WO2014101743A1 - 一种冻干赋型制剂及其制备方法 - Google Patents

一种冻干赋型制剂及其制备方法 Download PDF

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Publication number
WO2014101743A1
WO2014101743A1 PCT/CN2013/090291 CN2013090291W WO2014101743A1 WO 2014101743 A1 WO2014101743 A1 WO 2014101743A1 CN 2013090291 W CN2013090291 W CN 2013090291W WO 2014101743 A1 WO2014101743 A1 WO 2014101743A1
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Prior art keywords
freeze
binder
suspension
active ingredient
dried excipient
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PCT/CN2013/090291
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English (en)
French (fr)
Inventor
李和伟
Original Assignee
Li Hewei
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Application filed by Li Hewei filed Critical Li Hewei
Priority to EP13868552.4A priority Critical patent/EP2939664A4/en
Priority to US14/651,547 priority patent/US20150314004A1/en
Publication of WO2014101743A1 publication Critical patent/WO2014101743A1/zh
Priority to HK16102693.8A priority patent/HK1215667A1/zh

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    • 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
    • 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
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4545—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with nitrogen as a ring hetero atom, e.g. pipamperone, anabasine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/60—Salicylic acid; Derivatives thereof
    • A61K31/612—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid
    • A61K31/616—Salicylic acid; Derivatives thereof having the hydroxy group in position 2 esterified, e.g. salicylsulfuric acid by carboxylic acids, e.g. acetylsalicylic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/66—Phosphorus compounds
    • A61K31/675—Phosphorus compounds having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A61K33/10—Carbonates; Bicarbonates
    • 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
    • A61K36/16—Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
    • 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)
    • A61K36/25—Araliaceae (Ginseng family), e.g. ivy, aralia, schefflera or tetrapanax
    • A61K36/258—Panax (ginseng)
    • 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)
    • A61K36/45—Ericaceae or Vacciniaceae (Heath or Blueberry family), e.g. blueberry, cranberry or bilberry
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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

Definitions

  • the invention relates to a formula and a preparation method of a freeze-dried preparation, in particular to a jelly containing only a binder and an active ingredient, and no skeleton support agent (such as amino acid, sugar, sugar alcohol and inorganic salt) Formulation and preparation method of dry formulation.
  • a skeleton support agent such as amino acid, sugar, sugar alcohol and inorganic salt
  • Freeze-drying technique refers to the addition of a matrix support agent and a binder to a flowable liquid, semi-solid or solid active ingredient, or the flowable liquid, semi-solid or solid itself contains a binder and a skeleton.
  • the support agent is then poured into a molding die, and the process is formed by a freeze-drying process.
  • the formulation prepared by the freeze-drying technique is referred to as a freeze-dried formulation.
  • the heat sensitive component can be protected from being destroyed, and a large number of micropores and pores are generated by sublimation of water, which can have a rapid disintegration and dissolution rate, and thus has been widely used and can be applied to the oral cavity.
  • Traditional freeze-dried shaped preparations consist of a matrix consisting of a matrix and an active ingredient, wherein the matrix comprises a backbone support and a binder, and the backbone support is mostly selected from the group consisting of sugars, sugar alcohols and amino acids of 2 to 12 carbon atoms and inorganic salts (eg Sodium phosphate, aluminum silicate, etc. (see Chinese patents)
  • sugars, sugar alcohols, inorganic salts such as sodium phosphate, aluminum silicate, etc.
  • inorganic salts such as sodium phosphate, aluminum silicate, etc.
  • it is very easy to absorb the moisture in the air during the production process, causing the skeleton structure of the preparation to collapse or completely collapse, or to cause adverse effects, while It also has many defects such as prolonging the disintegration process.
  • the amino acid as a skeleton agent reduces the hygroscopicity, it does not solve the problem fundamentally, and there is no good solution to the cost of the production process.
  • the technical problem to be solved by the present invention is to provide a new tubular formulation containing only a binder and an active ingredient which are not added to the matrix support agent in the process system, and the skeleton support agent includes but is not limited to sugar (such as maltose, trehalose, etc.), sugar alcohols (such as mannitol, sorbitol), amino acids of 2-12 carbon atoms (such as glycine, alanine, glutamic acid, etc.) and inorganic salts (such as sodium phosphate, silicic acid) Aluminum, etc.).
  • sugar such as maltose, trehalose, etc.
  • sugar alcohols such as mannitol, sorbitol
  • amino acids of 2-12 carbon atoms such as glycine, alanine, glutamic acid, etc.
  • inorganic salts such as sodium phosphate, silicic acid
  • the inventor was determined to innovate and carried out a lot of in-depth research and experimental work. It was found that controlling the ratio of binder and active ingredients in the freeze-dried formulation can make the formulation of the freeze-dried formulation not contain the skeleton support agent system. Only the two parts of the binder and the active ingredient can be obtained to obtain a freeze-dried preparation which meets the quality requirements. On the basis of this, other adjuvants such as antioxidants, flavoring agents and flavors, transdermal absorption enhancers, and pH adjusters may be added. By avoiding the use of skeletal support agents, it is possible to reduce the risk of moisture absorption, to reduce the cost of the process, and to increase the technical effect of the unit drug loading.
  • the weight ratio of the binder to the active ingredient may further preferably be 1:90 to 90:1, 1:80 to 80:1, 1:70 to 70:1, 1:60 to 60:1, 1:50 to 50:1, 1:40 to 40:1, 1:30 to 30:1, more preferably 1:20 to 20:1, 1:10 to 10:1, 1:9 to 9:1, 1:8 to 8:1, 1:7 to 7:1, most preferably 1:6 to 6:1, 1:5 to 5:1.
  • the lyophilized formulation provided by the present invention may further comprise other auxiliary materials, such as antioxidants, flavoring agents and flavors, transdermal absorption enhancers, pH adjusters, etc., and the contents of these other auxiliary materials may be prepared by the preparation.
  • the total content of the lyophilized formulation is from 0.1 to 5%, preferably from 0.1 to 3%.
  • the active ingredient may be dissolved in water or insoluble in water, and the active ingredient may be selected from one or one of a chemical pharmaceutical ingredient, a traditional Chinese medicine ingredient, a natural extract, a biological active ingredient, and a skin care benefit component. The combination above.
  • the active ingredient to be used in the present invention is not particularly limited and may be selected from the group consisting of, but not limited to, one or a combination of the following ingredients.
  • Antipyretic analgesic anti-inflammatory drugs such as aspirin, diflunisal, salicylate, acetaminophen, indomethacin, ibuprofen, tea, ketoprofen, pirfen, supprofen, fluoride Biprofen, 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 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.;
  • Anti-epileptic and anticonvulsant drugs such as phenytoin, carbamazepine, pumilidone, 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, aplol, etc.;
  • Cortic drugs 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.;
  • Autoactive substances such as dinoprostone, alprostadil, betahistine, etc.
  • digestive system drugs 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 aminoglutethimide, ampicillin, etc.
  • Antimicrobial agents such as ampicillin, sulfacillin sodium, etc.
  • Antibiotics such as amoxicillin, cephalexin, cefprozil, cefuroxime axetil, roxithromycin, erythromycin ethylsuccinate, josamycin, and the like.
  • the active ingredient monomers of traditional Chinese medicine such as: breviscapine, artemisinin, huperzine A, tetrahydropalmatine, 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, American ginseng total saponins, breviscapine, swollen wind extract, panax notoginseng saponins, capillaris extract, rhubarb extract, andrographolide, hawthorn leaf extract, centella asiatica, ginkgo biloba Extracts, etc.
  • Natural plant extracts such as aloe extract, yam extract, bilberry extract, bitter gourd extract, echinacea extract, feverfew extract, mangosteen extract, pine needle and pine bark extract, Brazilian blackberry extract, mulberry extract , elderberry extract, cranberry extract, astaxanthin, lycopene, green tea extract, grape seed and grape skin extract, licorice, paeoniflorin, licorice flavonoids, paeonol extract, etc.
  • Biologically active ingredients EGF, bFGF, aFGF, KGF, IGF, NGF, TGF, HGH, and the like.
  • Skin care beneficial ingredients vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, coenzymes, proteases, metallothionein, pearls and their hydrolysates, Milk and its extracts, pollen and its extracts, royal jelly, propolis, etc.
  • the binder is an edible or pharmaceutically acceptable water-soluble polymer material, which may be a polysaccharide, a polypeptide, a protein, or an artificially polymerized polymer, or a modified natural high. Molecular materials or mixtures thereof. Commonly used binders include, but are not limited to, gums (collagen, gelatin, hydrolyzed gelatin, gum arabic, xanthan gum, carrageenan, pectin, konjac gum, carrageenan, locust bean gum, gum, locust bean gum).
  • cellulose ethers (carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, etc.), modified starches (pullanose, hydroxypropyl) Base starch, etc., see RPScherer US4305502A), PVP, PVA, hyaluronic acid, albumin, chitosan, dextran, agar, polyamino acid, glycan, and combinations thereof, etc., characterized in that the gum
  • the binder is gelatin, hydrolyzed gelatin, gum arabic, xanthan gum, carrageenan, pectin, konjac gum, carrageenan, locust bean gum, gum, locust bean gum;
  • the agent is carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, etc.;
  • the modified starch type binder is selected from the group consisting of
  • the antioxidant includes, but is not limited to, a mixture of one or more of vitamin C and its derivatives, anthocyanins, resveratrol, and plant-derived polyphenolic compounds;
  • flavoring agents and flavors include, but are not limited to, mint, chocolate, fruit, vanilla, coffee, tea, corn, lemon, milk, etc. or a mixture of one or more of the above;
  • the transdermal absorption enhancer includes, but is not limited to, a mixture of any one or several of lecithin, saponin, sodium lauryl sulphate, azone, tween, and dips;
  • the pH adjusting agent includes, but is not limited to, a mixture of any one or more of citric acid, tartaric acid, carbonate, sodium carbonate, and phosphate.
  • Another aspect of the invention relates to a method of preparing the above lyophilized formulation, the method comprising: I. Preparation of lyophilized excipients without other excipients:
  • the weight ratio of the active ingredient and the binder to water is from 100:1 to 1:100, and further preferably from 1:90 to 90:1, 1:80 to 80:1, 1:70.
  • the liquid injection molding can adopt a pipetting device such as a precise quantitative pipette, a pipetting gun, an electronic pipetting gun, or a plunger pump, a gear pump, a peristaltic pump, etc., and the configured solution, suspension or suspension can be configured.
  • a pipetting device such as a precise quantitative pipette, a pipetting gun, an electronic pipetting gun, or a plunger pump, a gear pump, a peristaltic pump, etc.
  • the liquid is injected into the quantitative forming mold, and the solid injection molding can adopt the precise solid measuring tool and the vibration capillary powder flow controller;
  • 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 or casing circulating cooling device, and the turboexpansion machine In the cooling mode or cascade cooling mode, the solution, suspension or suspension is quickly frozen to a solid at a temperature of -20 ° C to -196 ° C;
  • the lyophilization is carried out using a vacuum of 0.01 to 20 mbar, and the temperature is lyophilized between -70 ° C and 50 ° C. detailed description
  • the invention discloses a freeze-dried forming preparation and a preparation method thereof, and those skilled in the art can learn from the contents of the paper and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and the application of the present invention have been described by the preferred embodiments, and it is obvious that the method and application described herein may be modified or appropriately modified and combined without departing from the scope of the present invention. The technique of the present invention is applied.
  • the preparation was placed in a test tube containing 2 ml of 37 ° C water, and the time at which the preparation completely disintegrated and passed through a 20-mesh sieve was observed;
  • the preparation was dropped from a one meter high position to a stainless steel platform in a free fall manner, and 100 pellets were dropped, and the total exfoliated powder was measured, and the weight was less than 3% of the total weight of the preparation.
  • Example 1 The prepared lyophilized formulation was taken out from the bottom of the aluminum nest with a finger, and the preparation was observed.
  • Example 1 The prepared lyophilized formulation was taken out from the bottom of the aluminum nest with a finger, and the preparation was observed.
  • Example 2
  • hyaluronic acid 1: 100, hyaluronic acid lOOmg, 90mg of hyaluronic acid and lmg pearl powder mixed, accurately filled into 0.5ml mold, 10mg hyaluronic acid dissolved in 0.3ml water, perfusion
  • a mold containing 90 mg of hyaluronic acid and 1 mg of pearl powder the water was dispersed in the powder by stirring, frozen to -196 ° C, and lyophilized to become a skin care solid essence.
  • Example 3 Example 3:
  • Example 4
  • PVA 25: 1, acetaminophen 500mg and PVA20mg, infused into 1ml molding die, the mixture is divided into two parts, acetaminophen 500mg powder is filled into 0.6ml molding die, PVA20mg is 0.4ml water Dissolved, infused into 500mg powder, stirred and lyophilized to become acetaminophen drug.
  • Example 11 Example 11:
  • Example 12 Example 12:
  • Aspirin: xanthan gum + pullulan 10:1, aspirin 500mg, xanthan gum 10mg, pullulan 40mg, of which aspirin 500mg perfused into 0.5ml mold, xanthan gum 10mg, pullulan 40mg dissolved in 0.5ml water After dispersion, it is infused into 500 mg of aspirin powder, stirred and lyophilized to become an aspirin drug.
  • Example 1 Test Results Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Disintegration time 5S 5S 3S 15S 15S 15S Appearance smooth and smooth Smooth flat smooth smooth smooth smooth smooth smooth smooth friability ⁇ 3 % ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% Example 7 Example 8 Example 9 Example 10 Example 11 Example 12 Disintegration time 5S 15S 15S 5S 3S 15S Appearance smooth and smooth Smooth flat smooth smooth smooth smooth smooth smooth flat smooth friability ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3% ⁇ 3%

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  • Alternative & Traditional Medicine (AREA)
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Abstract

一种冻干赋型制剂及其制备方法，该冻干赋型制剂只含有活性成分和粘结剂，不含骨架支持剂，其中粘结剂与活性成分的重量配比为1:100至100:1，所述粘结剂为胶类、纤维素醚类、改性淀粉类、PVP、卡波姆、PVA、透明质酸类、白蛋白、壳聚糖、右旋糖酐、琼脂、聚氨基酸、聚糖或它们的组合。

Description

一种冻干赋型制剂及其制备方法
本申请要求于 2012年 12月 26日提交中国专利局、 申请号为
201210572660.8、发明名称为"一种冻干赋型制剂及其制备方法"的中国专 利申请的优先权， 其全部内容通过引用结合在本申请中。 技术领域
本发明涉及一种冻干赋型制剂的配方和制备方法，特别是一种只含有 粘结剂和活性成分， 而不含骨架支持剂（如氨基酸、糖、糖醇及无机盐等） 的冻干赋型制剂的配方和制备方法。 背景技术
冻干赋型技术是指在可流动的液体、半固体或固体的活性成分中加入 骨架支持剂以及粘结剂，或所述可流动的液体、半固体或固体中本身含有 粘结剂及骨架支持剂，然后将其灌注到成型模具中，通过冷冻干燥工艺得 以成型的技术， 通过冻干赋型技术制备的制剂称作冻干赋型制剂。
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 时通过水分升华产生大量微孔和孔道， 可以具有很快的崩解和溶解速度， 因此受到了广泛应用， 可以应用于口腔崩解片、 速释片、 咀嚼片、 特殊化 妆品等多个领域。
传统的冻干赋形制剂由基质和活性成分两部分组成，其中基质包括骨 架支持剂和粘结剂， 骨架支持剂大多选自糖、 糖醇和 2-12个碳原子的氨 基酸以及无机盐 （如磷酸钠、 硅酸铝等）等 (参见中国专利
CN200580013010.8)。
糖、 糖醇、 无机盐（如磷酸钠、 硅酸铝等）作为骨架支持剂时， 由于 糖、 糖醇和无机盐（如磷酸钠、 硅酸铝等）的吸湿性， 在生产过程中非常 容易吸收空气中的水分而导致制剂的骨架结构成分塌陷或完全坍塌，或使 不好影响， 同时还具有使崩解过程延长等诸多缺陷； 而氨基酸作为骨架剂 时虽降低了吸湿性的这个问题，但并不能根本解决这个问题，且生产工艺 的成本问题也尚无 4艮好的解决办法。
因此，本领域中存在冻干赋形制剂中不使用骨架支持剂的需求。但是 由于技术限制和传统观念，并未见有文献报道仅使用活性成分和粘结剂即 可以制成冻干赋形制剂。 专利： 200580013010和专利 200410038822在这 方面有明确的说明。 发明内容
本发明所要解决的技术问题是提供一种新的筒化配方，配方中只含有 粘结剂和活性成分，其不添加入工艺体系中的骨架支持剂，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。
发明人锐意创新，进行了大量深入的研究和试验工作，发现控制冻干 赋型制剂中粘结剂和活性成分的配比，可以使冻干赋型制剂配方材料中不 含有骨架支持剂体系，而只由粘结剂和活性成分两部分构成即可得到符合 质量要求的冻干赋型制剂。 在此基础上， 可以添加抗氧化剂、矫味剂及香 精、透皮吸收促进剂、 PH调节剂等其它辅料。通过避免使用骨架支持剂， 可以达到减少吸潮风险， 筒化制备工艺， 降低成本， 提高单位载药量的技 术效果。
以下， 对本发明进行详细阐述。 本发明所提供的冻干赋型制剂仅由粘结剂和活性成分两部分组成，其 中粘结剂与活性成分的重量配比为粘结剂： 活性成分 =1:100至 100:1。 实 验显示， 超出这个配比范围将无法制备得到符合质量要求的冻干赋型制 剂。 粘结剂与活性成分的重量配比可以进一步地优选 1:90至 90:1 , 1:80 至 80:1 , 1:70至 70:1 , 1:60至 60:1 , 1:50至 50:1 , 1:40至 40:1 , 1:30至 30:1 , 更优选 1:20至 20:1,1:10至 10:1 , 1:9至 9:1,1:8至 8:1,1:7至 7:1 , 最优选 1: 6至 6:1,1:5至 5:1。 本发明所提供的冻干赋型制剂还可进一步 包含其它辅料， 例如抗氧化剂、 矫味剂及香精、 透皮吸收促进剂、 PH调 节剂等，这些其它辅料的含量范围可以是占制备得到的冻干赋型制剂的总 含量的 0.1-5%,优选 0.1-3%.。
活性成分可以是溶于水也可以是不溶于水的物质，所述的活性成分可 以选自化学药物成分、 中药成分、 天然提取物、 生物活性成分、 皮肤护理 有益成分中的一种或一种以上的组合。
本发明所涉及的活性成分没有特别的限定，可以选自但不限于下列一 种或几种成分的组合物。
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、 茶普生、 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、朴米酮、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 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、 石杉碱甲、 延胡索乙素 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、 西洋参总皂苷、灯盏花素、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、 银杏叶提取物等。
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、 紫锥菊提取物、 小白菊提取物、 山竹提取物、松针及松树皮提取 物、 巴西黑莓提取物、 桑葚提取物、 接骨木果提取物、 蔓越莓提取物、 虾 青素、 番茄红素、 绿茶提取物、 葡萄籽及葡萄皮提取物、 光甘草定、 芍药 苷、 甘草黄酮、 丹皮提取物等。
生物活性成分： EGF、 bFGF、 aFGF、 KGF、 IGF、 NGF、 TGF、 HGH 等。
皮肤护理有益成分： 维生素 A、 维生素 Bl、 维生素 B2、 维生素 B3、 维生素 B6、 维生素 B12、 维生素 C、 维生素 D、 维生素 E、 维生素 K、 辅酶类、 蛋白酶、 金属硫蛋白、 珍珠及其水解物、 牛乳及其提取物、 花粉 及其提取物、 蜂王浆、 蜂胶等
所述粘结剂是可食用或者可药用的一种水溶性高分子材料,可以是多 糖、 多肽、 蛋白质、 也可能是人工聚合高分子， 或者是经过改型的天然高 分子材料或其混合物。 常用的粘结剂包括但不限于， 胶类 （胶原、 明胶、 水解明胶、 阿拉伯胶、 黄原胶、 卡拉胶、 果胶、 魔芋胶、 角叉菜胶、 刺槐 豆胶、 树胶、 槐豆胶等）、 纤维素醚类 （羧甲基纤维素， 羧乙基纤维素、 羟乙基甲基纤维素、 羟丙基甲基纤维素等）、 改性淀粉类 （普鲁兰糖、 羟 丙基淀粉等， 参见 R.P.Scherer US4305502A )、 PVP、 PVA、 透明质酸类、 白蛋白、 壳聚糖、右旋糖酐、琼脂、、聚氨基酸、聚糖及其它们的组合等；， 其特征在于所述的胶类粘结剂为明胶、 水解明胶、 阿拉伯胶、 黄原胶、 卡 拉胶、 果胶、 魔芋胶、 角叉菜胶、 刺槐豆胶、 树胶、 槐豆胶； 所述的纤维 素醚类粘结剂为羧甲基纤维素，羧乙基纤维素、 羟乙基甲基纤维素、 羟丙 基甲基纤维素等； 所述的改性淀粉类粘结剂选自普鲁兰糖、 羟丙基淀粉、 羟丙基甲基淀粉、 预胶化淀粉、 直链淀粉、 羧甲基淀粉、 羟乙基淀粉、 羟 丙基淀粉等； 所述的聚氨基酸选自聚谷氨酸、 聚丙氨酸、 聚赖氨酸等； 所 属聚糖选自岩藻多糖、 菊糖等。。
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数种的混合物；
所述矫味剂和香精包括但不限于薄荷味、 巧克力味、 果味、 香草味、 咖啡味、 茶味、 玉米味、 柠檬味、 牛奶味等香精或以上一种或几种香味的 混合物；
所述透皮吸收促进剂包括但不限于卵磷脂、皂苷、月桂醇酸钠、氮酮、 吐温、 司盘中的任一种或数种的混合物；
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 酸盐中的任何一种或数种的混合物。
本发明另一方面涉及的是制备上述冻干赋型制剂的方法， 该方法包 括： I.不含其它辅料的冻干赋型制剂的制备方法：
(a)将活性成分、 水和粘结剂形成的溶液或悬浊液注模； 或将固体活 性成分和 /或粘结剂注模， 再加入水配成悬浊液；
(b)将（a)得到的溶液或悬浊液在定量成型模具中进行脱气；
(c)将（b )得到的脱气后的悬浊液或不经脱气直接将（a)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， 得到冻干赋型制 剂。
II.含其它辅料的冻干赋型制剂的制备方法：
(a)将活性成分、 水、 粘结剂及其它辅料形成悬浊液注模； 或将固体 活性成分和 /或粘结剂和 /或其它辅料注模， 再加入水配成悬浊液；
(b)将（a)得到的溶液或悬浊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或悬浊液或不经脱气直接将（a)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。
以上两种方法中， 活性成分和粘结剂与水的重量配比为 100:1至 1:100, 可以进一步地优选 1:90至 90:1, 1:80至 80:1, 1:70至 70:1, 1:60 至 60:1, 1:50至 50:1, 1:40至 40:1, 1:30至 30:1,更优选 1:20至 20:1,1:10 至 10:1, 1:9至 9:1,1:8至 8:1,1:7至 7:1, 最优选 1: 6至 6:1,1:5至 5:1。
其中液体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、 悬浊液或 者悬浮液注入定量成型模具， 固体注模可以采用精确固体量具、震动毛细 管粉末流动控制器、； 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或者套管循环 冷却装置的方式， 透平膨长机制冷方式或复叠制冷方式， 在 -20°C--196°C 温度下， 迅速将溶液、 悬浊液或者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°C至 50°C范围之间 冻干。 具体实施方式
本发明公开了一种冻干赋型制剂及其制备方法，本领域技术人员可以 借鉴本文内容， 适当改进工艺参数实现。 特别需要指出的是， 所有类似的 替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本 发明。本发明的方法及应用已经通过较佳实施例进行了描述，相关人员明 显能在不脱离本发明内容、精神和范围内对本文所述的方法和应用进行改 动或适当变更与组合， 来实现和应用本发明技术。
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。 在以下实施例和比较例中， 冻干赋型制剂的评价方法如下：
1)崩解时间：
将制剂投入装有 2毫升 37度摄氏水的试管中， 观察制剂完全崩解并 过 20目筛的时间；
2)脆碎度：
将制剂从一米高的位置以自由落体方式，下降到不锈钢平台上，投下 100粒， 测定总脱落粉体， 重量小于制剂总重量的 3%为合格。
3)制剂外观：
将制备的冻干赋型制剂用手指从铝窝底部向上用力取出制剂，肉目艮观 实施例 1:
维生素 C: 胶原 =100:1 , 维生素 C lOOmg,精确灌装进入 0.3ml模具， 胶原 lmg,加入 0.2ml水中溶解后，灌注进含有 lOOmg维生素 C的模具中， 搅拌使水分散在粉体中， 速冻至 -100摄氏度， 冻干成为固体饮料。 实施例 2:
珍珠粉： 透明质酸 =1: 100, 透明质酸 lOOmg, 其中 90mg透明质酸 与 lmg珍珠细粉混合后， 精确灌装进入 0.5ml模具中， 10mg透明质酸于 0.3ml水溶解后， 灌注进含有 90mg透明质酸与 lmg珍珠粉的模具中， 搅 拌使水分散在粉体中， 速冻至 -196摄氏度， 冻干成为护肤固体精华。 实施例 3:
越橘提取物：普鲁兰 =5： 1 ,越橘提取物 60mg与普鲁兰 12mg加水 0.4ml 配制成溶液， 灌装进入 0.4 毫升成型模具， 冻干成为固体饮料。 实施例 4:
三七总皂苷： PVP=10:1 ,三七总皂苷 500mg,PVP50mg,其中 PVP40mg 加水 0.5ml配制成溶液， 三七总皂苷 lOOmg和 PVPlOmg以粉末形式灌注 进入 0.5毫升成型模具， 之后以 PVP40mg加水 0.5ml配制成的溶液分散， 在成型模具中冻干成为口含片。 实施例 5: 银杏总黄酮： PVA=1: 1 , 银杏总黄酮 20mg, PVA20mg, 加水 0.3ml 配制成溶液，灌注进入 0.3毫升成型模具，在成型模具中冻干成为口含片。 实施例 6:
白藜芦醇： 聚赖氨酸 =5:1 , 白藜芦醇 lOOmg, 聚赖氨酸 20mg,配制成 悬浊液， 灌注进入 0.4毫升成型模具， 在成型模具中冻干成为口含片。 实施例 7:
氯雷他定： 右旋糖酐 =1: 10, 氯雷他定 10mg, 右旋糖酐 lOOmg其中 氯雷他定 10mg与右旋糖酐 50mg作为粉末， 分散进入 0.2ml模具， 50mg 右旋糖酐与 0.2ml水配制成溶液，灌注进入 0.2ml成型模具，与粉末混合， 搅拌后在成型模具中冻干成为口含片。 实施例 8:
对乙酰氨基酚： PVA=25: 1 , 对乙酰氨基酚 500mg与 PVA20mg, 灌注 进入 1ml成型模具， 混合物分成两个部分， 对乙酰氨基酚 500mg粉末灌 装进入 0.6毫升成型模具， PVA20mg以 0.4ml水溶解， 灌注进入 500mg 粉末中， 搅拌后冻干， 成为对乙酰氨基酚药品。 实施例 9:
蔓越莓提取物： 羟丙基甲基纤维素 =25:1 , 蔓越莓提取物 500mg灌注 进入 0.8ml模具，羟丙基甲基纤维素 20mg ,加水 1ml溶解，灌注进入 500mg 粉末中， 搅拌后冻干， 成为对蔓越莓固体饮料。 司来吉兰： 聚谷氨酸 =1: 10, 司来吉兰 lmg, 聚谷氨酸 10mg,以 0.1ml 水分散后灌注进入 0.1ml模具， 冷冻后冻干， 成为司来吉兰药品。 实施例 11 :
维生素 B6: 羟丙基淀粉 =2:1 , 维生素 B6 10mg, 羟丙基淀粉 5mg, 以 0.1ml水分散后灌注进入 0.1ml模具， 冷冻后冻干， 成为维生素 B6药 口口 o 实施例 12:
阿司匹林： 黄原胶 +普鲁兰 =10:1 , 阿司匹林 500mg,黄原胶 10mg, 普 鲁兰 40mg, 其中阿司匹林 500mg灌注进入 0.5ml模具， 黄原胶 10mg, 普鲁兰 40mg以 0.5ml水溶解分散后， 灌注进入 500mg阿司匹林粉末中， 搅拌后冻干， 成为对阿司匹林药品。 表 1 : 测试结果 实施例 1 实施例 2 实施例 3 实施例 4 实施例 5 实施例 6 崩解时间 5S 5S 3S 15S 15S 15S 外观 光滑平整 光滑平整 光滑平整 光滑平整 光滑平整 光滑平整 脆碎度 <3% <3% <3% <3% <3% <3% 实施例 7 实施例 8 实施例 9 实施例 10 实施例 11 实施例 12 崩解时间 5S 15S 15S 5S 3S 15S 外观 光滑平整 光滑平整 光滑平整 光滑平整 光滑平整 光滑平整 脆碎度 <3% <3% <3% <3% <3% <3%
描述，相关技术人员明显能在不脱离本发明内容、精神和范围内对本文所 明技术。特别需要指出的是，所有相类似的替换和改动对本领域技术人员 来说是显而易见的， 它们都被视为包括在本发明的精神、 范围和内容中。

Claims

权 利 要 求
1、 一种冻干赋型制剂， 其特征在于， 仅由活性成分和粘结剂组成， 其中粘结剂与活性成分的重量配比为粘结剂：活性成分为 1:100至 100:1。
2、 权利要求 1所述的冻干赋型制剂， 其特征在于， 所述的活性成分 选自化学药物成分、 中药成分、 天然提取物、 生物活性成分、 皮肤护理有 益成分中的一种或一种以上的组合。
3、 权利要求 1所述的冻干赋型制剂， 其特征在于， 所述的粘结剂为 胶类、 纤维素醚类、 改性淀粉类、 PVP、 卡波姆、 PVA、 透明质酸类、 白 蛋白、 壳聚糖、 右旋糖酐、 琼脂、 聚氨基酸、 聚糖或它们的组合。
4、 权利要求 3所述的冻干赋型制剂， 其特征在于， 所述的胶类粘结 剂为胶原、 明胶、 水解明胶、 阿拉伯胶、 黄原胶、 卡拉胶、 果胶、魔芋胶、 角叉菜胶、 刺槐豆胶、 树胶、槐豆胶； 所述的纤维素醚类粘结剂为羧甲基 纤维素， 羧乙基纤维素、 羟乙基甲基纤维素、 羟丙基甲基纤维素； 所述的 改性淀粉类粘结剂选自普鲁兰糖、羟丙基淀粉、 羟丙基甲基淀粉、预胶化 淀粉、 直链淀粉、 羧甲基淀粉、 羟乙基淀粉、 羟丙基淀粉等； 所述的聚氨 基酸选自聚谷氨酸、 聚丙氨酸、 聚赖氨酸等； 所属聚糖选自岩藻多糖、 菊 糖等。
5、 如权利要求 1所述的冻干赋型制剂， 其特征在于， 其中还含有其 它辅料， 所述其它辅料为抗氧化剂、 矫味剂及香精、 透皮吸收促进剂、 PH调节剂中的一种或一种以上。
6、 如权利要求 5所述的冻干赋型制剂， 其特征在于， 所述的抗氧化 剂选自维生素 C、花青素、 白藜芦醇、植物来源的多元酚类化合物中的一 种或数种的混合物； 所述矫味剂和香精选自薄荷味、 巧克力味、 香草味、 咖啡味、 茶味、 玉米味、 柠檬味、 牛奶味等香精或以上一种或几种香味的 混合物； 所述的透皮吸收促进剂选自卵磷脂、 吐温、 司盘中的任一种或数 种的混合物； 所述的 PH调节剂选自柠檬酸、 酒石酸、 碳酸氢钠、 碳酸钠 中的任何一种或数种的混合物。
7、 如权利要求 1所述的冻干赋型制剂的制备方法， 其特征在于， 该 方法为：
(a)将活性成分、 水和粘结剂形成的溶液或者悬浊液注模； 或将固体 活性成分和 /或粘结剂注模， 再加入水配成悬浊液或者悬浮液；
(b)将（a )得到的溶液、 悬浊液或者悬浮液在定量成型模具中进行脱 气.
(c)将（a )直接或者（b )得到的脱气后的溶液、 悬浊液或者悬浮液 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， 得到冻干赋型制 剂。
8、 如权利要求 5所述的冻干赋型制剂的制备方法， 其特征在于， 该 方法为：
(a)将活性成分、 水、 粘结剂及其它辅料形成溶液或者悬浊液注模； 或将固体活性成分和 /或粘结剂和 /或其它辅料注模， 再加入水配成悬浊液 或者悬浮液；
(b)将（ a )得到的溶液、 悬浊液或悬浮液在定量成型模具中进行脱气；
(c)将（a )直接或者（b )得到的脱气后的溶液、 悬浊液或悬浮液在 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。
PCT/CN2013/090291 2012-12-26 2013-12-24 一种冻干赋型制剂及其制备方法 WO2014101743A1 (zh)

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