡胶材质的活塞4和橡胶材质的活塞2之间渗出，即得到包含冻干赋型制剂和溶剂的双腔混料腔体，与透明塑料材质的容纳舱、推动舱及手动推杆活塞一起组成双腔混料器装置。
使用时将一推杆活塞装置7、8、11装入推动舱12中，将推动舱12与容纳舱15锁合好，再将双腔混料腔体装入容纳舱15中，推动推头11驱动推杆7及活塞8向出料口方向运动，活塞8与活塞2之间的空气受到压缩驱动活塞2及液体制剂腔内的液体向出料口运动，液体又驱动活塞4向出料口方向运动，当活塞4底部运动超过旁路6下方时，液体制剂腔内的液体在活塞2的驱动下，通过旁路6直接绕开活塞4，进入固体制剂腔，与其中的冻干赋型制剂混合，继续向前推动推杆至活塞2顶部与活塞4底部接触，液体制剂腔内的2毫升3％的透明质酸溶液全部与冻干赋型制剂混合，形成含有2.5ppm的EGF、0.25％明胶与水解明胶、3％透明质酸的溶液；打开出料盖10，继续推动推杆活塞装置7、8、11，带动活塞2紧压活塞4，观察刻度将定量的前述混合溶液从出料口17中挤出，直接涂于脸部，成为现代生物化妆品。
使用后可将已用完的双腔混料腔体取出丢弃，下次再用时装上新的双腔混料腔体即可。
实施例3：
三七总皂苷：PVP＝30mg:15mg，配制成溶液，灌装入0.3ml成型模具，冻干后装入复合铝材质的双腔体的固体制剂腔中，然后将硅胶材质的活塞4装配入固体制剂腔的底部、旁路6的下方；再将含天然香精的去离子水1毫升灌装入硅胶材质的活塞2隔离出的液体制剂腔中；之后加入硅胶材质的活塞2，使液体完整保存于液体制剂腔内，不会从硅胶材质的活塞2和硅胶材质的活塞4之间渗出，即得到包含冻干赋型制剂和溶剂的双腔混料腔体，与铝制材质的容纳舱、推动舱及电动推杆活塞一起组成双腔混料器装置。
使用时将电动推杆活塞装置7、8、11装入推动舱12中，将推动舱12与容纳舱15锁合好，再将双腔混料腔体装入容纳舱15中，按住电动按钮，电动装置推动推头11驱动推杆7及活塞8向出料口方向运动，活塞8与活塞2之间的空气受到压缩驱动活塞2及液体制剂腔内的液体向出料口运动，液体又驱动活塞4向出料口方向运动，当活塞4底部运动超过旁路6下方时，液体制剂腔内的液体在活塞2的驱动下，通过旁路6直接绕开活塞4，进入固体制剂腔，与其中的冻干赋型制剂混合，继续按住电动按钮向前推动推杆至活塞2顶部与活塞4底部接触，液体制剂腔内的1毫升去离子水全部与冻干赋型制剂混合，形成含有3％三七总皂苷的溶液；打开出料盖10，继续按住电动按钮推动推杆7及活塞8，带动活塞2紧压活塞4，将前述的混合溶液通过出料口17中挤出，直接口服,成为保健食品。
使用后可将已用完的双腔混料腔体取出丢弃，下次再用时装上新的双腔混料腔体即可。
实施例4：
越橘提取物：普鲁兰＝100mg:15mg，配制成溶液，灌注进入0.5毫升成型模具，冻干后装入塑料材质的双腔体的固体制剂腔内，然后将硅胶材质的活塞4装配入固体制剂腔的底部、旁路6的下方；再将含有天然色素的20毫升去离子水灌装入硅胶材质的活塞2隔离出的液体制剂腔中，之后加入硅胶材质的活塞2；使液体完整保存于液体制剂腔内，不会从硅胶材质的活塞2和硅胶材质的活塞4之间渗出，即得到包含冻干赋型制剂和溶剂的双腔混料腔体，与铝制材质的容纳舱、推动舱及全自动混合计量推杆活塞一起组成双腔混料器装置。
使用时将全自动混合计量推杆活塞装置7、8、11装入推动舱12中，将推动舱12与容纳舱15锁合好，再将双腔混料腔体装入容纳舱15中，按住电动按钮，电动装置推动推头11驱动推杆7及活塞8向出料口方向运动，活塞8与活塞2之间的空气受到压缩驱动活塞2及液体制剂腔内的液体向出料口运动，液体又驱动活塞4向出料口方向运动，当活塞4底部运动超过旁路6下方时，液体制剂腔内的液体在活塞2的驱动下，通过旁路6直接绕开活塞4，进入固体制剂腔，与其中的冻干赋型制剂混合，当活塞2顶部与活塞4底部接触，液体制剂腔内的20毫升含有天然色素的去离子水完全与冻干赋型制剂混合，形成含有0.5％越橘提取物的溶液；打开出料盖10，调节需要的计量，再次按下电动按钮，推杆7带动活塞2紧压活塞4，将定量的前述混合溶液从出料口17中挤出，直接口服，形成固体饮料食品。
使用后可将已用完的双腔混料腔体取出丢弃，下次再用时装上新的双腔混料腔体即可。
本发明的包装结构并不限于实施例中所列举的形式，实施例仅为 本发明的较佳实施例而已，不能以此限定保护范围。凡以本发明的权利要求范围所述的简单的或等效的变化及修饰，皆属于本发明的保护范围。

Claims (16)

  1. 一种冻干赋型制剂的包装和递送系统，包括冻干赋型制剂、溶剂以及所述冻干赋型制剂和溶剂的包装和递送装置，其特征在于，所述包装和递送装置中包含一个双腔混料装置，其中溶剂以及冻干赋型制剂分别保存于双腔混料装置中的双腔混料腔体(9)的不同腔体中，通过双腔混料装置各部件的相互作用使溶剂和冻干赋型制剂在使用时可以即时混合并导出。
  2. 如权利要求1所述的冻干赋型制剂的包装和递送系统，其特征在于，所述冻干赋型制剂含有活性成分和粘结剂。
  3. 如权利要求2所述的冻干赋型制剂的包装和递送系统，其特征在于，所述粘结剂与活性成分的重量比为1:10至10:1。
  4. 如权利要求2或3所述的冻干赋型制剂的包装和递送系统，其特征在于，所述粘结剂是可食用、可做化妆品用或者可药用的一种水溶性高分子材料。
  5. 如权利要求2或3所述的冻干赋型制剂的包装和递送系统，其特征在于，所述活性成分为化学药物、生物药物、中药提取物、维生素、矿物质、化妆有益成分以及其它对人体有益的活性成分中的一种或一种以上。
  6. 如权利要求2-5任意一项所述的冻干赋型制剂的包装和递送系统，其特征在于，所述冻干赋型制剂还含有骨架支持剂、增稠混悬剂、抗氧化剂、矫味剂和香精、透皮吸收促进剂、pH调节剂中的一种或者一种以上。
  7. 如权利要求1所述的冻干赋型制剂的包装和递送系统，其特 征在于，所述双腔混料装置包括推动装置(1)及双腔混料腔体(9)。
  8. 如权利要求7所述的冻干赋型制剂的包装和递送系统，其特征在于，所述推动装置(1)由推动舱(12)、容纳舱(15)和推杆活塞装置(7、8、11)组成，
  9. 如权利要求8所述的冻干赋型制剂的包装和递送系统，其特征在于，所述推动舱(12)为一两端开口装置；其尺寸大小与所述推杆活塞装置(7、8、11)外形及体积相适应；推动舱(12)的下端具有一锁合装置(14)。
  10. 如权利要求8所述的冻干赋型制剂的包装和递送系统，其特征在于，所述容纳舱(15)为一两端开口装置；其尺寸大小与双腔混料腔体(9)外形及体积相适应；容纳舱(15)的上端具有另一锁合装置(13)；容纳舱(15)具有可掀开的保护盖(16)，打开保护盖(16)就能够将双腔混料腔体放入，合上保护盖(16)就能够固定并保护双腔混料腔体，所述保护盖(16)的下端具有卡口或螺旋口，所述卡口或螺旋口与双腔混料腔体(9)的下端相吻合，能够将双腔混料腔体(9)固定于所述容纳舱(15)内。
  11. 如权利要求8所述的冻干赋型制剂的包装和递送系统，其特征在于，所述的推动舱(12)及容纳舱(15)通过锁合装置(13、14)的锁合能够形成一个牢固的整体。
  12. 如权利要求7所述的冻干赋型制剂的包装和递送系统，其特征在于，所述双腔混料腔体(9)由双腔体(N1、N2)、二活塞(2、4)、一旁路(6)、一出料口(17)和一出料盖(10)组成。
  13. 如权利要求12所述的冻干赋型制剂的包装和递送系统，其特征在于，所述双腔体(N1、N2)具有固体制剂腔(N1)和液体制剂 腔(N2)；固体制剂腔(N1)为靠近出料器盖(10)部分的腔体，液体制剂腔(N1)为远离出料盖(10)部分的腔体；固体制剂腔及液体制剂腔为单个整体腔体通过活塞分隔成的两个独立空间。
  14. 如权利要求12所述的冻干赋型制剂的包装和递送系统，其特征在于，冻干赋型制剂(5)位于固体制剂腔(N1)中，冻干赋型制剂(5)为各种配方、形态的冻干赋型制剂，并可以为在成型模具中进行冻干后分装入固体制剂腔中的制剂，也可以为在固体制剂腔中原位冻干的制剂；溶剂位于液体制剂腔(N2)中；溶剂为水、具有一定功效成分的营养液或精华液及可与冻干赋型直接配合使用的其它各种溶剂。
  15. 如权利要求12所述的冻干赋型制剂的包装装置，其特征在于所述一旁路(6)，位于固体制剂腔(N1)侧面，能够使腔体中的溶剂通过活塞运动至旁路处时形成开口从而与冻干赋型制剂进行混合。
  16. 如权利要求1-14任意一项所述的冻干赋型制剂的包装和递送系统的制备方法，其包括以下步骤：
    (a)将活性成分、粘结剂及其它辅料配制成溶液、乳浊液或者悬浮液注模；或将固体活性成分注模，再加入粘结剂及其它辅料配成溶液、乳浊液或悬浮液；
    (b)将(a)得到的溶液或悬浮液在定量成型模具中进行脱气；
    (c)将(b)得到的脱气后的溶液、乳浊液或悬浮液或直接将(a)得到的溶液乳浊液或悬浮液、在低温下冷冻；
    (d)将(c)得到的制剂在定量成型模具中冷冻干燥、除去溶剂，得到冻干赋型制剂；
    (e)将(d)得到的冻干赋型制剂脱离成型模具并装入包装装置 或其成型模具就是其中一个腔体，以此直接进行装配。
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