WO2017016506A1 - 一种任意形状的冻干赋形制剂及其制备方法 - Google Patents

一种任意形状的冻干赋形制剂及其制备方法 Download PDF

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Publication number
WO2017016506A1
WO2017016506A1 PCT/CN2016/092074 CN2016092074W WO2017016506A1 WO 2017016506 A1 WO2017016506 A1 WO 2017016506A1 CN 2016092074 W CN2016092074 W CN 2016092074W WO 2017016506 A1 WO2017016506 A1 WO 2017016506A1
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preparation
mold
freeze
lyophilized
shaped preparation
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PCT/CN2016/092074
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English (en)
French (fr)
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董玲
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Individual
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Individual
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Priority claimed from CN201510497752.8A external-priority patent/CN106466228A/zh
Application filed by Individual filed Critical Individual
Priority to EP16829871.9A priority Critical patent/EP3329897A4/en
Priority to US15/744,436 priority patent/US20180200150A1/en
Publication of WO2017016506A1 publication Critical patent/WO2017016506A1/zh
Anticipated expiration legal-status Critical
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    • 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
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    • A23G3/0252—Apparatus in which the material is shaped at least partially in a mould, in the hollows of a surface, a drum, an endless band, or by a drop-by-drop casting or dispensing of the material on a surface, e.g. injection moulding, transfer moulding
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Definitions

  • the invention relates to a lyophilized shaped preparation of arbitrary shape and a preparation method thereof, in particular to a preparation method of preparing a lyophilized shaped preparation mainly containing an active ingredient and a binder by using a multi-die, and preparing the same The product obtained by the method.
  • 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.
  • a support agent which is then poured into a molding die, and a process formed by a freeze-drying process, a formulation prepared by a freeze-drying formulation technique is referred to as a freeze-dried shaped formulation. Since the preparation adopts a freeze-drying process, 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. Disintegration tablets, immediate release tablets, chewable tablets, special cosmetics and other fields.
  • freeze-dried shaped preparations on the market are in a single shape, and the molding die used is a conventional mold, that is, a common groove type mold.
  • the conventional freeze-dried shaped preparation and its preparation method exist in the following Disadvantages:
  • the shape of the preparation is single because the shape of the mold is fixed and can only be released from the mold or released from the single direction, wherein the mold release means that the mold is directly formed in a certain shape of the packaging material.
  • the prepared tablet has an acute angle, and a plurality of tablets having sharp edges obtained after demolding are easily worn together between the acute edges after entering the same package, resulting in inaccurate drug dosage.
  • the preparation structure is single.
  • the present invention provides a freeze-dried shaped preparation of any shape and a preparation method thereof.
  • the invention solves the problem that the freeze-dried shaped preparation has a single shape and is difficult to prepare into a spherical, ellipsoidal or irregular spherical shape, and realizes the production, so that the freeze-dried shaped preparation exhibits a more diverse form, and Production costs are controlled within a manageable range.
  • the present invention provides the following technical solutions:
  • the invention provides a method for preparing a lyophilized shaped preparation of any shape by using a multi-die, comprising the following steps:
  • the mold is pre-cooled, the pre-cooling temperature is not higher than 0 ° C;
  • the pre-cooled mold freezes and solidifies the lyophilized shaped preparation liquid
  • the frozen and solidified lyophilized preparation preparation stock solution is taken out, freeze-dried, and the solvent is removed to obtain a lyophilized shaped preparation product.
  • the mold is assembled from two or more parts, and the maximum number has no upper limit.
  • the mold is assembled from 2-10 parts.
  • the material of the mold described in the preparation method should have a certain hardness and a good thermal conductivity.
  • the hardness of the material is expressed by the indentation hardness, and the indentation hardness value is 0.1 N or more, 100000 N or less, preferably 90,000 N, 80,000 N, 70,000 N, 60,000 N, 50,000 N, 40,000 N, 30000 N or Below 20000N.
  • the thermal conductivity of the material needs to be above 0.01 W/(mk), among which materials with a thermal conductivity of 0.05 W/(mk)-1000 W/(mk) are preferred, and the thermal conductivity is most preferably between 0.2 W/(mk) and 500 W/(mk). )s material.
  • the material may be one of a metal, a polymer material, a ceramic, a glass, or the like, or may be composed of one or more of them.
  • the surface of the mold can be further surface treated.
  • the surface treatment of the mold may be coating, electroplating, acid-base washing, polishing, wire drawing, electrophoresis, PVD and other surface treatment methods, so that the lyophilized forming preparation liquid solution is well separated from the mold after freezing.
  • substantially full as used in the above method means 95% or more, preferably 98% or more, more preferably 99% or more, and most preferably 99.5% or more of the space defined by the mold.
  • the filling hole in the mold may be a filling connection port integrated with the upper mold or any shape independent of the upper and lower molds, and the shape may be a single inlet single outlet, a single inlet multiple outlet, a multi-inlet single outlet One of the multi-inlet and multi-outlet, multi-layer inner and outer casing type filling connection ports, the meaning of which is 2-100.
  • the weight ratio of the binder to the active ingredient may further preferably be from 1:90 to 90:1, from 1:80 to 80:1, from 1:70 to 70:1, from 1:60 to 60:1, and from 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 freeze-dried shaped preparation provided by the present invention may further comprise other auxiliary materials, such as a skeleton support agent, an antioxidant, a flavoring agent and a fragrance, a transmucosal or transdermal absorption enhancer, a pH adjuster, etc., and the contents of these other excipients.
  • auxiliary materials such as a skeleton support agent, an antioxidant, a flavoring agent and a fragrance, a transmucosal or transdermal absorption enhancer, a pH adjuster, etc.
  • the range may be from 0.1 to 5%, preferably from 0.1 to 3%, based on the total amount of the lyophilized shaped preparation obtained.
  • the active ingredient used in the preparation method may be dissolved in water or insoluble in water, and the active ingredient may be selected from chemical pharmaceutical ingredients, traditional Chinese medicine ingredients, natural extracts, biologically active ingredients, and skin care benefits. One or a combination of the ingredients.
  • the active ingredient is not particularly limited and may be selected from, 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, naproxen, 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 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, and the like.
  • Traditional Chinese medicine active ingredient monomers 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.
  • aloe extract yam extract, cranberry 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, and the like.
  • EGF EGF, bFGF, aFGF, KGF, IGF, NGF, TGF, HGH, and the like.
  • Vitamin A 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 extracts thereof , pollen and its extracts, royal jelly, propolis and so on.
  • 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.
  • the binder includes, but is not limited to, gelatin (gelatin, fish gelatin, bird gelatin, hydrolyzed gelatin, etc.), cellulose ethers (methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose) , carboxyethyl methylcellulose, etc.), modified starch (pulrum, hydroxymethyl starch, etc.), hyaluronic acid, albumin, dextran, chitosan and their different molecular weight products, sodium alginate, PVP, PVA, polyethylene glycol, gum arabic, guar gum, xanthan gum, konjac gum, carrageenan, carbomer, agar, carrageenan, pectin or combinations thereof.
  • the gel binder is collagen, gelatin, hydrolyzed gelatin, gum arabic, xanthan gum, carrageenan, pectin, konjac gum, carrageenan, locust bean gum, gum, locust bean gum;
  • the cellulose ether type binder is carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl methyl cellulose, hydroxypropyl methyl cellulose, etc.;
  • the modified starch type binder Selected from pullulan, hydroxypropyl starch, hydroxypropyl methyl starch, pregelatinized starch, amylose, carboxymethyl starch, hydroxyethyl starch, hydroxypropyl starch, etc.; From polyglutamic acid, polyalanine, polylysine, etc.; the glycan is selected from the group consisting of fucoidan, inulin and the like.
  • the lyophilized shaped preparation further comprises other excipients, wherein the other auxiliary materials are one or one of a skeleton support agent, an antioxidant, a flavoring agent and a fragrance, a transmucosal or transdermal absorption enhancer, and a pH adjuster. More than one species.
  • the skeleton support agent includes amino acids (such as glycine, alanine, glutamic acid, etc.) which are not limited to sugars (such as maltose, trehalose, etc.), sugar alcohols (such as mannitol, sorbitol), and 2-12 carbon atoms. And inorganic salts (such as sodium phosphate, aluminum silicate, etc.) and the like.
  • amino acids such as glycine, alanine, glutamic acid, etc.
  • sugars such as maltose, trehalose, etc.
  • sugar alcohols such as mannitol, sorbitol
  • 2-12 carbon atoms such as mannitol, sorbitol
  • inorganic salts such as sodium phosphate, aluminum silicate, etc.
  • 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 transmucosal or transdermal absorption enhancer includes, but is not limited to, a mixture of any one or several of lecithin, saponin, sodium lauryl carbonate, azone, Tween, and Span;
  • the pH adjusting agent includes, but is not limited to, any one or a mixture of several of citric acid, tartaric acid, sodium hydrogencarbonate, carbonate, sodium carbonate, and phosphate.
  • the product prepared by the method of the present invention is different according to the cavity enclosed by the mold.
  • Its shape can be any shape.
  • the shape is a tablet shape, a capsule shape, a soft capsule shape, a sphere, an ellipsoid or various characters, animals, plants, foods, graphic logos or cartoon characters.
  • the product obtained by the method of the present invention may have no sharp edges depending on the shape of the mold.
  • the invention also provides a spherical freeze-dried shaped preparation prepared by the preparation method, wherein the spherical freeze-dried shaped preparation is mainly composed of an active ingredient and a binder, and the shape is a sphere without an acute angle, Special shapes such as ellipsoids and irregular spheres.
  • the weight ratio of the binder to the active ingredient may further preferably be from 1:90 to 90:1, from 1:80 to 80:1, from 1:70 to 70:1, from 1:60 to 60:1, and from 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 mold described in the preparation method (1) is supported by a material having a certain hardness and good thermal conductivity, including one or more of a metal, a polymer material, a ceramic, a glass, and the like.
  • a material having a certain hardness and good thermal conductivity including one or more of a metal, a polymer material, a ceramic, a glass, and the like.
  • the material of the mold may be further surface treated to allow the lyophilized shaped preparation stock to leave the mold well after freezing.
  • the lyophilized shaped preparation filling head described in the preparation method (2) may be a pipetting device such as a precise quantitative pipette, a pipetting gun, an electronic pipetting gun, or the like.
  • a plunger pump, a gear pump, and a peristaltic pump are used.
  • Another aspect of the invention relates to a method of preparing the above spherical freeze-dried shaped preparation, which may be one of the following two preparation methods:
  • the mold is prepared by using a material having a certain hardness and good thermal conductivity, and the mold is assembled by multiple parts, and the assembly gap must not exceed 10 mm;
  • the mold is pre-cooled, the pre-cooling temperature can not be higher than 0 ° C;
  • C including but not limited to the active ingredient, water, binder, skeleton support agent and / or other auxiliary materials formulated into a solution or suspension, degassing treatment, preparing a lyophilized shaping preparation stock solution;
  • the mold device is provided with a feeding port, and the raw liquid of the freeze-dried forming preparation is filled by the feeding port, and the liquid horizontal plane of the mold directly contacting the filling liquid is an obtuse angle;
  • A including but not limited to the active ingredient, water, binder, skeleton support agent and / or other auxiliary materials formulated into a solution or suspension, degassing treatment, preparing a lyophilized shaping preparation stock solution;
  • the cured lyophilized shaped preparation is freeze-dried and the solvent is removed to obtain a freeze-dried shaped preparation product.
  • Another aspect of the invention relates to a method of preparing the above spherical freeze-dried shaped preparation, which may be one of the following two preparation methods:
  • the mold is prepared by using a material having a certain hardness and good thermal conductivity, and the mold is assembled by multiple parts, and the assembly gap must not exceed 5 mm;
  • the mold is pre-cooled, the pre-cooling temperature can not be higher than -20 ° C;
  • C including but not limited to the active ingredient, water, binder, skeleton support agent and / or other auxiliary materials formulated into a solution or suspension, degassing treatment, preparing a lyophilized shaping preparation stock solution;
  • the mold device is provided with a feeding port, and the raw liquid of the freeze-dried forming preparation is filled by the feeding port, and the liquid horizontal plane of the mold directly contacting the filling liquid is an obtuse angle;
  • A including but not limited to the active ingredient, water, binder, skeleton support agent and / or other auxiliary materials formulated into a solution or suspension, degassing treatment, preparing a lyophilized shaping preparation stock solution;
  • the cured lyophilized shaped preparation is freeze-dried and the solvent is removed to obtain a freeze-dried shaped preparation product.
  • 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 raw liquid degassing method may adopt a centrifugal degassing method, a vacuum degassing method, an ultrasonic degassing method, etc.; the freezing may be performed by means of liquid nitrogen or liquid, solid carbon dioxide spray cooling or casing circulating cooling device, and the turboexpander Cooling method or cascade cooling method, rapidly freezing the solution, suspension 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 to 20 mbar, and the temperature is lyophilized between -70 ° C and 50 ° C.
  • the mold described in the production method (1) is made of a material having a certain hardness and good thermal conductivity, and may be composed of one or more of a metal, a polymer material, a ceramic, a glass, and the like. At the same time, the material of the mold can be further subjected to surface treatment, so that the lyophilized shaped preparation stock solution is well separated from the mold after freezing.
  • the preparation filling head according to the preparation method (2) 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 or the like.
  • 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 or the like.
  • the invention provides a spherical freeze-dried forming preparation and a preparation method thereof, and solves the problem that the freeze-dried forming preparation has a single shape and is difficult to prepare into a spherical shape, an ellipsoidal shape or an irregular spherical shape, and realizes the production thereof.
  • the freeze-dried shaped preparations exhibit a more diverse form and control the production cost within a controllable range.
  • Figure 1 is a cross-sectional view of a spherical freeze-dried shaped preparation in a mold; wherein 1 is a feed port, 2 is an assembled mold, and 3 is a frozen freeze-dried shaped preparation stock solution;
  • 2 is a cross-sectional view of a mold part assembly capable of producing a product without an acute angle; wherein 11 and 12 together form an upper mold, 13 is a filling hole, 2 is a lower mold, and 3 is a freeze-dried forming preparation;
  • Figure 3 is a cross-sectional view of the mold component assembly in which the filling connection is independent and can produce products without sharp edges; 131 is a single-input single-out filling connection, 13 is a filling hole, 11 and 12 Co-constituting the mold, 2 is the lower mold, and 3 is the freeze-dried preparation;
  • Figure 4 is a combination view of the mold parts of Embodiment 3; wherein 1 is an upper mold, 13 is a filling hole, and 2 is a lower mold;
  • Figure 5 is a combination view of the mold parts of Embodiment 4; wherein 1 is an upper mold, 13 is a filling hole, and 2 is a rose type lower mold;
  • Fig. 6 is a view showing a combination of mold parts of the fifth embodiment.
  • 131 is a single-input single-out type filling connection port
  • 13 is a filling hole
  • 11 and 12 together form an upper mold
  • 2 is a lower mold
  • 4 is a spacer
  • Figure 7 is a combination view of the mold parts of Embodiment 6; wherein 132 is a separately existing double-input single-out type filling connection port, 13 is a filling hole, 11 and 12 together constitute an upper mold, and 2 is a lower mold;
  • Figure 8 is a combination view of the mold parts of Embodiment 7; wherein 1321 is a double-input and double-out type filling connection port, 13 is a filling hole, 11 and 12 are together to form an upper mold, and 2 is a mango type lower mold;
  • Figure 9 is a combination view of the mold parts of Embodiment 8; wherein 11 and 12 together constitute the upper mold, 13 is a filling hole, 2 is a lower mold, and 5 is a middle shaft;
  • Figure 10 is a combination view of the mold parts of Embodiment 9; wherein 1331 is a separately existing three-in, three-out type filling connection port, 13 is a filling hole, 11 and 12 together constitute an upper mold, and 2 is a lower mold;
  • Fig. 11 is a view showing a combination of mold parts of the tenth embodiment.
  • 1321 is a separate double-inlet and double-out filling connection port
  • 13 is a filling hole
  • 11 and 12 together form an upper mold
  • 2 is an avocado-type lower mold
  • Figure 12 is a combination view of the mold parts of the embodiment 11; wherein 1 is an upper mold, 13 is a filling hole, 131 is a single-input single-out type filling connection port, and 2 is a lower mold;
  • Figure 13 is a combination view of the mold parts of Embodiment 12; wherein 1311 is a separately existing casing type filling connection port, 13 is a filling hole, 11 and 12 together constitute an upper mold, and 2 is a lower mold;
  • Figure 14 is a combination view of a mold part of Embodiment 13; wherein 1 is an upper mold and 13 is a filling Hole, 2 is an oval lower mold;
  • Figure 15 is a combination view of the mold parts of Embodiment 14; wherein 1331 is a separately existing three-in, three-out type filling connection port, 13 is a filling hole, 11 and 12 together constitute an upper mold, and 2 is a Mabe pearl type lower mold. .
  • the invention discloses a spherical 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 raw materials and reagents used in the spherical freeze-dried shaped preparation and the preparation method thereof provided by the present invention are commercially available.
  • (a) consisting of two parts, can produce a combination of rose-shaped molds without sharp-edged tablets, and pre-cooled to -10 ° C;
  • the inner packaging is dissolved in water at the time of use to form a ready-to-use skin care product.
  • (a) consisting of three parts, can produce a combination of molds without sharp-edged tablets, the appearance of a two-layer shape, and pre-cooled to 0 ° C;
  • the inner packaging is carried out to form a ginseng velvet lozenge.
  • the filling connection port 132 is a separately assembled, double-input single-out type filling connection port, which can produce a mold combination with a double-sided shape without an acute-angled side piece. And pre-cooled to -10 ° C;
  • the frozen lyophilized shaped preparation stock solution is in the form of a swimming lap type.
  • the outer diameter of the preparation is 10 mm, and the inner diameter is 8 mm;
  • a three-in, three-out type filling connection port 1331 consisting of three molds can be used to produce a mold assembly capable of producing a spherical preparation without an acute-angled tablet, and pre-cooling To -20 ° C;
  • the components one, two, and three are injected into the mold through the filling connection port in the order of three, two, and one, forming the outermost layer as the component three, the intermediate layer as the component two, and the most
  • the central layer is the composition of component one, to completely freeze; the sum of the mass of component one and component three accounts for 1% of the total content of the spherical freeze-dried shaped preparation;
  • the outermost layer of the preparation has an outer diameter of 30 mm, the outer layer has an outer diameter of 20 mm, and the outermost layer has an outer diameter of 10 mm.
  • the components one, two, and three are injected into the mold through the filling connection port in the order of three, two, and one, forming the outermost layer as the component three, the intermediate layer as the component two, and the most Central layer For the structure of component one, to completely freeze; the sum of the mass of component one and component three accounts for 0.5% of the total content of the spherical freeze-dried shaped preparation;
  • the filling connection port 131 is a separately assembled, single-input single-out type filling connection port, and can produce a mold combination of a sheet-like shape without an acute-angled side sheet, and Pre-cool it to -40 ° C;
  • the components one, two, and three are injected into the mold through the filling connection port in the order of one, two, and three, forming the outermost layer as the component one, the intermediate layer as the component two, and the most
  • the central layer is the structure of component three, to completely freeze; the sum of the mass of component two and component three accounts for 2% of the total content of the spherical freeze-dried shaped preparation;
  • the preparation plane has a diameter of 4 mm and a convex surface height of 3 mm;
  • milk protein: pullulan 20:1, add water to prepare a solution, centrifugal degassing, to obtain a freeze-dried shaped preparation stock solution;
  • the preparation method provided by the invention has extremely significant (P ⁇ 0.01), reduces the production cost, and enriches the form of the lyophilized preparation.

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Abstract

一种任意形状的冻干赋形制剂及其制备方法，特别是一种使用多模具制备任意形状的主要含有活性成分和粘结剂的冻干赋形制剂的方法，以及由该方法制得的产品。

Description

[根据细则37.2由ISA制定的发明名称]　一种任意形状的冻干赋形制剂及其制备方法
本申请要求于2015年07月28日提交中国专利局、申请号为201510450377.1、发明名称为“一种球形冻干赋形制剂及其制备方法”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。
本申请要求于2015年08月14日提交中国专利局、申请号为201510497752.8、发明名称为“一种多模具制备任意形状的冻干赋形制剂的方法及其产品”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
本发明涉及一种任意形状的冻干赋形制剂及其制备方法，特别是一种使用多模具制备得到任意形状的主要含有活性成分和粘结剂的冻干赋形制剂的制备方法及依该方法制得的产品。
背景技术
冻干赋形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形制剂。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。
现在市场上的冻干赋形制剂大多形态单一，所使用的成型模具是传统意义上的模具，即普通的凹槽型模具，这种传统的冻干赋形制剂及其制备方法存在以下几个缺点：
(1)制剂形状单一，原因在于模具形状都是固定的，且只能不脱模或从单方向脱模，其中不脱模是指直接在一定形状的包装材料中进行成型。
(2)罕见球形、椭球形、不规则球体型等特殊形状，因为传统的制备方 法，难以制得特殊形状的冻干赋形制剂。
(3)制得的片剂具有锐角边，脱模后得到的具有锐角边的众多片剂一同进入同一个包装后锐角边之间容易发生磨损，造成药物剂量的不准确。(4)因为单方向灌装，难以成为多层结构，因此，制剂结构单一。
发明内容
有鉴于此，本发明提供本发明涉及一种任意形状的冻干赋形制剂及其制备方法。解决了冻干赋形制剂形态单一、且很难制备成球形、椭球形或不规则球体型形态的问题，并将其实现生产化，让冻干赋形制剂呈现出更加多样的形态，并将生产成本控制在了一个可控范围内。
为了实现上述发明目的，本发明提供以下技术方案：
本发明所提供的一种多模具制备任意形状的冻干赋形制剂的方法，包括如下步骤：
A、使用具有一定硬度且导热性能较好的材料制备模具，所述模具由2块或2块以上部件组装而成，其设有灌装孔13，且存在组装缝隙，所述组装缝隙不超过10mm，优选不超过5mm；
B、将该模具进行预冷，所述预冷温度不高于0℃；
C、将含有水和粘结剂的溶液配制成溶液、乳浊液或悬浊液，制备成冻干赋形制剂原液；
D、将冻干赋形制剂原液由灌装孔13进行灌装至完全或基本充满模具所限定的空间；
E、已预冷的模具使冻干赋形制剂原液发生冻结固化；
F、将已冻结固化的冻干赋形制剂原液取出，进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品。
所述模具由2个以上部件组装而成，其最大个数没有上限，优选模具由2-10个部件组装而成。
制备方法中所述的模具的材料应具有一定硬度且导热性能较好。材料的硬度用压入硬度表示，其压入硬度值在0.1N以上，100000N以下，优选90000N、80000N、70000N、60000N、50000N、40000N、30000N或 20000N以下。材料的导热系数需在0.01W/(m.k)以上，其中优选导热系数在0.05W/(m.k)-1000W/(m.k)的材料，最优选导热系数在0.2W/(m.k)-500W/(m.k)的材料。该材料可以是金属、高分子材料、陶瓷、玻璃等其中的一种或由其中的一种以上共同构成。同时，模具的表面还可以进一步进行表面处理。所述模具表面处理，可以为涂层、电镀、酸碱洗、抛光、拉丝、电泳、PVD及其他表面处理方法，使冻干赋形制剂原液在冷冻后很好的脱离模具。上述方法中所称“基本充满”是指充满模具所限定的空间的95％以上，优选98％以上，更优选99％以上，最优选99.5％以上。
所述模具中的灌装孔，可以为与上模具一体化或为独立于上下模具存在的任意形状的灌装连接口，其形状可以为单进口单出口、单进口多出口、多进口单出口、多进口多出口、多层内外套管型灌装连接口中的其中一种，其中多的含义为2-100。
制得的所述的冻干赋形制剂主要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＝1:100至100:1。
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形制剂还可进一步包含其它辅料，例如骨架支持剂、抗氧化剂、矫味剂及香精、跨黏膜或透皮吸收促进剂、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形制剂的总含量的0.1-5％，优选0.1-3％。
制备方法中所使用的所述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。
所述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、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、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B1、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。所述的粘结剂包括但不限于，明胶类(明胶、鱼明胶、鸟明胶、水解明胶等)、纤维素醚类(甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羧乙基甲基纤维素等)、改性淀粉(普鲁兰糖、羟甲基淀粉等)、透明质酸类、白蛋白、右旋糖酐、壳聚糖及其不同分子量产物、海藻酸钠、PVP、PVA、聚乙二醇，阿拉伯胶、瓜尔豆胶、黄原胶、魔芋胶、卡拉胶、卡波姆、琼脂、角叉菜胶、果胶或它们的组合等。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。
所述的冻干赋形制剂其中还含有其它辅料，所述其它辅料为骨架支持剂、抗氧化剂、矫味剂及香精、跨黏膜或透皮吸收促进剂、pH调节剂中的一种或一种以上。
所述骨架支持剂包含并不限于糖(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。
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；
所述跨黏膜或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、碳酸氢钠、碳酸盐、碳酸钠、磷酸盐中的任何一种或数种的混合物。
使用本发明的方法制备得到的产品，根据模具所围成的空腔的不同， 其形状可以为任意形状。优选的，其形状为片剂形状、胶囊剂形状、软胶囊形状、球形、椭球形或者各种人物、动物、植物、食物、图形标识或卡通形象。使用本发明的方法制备得到的产品，根据模具的形状，可以没有锐角边。
本发明还提供了一种所述制备方法制得的球形冻干赋形制剂，所述的球形冻干赋形制剂主要由活性成分和粘结剂组成，其形状为不含锐角边的球形、椭球形、不规则球体型等特殊形状。
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。
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。
在本发明的一些具体实施方案中，制备方法(1)中所述的模具由具有一定硬度且导热性较好的材料支撑，包括金属、高分子材料、陶瓷、玻璃等其中的一种或多种共同构成。
在本发明的一些具体实施方案中，所述模具的材料还可以进一步进行表面处理，使冻干赋形制剂原液在冷冻后很好的脱离模具。
在本发明的一些具体实施方案中，制备方法(2)中所述的冻干赋形制剂灌装头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。
本发明另一方面涉及的是制备上述球形冻干赋形制剂的方法，可以是以下两种制备方法中的一种：
制备方法(1)：
A、使用具有一定硬度且导热性能较好的材料制备模具，其模具由多部件组装而成，且组装缝隙不得超过10mm；
B、将该模具进行预冷，其预冷温度不能高于0℃；
C、将包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
D、模具装置设有进料口，将冻干赋形制剂原液由进料口进行灌装，且模具与灌装液直接接触的液体水平面切角为钝角；
E、将模具和其中冻干赋形制剂原液进行冷冻，至完全冻结固化；
F、打开模具装置，取出已固化的冻干赋形制剂原液，将其进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品。
制备方法(2)：
A、将包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
B、利用特殊的冻干赋形制剂灌装头，以一定速度将一定量的冻干赋形制剂原液释放到超低温环境中，使得冻干赋形制剂原液迅速凝固成球形、椭球形、不规则球体型等特殊形状。
C、将固化的冻干赋形制剂冷冻干燥、除去溶剂，即得到冻干赋形制剂产品。
本发明另一方面涉及的是制备上述球形冻干赋形制剂的方法，可以是以下两种制备方法中的一种：
制备方法(1)：
A、使用具有一定硬度且导热性能较好的材料制备模具，其模具由多部件组装而成，且组装缝隙不得超过5mm；
B、将该模具进行预冷，其预冷温度不能高于-20℃；
C、将包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
D、模具装置设有进料口，将冻干赋形制剂原液由进料口进行灌装，且模具与灌装液直接接触的液体水平面切角为钝角；
E、将模具和其中冻干赋形制剂原液进行冷冻，至完全冻结固化；
F、打开模具装置，取出已固化的冻干赋形制剂原液，将其进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品。
制备方法(2)：
A、将包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
B、利用特殊的冻干赋形制剂灌装头，以一定速度将一定量的冻干赋形制剂原液释放到超低温环境中，使得冻干赋形制剂原液迅速凝固成球形、椭球形、不规则球体型等特殊形状。
C、将固化的冻干赋形制剂冷冻干燥、除去溶剂，即得到冻干赋形制剂产品。
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。
原液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；所述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，透平膨胀机制冷方式或复叠制冷方式，在-20℃-196℃温度下，迅速将溶液、悬浊液或者悬浮液冷冻成为固体；
所述冻干采用0.01-20毫巴的真空度，温度在-70℃至50℃范围之间冻干。
制备方法(1)中所述的模具由具有一定硬度且导热性较好的材料制成，可以是金属、高分子材料、陶瓷、玻璃等其中的一种或多种共同构成。同时，模具的材质还可以进一步进行表面处理，使冻干赋形制剂原液在冷冻后很好的脱离模具。
制备方法(2)所述的制剂灌装头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。
本发明提供了一种球形冻干赋形制剂及其制备方法，解决了冻干赋形制剂形态单一、且很难制备成球形、椭球形或不规则球体型形态的问题，并将其实现生产化，让冻干赋形制剂呈现出更加多样的形态，并将生产成本控制在了一个可控范围内。
附图说明
图1为球形冻干赋形制剂在模具中的剖面图；其中1为进料口，2为组装型模具，3为已经冻结的冻干赋形制剂原液；
图2为可以生产出无锐角边产品的模具部件组合剖面图；其中11和12共同组成上模具，13为灌装孔，2为下模具，3为冻干赋形制剂；
图3为灌装连接口为独立存在的、可以生产无锐角边产品的模具部件组合剖面图；其中131为单独存在的单进单出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为下模具，3为冻干赋型制剂；
图4为实施例3的模具部件组合图；其中1为上模具，13为灌装孔，2为下模具；
图5为实施例4的模具部件组合图；其中1为上模具，13为灌装孔，2为玫瑰型下模具；
图6为实施例5的模具部件组合图。其中131为单独存在的单进单出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为下模具，4为隔片；
图7为实施例6的模具部件组合图；其中132为单独存在的双进单出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为下模具；
图8为实施例7的模具部件组合图；其中1321为单独存在的双进双出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为芒果型下模具；
图9为实施例8的模具部件组合图；其中11和12共同组成上模具，13为灌装孔，2为下模具，5为中轴；
图10为实施例9的模具部件组合图；其中1331为单独存在的三进三出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为下模具；
图11为实施例10的模具部件组合图。其中1321为单独存在的双进双出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为鳄梨型下模具；
图12为实施例11的模具部件组合图；其中1为上模具，13为灌装孔，131为单独存在的单进单出型灌装连接口，2为下模具；
图13为实施例12的模具部件组合图；其中1311为单独存在的套管型灌装连接口，13为灌装孔，11和12共同组成上模具，2为下模具；
图14为实施例13的模具部件组合图；其中1为上模具，13为灌装 孔，2为椭圆形下模具；
图15为实施例14的模具部件组合图；其中1331为单独存在的三进三出型灌装连接口，13为灌装孔，11和12共同组成上模具，2为马贝珍珠型下模具。
具体实施方式
本发明公开了一种球形冻干赋形制剂及其制备方法，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。
本发明提供的球形冻干赋形制剂及其制备方法中所用原料及试剂均可由市场购得。
下面结合实施例，进一步阐述本发明：
实施例1：
(a)将球形金属模具进行-40℃预冷；
(b)将越橘提取物：普鲁兰＝5:1，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为球形，直径为5mm；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到越橘固体速溶饮料。
实施例2
(a)将玫瑰提取物：海藻糖＝1:10，加水搅拌制成溶液，真空脱气，制备冻干赋形制剂原液；
(b)用液压泵将0.1ml的冻干赋形制剂原液释放到-80℃的环境中，使得冻干赋形制剂原液迅速冻结成椭球形，长：宽＝2:1。
(c)将冻结后的冻干赋形制剂原液进行冻干，后容装到西林瓶中，使用时向西林瓶中注入纯水，即形成即配即用型护肤品。
实施例3：
(a)取由2部分所组成的，可以生产无锐角边片剂的模具组合，并将其预冷至-40℃；
(b)将阿魏酸钠：普鲁兰＝1:5，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液泵将冻干赋形制剂原液缓慢从模具灌装孔13注入模具内部灌装；
(d)待冻干赋形制剂原液冻结固化，打开模具将其取出，盛放于托盘；
(e)对托盘内的、冻结后的冻干赋形制剂原液进行冻干，去除溶剂，得到冻干赋形制剂；
(f)进行内包装，即得到阿魏酸钠药品。
实施例4：
(a)取由2部分所组成的，可以生产无锐角边片剂的、外观为玫瑰花型的模具组合，并将其预冷至-10℃；
(b)将玫瑰提取物：海藻糖＝1:10，搅拌制成溶液，真空脱气，制得冻干赋形制剂原液；
(c)使用灌注泵将冻干赋形制剂原液缓慢从模具灌装孔13注入模具内部灌装；
(d)将模具中的冻干赋形制剂原液进行冷冻，至原液完全冻结成固体；
(e)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(f)进行冻干，去除溶剂，得到冻干赋形制剂；
(g)进行内包装，使用时与水溶解，形成即配即用型的护肤品。
实施例5：
(a)取由3部分所组成的，可以生产无锐角边片剂的、外观为双层片形状的模具组合，并将其预冷至0℃；
(b)将鲜鹿茸匀浆：人参提取物＝2:1，制得组分一；将鲜鹿茸匀浆：人参提取物＝1:2，制得组分二；
(c)将溶液一和二分别加水配制，搅拌制成溶液，真空脱气，制得冻干赋形制剂原液一和二；组分二的质量占球形冻干赋形制剂的总含量的0.1％；
(d)使用移液管将冻干赋形制剂原液一缓慢从模具灌装连接口131注入模具内部灌装；完全冻结；
(e)取出隔片，使用移液管将冻干赋形制剂原液二缓慢从模具灌装连接口131注入模具内部灌装进行冷冻，至原液完全冻结成固体；
(f)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(g)进行冻干，去除溶剂，得到冻干赋形制剂；
(h)进行内包装，形成人参鹿茸含片。
实施例6：
(a)取由3部分所组成的，灌装连接口132为单独装配的、双进单出型灌装连接口，可以生产无锐角边片剂的、外观为双层片形状的模具组合，并将其预冷至-10℃；
(b)配置10％的普鲁兰溶液作为组分一，取PC：吐温80＝5:1制得组分二；组分二、组分三的质量之和占球形冻干赋形制剂的总含量的5％；
(c)将溶液一和二分别进行搅拌配制、离心脱气，制得冻干赋形制剂原液一和二；
(d)使用移液管同时将冻干赋形制剂原液一和二通过双进单出型灌 装连接口前后注入模具内部灌装，至完全冻结；
(e)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(f)进行冻干，去除溶剂，得到冻干赋形制剂；
(g)进行内包装，形成口服PC含片药品。
实施例7:
(a)取由3块模具所组成的，灌装连接口1321为单独装配的、双进双出型灌装连接口，可以生产无锐角边片剂的、外观为芒果型片形状的模具组合，并将其预冷至-20℃；
(b)将浓缩果汁：普鲁兰＝10:1充分搅拌、真空脱气后配制成组分一，VC粉作为组分二；组分二的质量占球形冻干赋形制剂的总含量的3％；
(c)使用灌注泵将组分一和组分二分别通过双进双出型灌装连接口1321前后分别注入模具内部灌装，至完全冻结；
(d)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到冻干赋型制剂；
(f)进行内包装，形成水果型糖果含片。
实施例8：
(a)取由4块模具所组成的、灌装连接口13不单独装配的、且可以生产无锐角边片剂的、下模具中带有中轴的、可生产出环形片形的模具组合，并将其预冷至-40℃；
(b)将西地那非：普鲁兰：甘露醇＝3:1:1充分搅拌、真空脱气后配置成冻干赋形制剂原液；
(c)使用灌注泵将冻干赋形制剂原液通过灌装连接口注入模具内部灌装，完全冻结；
(d)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；且由于下模具带有中轴的缘故，冻结后的冻干赋形制剂原液为泳圈型的形态。制剂外直径为10mm，内直径为8mm；
(e)进行冻干，去除溶剂，得到环形的冻干赋型制剂；
(f)进行内包装，形成药品。
实施例9:
(a)取由3块模具所组成的、单独装配的、三进三出型灌装连接口1331、可以生产无锐角边片剂的、可生产出球形制剂的模具组合，并将其预冷至-20℃；
(b)将GTCC：维生素D：卵磷脂＝5:1:1充分搅拌、真空脱气后配制成组分一；将水解明胶：普鲁兰＝1:1加水充分搅拌、离心脱气后配制成组分二；将浓缩果汁：香精＝10:1加水充分搅拌、真空脱气后制成组分三；
(c)使用灌注泵将组分一、二、三按照三、二、一的顺序通过灌装连接口注入模具内部灌装，形成最外层为组分三、中间层为组分二、最中心层为组分一的结构，至完全冻结；组分一、组分三的质量之和占球形冻干赋形制剂的总含量的1％；
(d)打开模具，取出已经冻结完全的球形冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到球形的冻干赋型制剂；
(f)进行内包装，形成夹心球型的营养补充剂。制剂最外层外直径为30mm，中间层外直径为20mm，最中心层外直径为10mm。
实施例10:
(a)取由3块模具所组成的，灌装连接口1321为单独装配的、双进双出型灌装连接口，可以生产无锐角边片剂的、外观为鳄梨型立体形状的模具组合，并将其预冷至-30℃；
(b)将乳木果油：吐温80＝3:1充分搅拌、真空脱气后配制成组分一；将谷胱甘肽：普鲁兰＝5:1加水充分搅拌、真空脱气后配制成组分二；将月桂氮酮：改性卵磷脂＝1:3充分搅拌、真空脱气后配制成组分三；
(c)使用灌注泵将组分一、二、三按照三、二、一的顺序通过灌装连接口注入模具内部灌装，形成最外层为组分三、中间层为组分二、最中心层 为组分一的结构，至完全冻结；组分一、组分三的质量之和占球形冻干赋形制剂的总含量的0.5％；
(d)打开模具，取出已经冻结完全的立体形态的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到直径为10mm的球形的冻干赋型制剂；
(f)进行内包装，形成鳄梨型的保湿护肤品。
实施例11：
(a)取由2块模具所组成的，灌装连接口131为单独装配的、单进单出型灌装连接口，可以生产无锐角边片剂的、外观为片状的模具组合，并将其预冷至-40℃；
(b)将维生素C：普鲁兰＝10:1加水充分搅拌、真空脱气后配制成冻干赋形制剂原液；
(c)使用灌注泵通过灌装连接口注入模具内部灌装，完全冻结；
(d)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到冻干赋型制剂；
(f)进行内包装，维生素C营养补充剂。
实施例12：
(a)取由3块模具所组成的，灌装连接口1311为单独装配的、内外套管型灌装连接口，可以生产无锐角边片剂的、外观为球形的模具组合，并将其预冷至-30℃；
(b)将可可脂：卵磷脂＝3:1充分搅拌、真空脱气后配制为组分一；将牛奶提取物：普鲁兰＝5:1加水充分搅拌、真空脱气后配制成组分二；组分一的质量之和占球形冻干赋形制剂的总含量的2.5％；
(c)使用灌注泵首先将冻干赋形制剂原液按照组分二在先、然后是组分一的顺序分别通过套管型灌装连接口的外管灌装入模具中，灌装的同时通过内管向内充气，使冻干赋形制剂原液在灌装时形成空心结构；
(d)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到冻干赋型制剂；
(f)进行内包装，形成空心糖食品。
实施例13:
(a)取由2块模具所组成的，灌装连接口13不单独装配的、可以生产无锐角边片剂的、外观为椭圆形状的模具组合，并将其预冷至-40℃；
(b)将酒石酸唑吡坦：普鲁兰：甘露醇＝10:1:1充分搅拌、真空脱气后配制成冻干赋形制剂原液；
(c)使用灌注泵将冻干赋形制剂原液通过灌装连接口注入模具中；
(d)打开模具，取出已经冻结完全的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到冻干赋型制剂；
(f)进行内包装，形成药品。
实施例14:
(a)取由3块模具所组成的，灌装连接口1331为单独装配的、三进三出型灌装连接口，可以生产无锐角边片剂的、外观为马贝珍珠形的模具组合，并将其预冷至-50℃；
(b)将珍珠水解液：普鲁兰＝10:1加水充分搅拌、真空脱气后配制成组分一；纳米级珍珠粉作为组分二；GTCC：卵磷脂＝3:1充分搅拌、真空脱气后配制成组分三；
(c)使用灌注泵将组分一、二、三按照一、二、三的顺序通过灌装连接口注入模具内部灌装，形成最外层为组分一、中间层为组分二、最中心层为组分三的结构，至完全冻结；组分二、组分三的质量之和占球形冻干赋形制剂的总含量的2％；
(d)打开模具，取出已经冻结完全的立体形态的冻干赋形制剂原液，置于托盘内；
(e)进行冻干，去除溶剂，得到马贝珍珠形的冻干赋型制剂。制剂平面直径4mm，凸面高3mm；
(f)进行内包装，形成的护肤品。
实施例15：
(a)将球形金属模具进行-40℃预冷；
(b)将右旋糖酐：透明质酸＝1:100，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为直径15mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到冻干制剂。
实施例16：
(a)将球形金属模具进行-30℃预冷；
(b)将人参提取物：卡波姆＝100:1，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为直径为30mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到冻干制剂。
实施例17：
(a)将球形金属模具进行-50℃预冷；
(b)将维生素C：PVM/MA共聚物＝1:6，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固 定为直径为50mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到冻干制剂。
实施例18：
(a)将球形金属模具进行-70℃预冷；
(b)将聚谷氨酸：甘露醇＝6:1，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为直径为100mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到冻干制剂。
实施例19：
(a)将球形金属模具进行-60℃预冷；
(b)将牛奶蛋白：普鲁兰＝20:1，加水配制成溶液，离心脱气，制得冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为直径为25mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到冻干制剂。
实施例20：
(a)将球形金属模具进行-80℃预冷；
(b)将水溶性虾青素：甘露醇＝1:20，加水配制成溶液，离心脱气，制得 冻干赋形制剂原液；
(c)使用移液管将冻干赋形制剂原液缓慢从模具进料口注入模具内部灌装；
(d)将含有冻干赋形制剂原液的模具进行速冻，使冻干赋形制剂原液固定为直径为18mm的球形；
(e)打开模具，取出已冷冻完成的球形冻干赋形制剂原液，进行冻干，后进行内包装，即得到越橘固体速溶饮料。
实施例21：
以生产100万粒为例，本发明提供的方法与现有方法的生产成本比较见表1。
表1生产成本比较表
Figure PCTCN2016092074-appb-000001
Figure PCTCN2016092074-appb-000002
本发明提供的制备方法与现有技术相比，极显著(P＜0.01)降低了生产成本，且丰富了冻干制剂形态。
以上对本发明所提供的一种球形冻干赋形制剂及其制备方法进行了详细介绍。本文应用了具体个例对本发明的原理及实施方式进行了阐述，以上实施例的说明只是用于帮助理解本发明的方法及其核心思想。应当指出，对于本技术领域技术人员来说，在不脱离本发明原理的前提下，还可以对本发明进行若干改进和修饰，这些改进和修饰也落入本发明权利要求的保护范围内。

Claims (25)

  1. 一种多模具制备任意形状的冻干赋形制剂的方法，其特征在于，包括如下步骤：
    A、使用具有一定硬度且导热性能较好的材料制备模具，所述模具由2块或2块以上部件组装而成，其设有灌装孔13，且因加工精度原因可能存在组装缝隙，所述组装缝隙不超过10mm，优选不超过5mm；
    B、将该模具进行预冷，所述预冷温度不高于0℃；
    C、将含有水和粘结剂的溶液配制成溶液、乳浊液或悬浊液，制备成冻干赋形制剂原液；
    D、将冻干赋形制剂原液由灌装孔13进行灌装至完全或基本充满模具所限定的空间；
    E、已预冷的模具使冻干赋形制剂原液发生冻结固化；
    F、将已冻结固化的冻干赋形制剂原液取出，进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品。
  2. 根据权利要求1所述的方法，其特征在于，步骤C为含有水和粘结剂的溶液增加活性成分，包括但不限于对人体和动物有益的化学药物成分、中药成分、天然提取物、生物活性成分、口服食品补充剂和对皮肤护理有益成分中的一种或一种以上的组合。
  3. 根据权利要求1或2所述的方法，其特征在于，步骤C中含有水和粘结剂的溶液可以进一步增加其它辅料，其它辅料为骨架支持剂、抗氧化剂、矫味剂和香精、跨黏膜或者透皮吸收促进剂、pH调节剂中的一种或一种 以上。
  4. 根据权利要求3所述的方法，其特征在于，所述的骨架支持剂包含并不限于糖(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(如氯化钠、磷酸钠、硅酸铝等)等物质；所述的抗氧化剂选自维生素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；所述的矫味剂和香精选自薄荷味、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；所述的跨黏膜或透皮吸收促进剂选自卵磷脂、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；所述的pH调节剂选自柠檬酸、酒石酸、碳酸氢钠、碳酸盐、碳酸钠、磷酸盐中的任何一种或数种的混合物。
  5. 根据权利要求1－4任意一项所述的方法，其特征在于，所述步骤E为：已预冷的模具使冻干赋形制剂原液发生冻结固化；如果原液未能完全冻结固化，也可以将带有原液的模具进一步冷却直至原液完全冻结。
  6. 根据权利要求1-5任意一项所述的方法，其特征在于，所述的模具由压入硬度在0.1N以上、导热系数在0.01W/(m.k)以上的材料制成，其选自金属、高分子材料、陶瓷、玻璃中的一种或由所述材料的一种以上共同构成。
  7. 根据权利要求1-6任意一项所述的方法，其特征在于，所述模具中的灌装孔13为与上模具一体化的开口或为独立于上下模具存在的具有任意形状的灌装连接口131，所述灌装连接口131的形状可以为单进口单出口、单进口多出口、多进口单出口、多进口多出口、多层内外套管型灌装口中 的一种，其中多的含义为2-100。
  8. 根据权利要求1-7任意一项所述的方法，其特征在于，所述模具的表面还可以进一步进行表面处理，使冻干赋形制剂原液在冷冻后能很好地脱离模具。
  9. 根据权利要求1-8任意一项所述的方法，其特征在于，所述的粘结剂是可食用或者可药用的一种水溶性高分子材料或其混合物，可以是多糖、多肽、蛋白质，也可以是人工聚合高分子，或者是经过改型的天然高分子材料或其混合物，还可以是含有水溶性高分子的天然材料。
  10. 根据权利要求1-9任意一项所述的方法，其特征在于所述的粘结剂包括但不限于明胶类(明胶、鱼明胶、鸟明胶、水解明胶等)、纤维素醚类(甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羧乙基甲基纤维素等)、改性淀粉(普鲁兰糖、羟甲基淀粉等)、透明质酸类、白蛋白、右旋糖酐、壳聚糖及其不同分子量产物、海藻酸钠、PVP、PVA、聚乙二醇，阿拉伯胶、瓜尔豆胶、黄原胶、魔芋胶、卡拉胶、卡波姆、琼脂、角叉菜胶、果胶或它们的组合等，以及含有水溶性高分子的天然材料。
  11. 由权利要求1-10中任意一项方法制备得到的产品。
  12. 根据权利要求11所述的产品，其特征在于，其为任意形状。
  13. 根据权利要求12所述的产品，其特征在于，所述产品没有锐角边。
  14. 根据权利要求12或13所述的产品，其特征在于，其为片剂形状、胶囊剂形状、软胶囊形状、球形、椭球形或者各种人物、动物、植物、食物、图形标识或卡通形象。
  15. 根据权利要求14所述的一种球形冻干赋形制剂，特征在于，所述的 球形冻干赋形制剂主要由活性成分和粘结剂组成，其形状为不含锐角边的球形、椭球形、不规则球体型等特殊形状。
  16. 根据权利要求15所述的球形冻干赋形制剂，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；
    所述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。
  17. 根据权利要求15所述的球形冻干赋形制剂，其特征在于，所述的粘结剂是可食用或者可药用的一种水溶性高分子材料或其混合物，包括多糖、多肽、蛋白质、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；
    粘结剂与活性成分的重量配比为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。
  18. 根据权利要求17所述的球形冻干赋形制剂，其特征在于，所述的粘结剂包括但不限于明胶类、纤维素醚类、改性淀粉、透明质酸类、白蛋白、右旋糖酐、壳聚糖及其不同分子量产物、海藻酸钠、PVP、PVA、聚乙二醇，阿拉伯胶、瓜尔豆胶、黄原胶、魔芋胶、卡拉胶、卡波姆、琼脂、角叉菜胶、果胶中的一种或两者以上的混合物；
    所述明胶类包括明胶、鱼明胶、鸟明胶、水解明胶中的一种或两者以上的混合物；
    所述纤维素醚类包括甲基纤维素、羧甲基纤维素、羟丙基甲基纤维素、羧乙基甲基纤维素中的一种或两者以上的混合物；
    所述改性淀粉包括普鲁兰糖、羟甲基淀粉中的一种或两者的混合物。
  19. 根据权利要求15所述的球形冻干赋形制剂，其特征在于，还含有其它辅料，所述其它辅料为骨架支持剂、抗氧化剂、矫味剂及香精、透皮吸 收促进剂、pH调节剂中的一种或两者以上的混合物；
    所述其它辅料的含量范围占所述球形冻干赋形制剂的总含量的0.1-5％，优选0.1-3％。
  20. 根据权利要求19所述的球形冻干赋形制剂，其特征在于，所述的骨架支持剂包含并不限于糖、糖醇、2-12碳原子的氨基酸和/或无机盐；
    所述糖包括麦芽糖、海藻糖中的一种或两者以上的混合物；
    所述糖醇包括甘露醇、山梨醇中的一种或两者以上的混合物；
    所述2-12碳原子的氨基酸包括甘氨酸、丙氨酸、谷氨酸中的一种或两者以上的混合物；
    所述无机盐包括磷酸钠、硅酸铝中的一种或两者以上的混合物；
    所述的抗氧化剂选自维生素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；所述的矫味剂和香精选自薄荷味、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；所述的透皮吸收促进剂选自卵磷脂、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；所述的pH调节剂选自柠檬酸、酒石酸、碳酸氢钠、碳酸盐、碳酸钠、磷酸盐中的任何一种或数种的混合物。
  21. 根据权利要求15所述的制备方法，其特征在于，所述的制备方法可以是以下两种制备方法中的一种：
    制备方法(1)：
    A、使用具有一定硬度且导热性能较好的材料制备模具，其模具由多部件组装而成，且组装缝隙不得超过10mm；
    B、将该模具进行预冷，其预冷温度不能高于0℃；
    C、将原料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
    D、模具装置设有进料口，将冻干赋形制剂原液由进料口进行灌装，且模具与灌装液直接接触的液体水平面切角为钝角；
    E、将模具和其中冻干赋形制剂原液进行冷冻，至完全冻结固化；
    F、打开模具装置，取出已固化的冻干赋形制剂原液，将其进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品；
    所述原料包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料；
    制备方法(2)：
    A、将原料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
    B、利用特殊的冻干赋形制剂灌装头，以一定速度将一定量的冻干赋形制剂原液释放到超低温环境中，使得冻干赋形制剂原液迅速凝固成球形、椭球形、不规则球体型等特殊形状；
    C、将固化的冻干赋形制剂冷冻干燥、除去溶剂，即得到冻干赋形制剂产品
    所述原料包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料。
  22. 根据权利要求15所述的制备方法，其特征在于，所述的制备方法可以是以下两种制备方法中的一种：
    制备方法(1)：
    A、使用具有一定硬度且导热性能较好的材料制备模具，其模具由多部件组装而成，且组装缝隙不得超过5mm；
    B、将该模具进行预冷，其预冷温度不能高于-20℃；
    C、将原料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
    D、模具装置设有进料口，将冻干赋形制剂原液由进料口进行灌装，且模具与灌装液直接接触的液体水平面切角为钝角；
    E、将模具和其中冻干赋形制剂原液进行冷冻，至完全冻结固化；
    F、打开模具装置，取出已固化的冻干赋形制剂原液，将其进行冷冻干燥，除去溶剂，即得到冻干赋形制剂产品；
    所述原料包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料；
    制备方法(2)：
    A、将原料配制成溶液或悬浊液，进行脱气处理，制备冻干赋形制剂原液；
    B、利用特殊的冻干赋形制剂灌装头，以一定速度将一定量的冻干赋形制剂原液释放到超低温环境中，使得冻干赋形制剂原液迅速凝固成球形、椭 球形、不规则球体型等特殊形状；
    C、将固化的冻干赋形制剂冷冻干燥、除去溶剂，即得到冻干赋形制剂产品；
    所述原料包括但不限于活性成分、水、粘结剂、骨架支持剂和/或其他辅料。
  23. 根据权利要求21或22所述的制备方法，其特征在于，制备方法(1)中所述的模具由具有一定硬度且导热性较好的材料支撑，包括金属、高分子材料、陶瓷、玻璃等其中的一种或多种共同构成。
  24. 根据权利要求23所述的制备方法，其特征在于，所述模具的材料还可以进一步进行表面处理，使冻干赋形制剂原液在冷冻后很好的脱离模具。
  25. 根据权利要求21或22所述的制备方法，其特征在于，制备方法(2)中所述的冻干赋形制剂灌装头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。
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