WO2018028531A1 - Lyophilized preparation and preparation method therefor - Google Patents

Abstract

Provided are a lyophilized preparation and a preparation method therefor. The method comprises the following steps: a) mixing and freezing raw materials for preparation to obtain a soft ice mixture, the raw materials for preparation comprising an active ingredient, a binder and water; The mass ratio of the active ingredient to the binder is 0～100:0～100, and the content of the two cannot be 0 simultaneously; b) processing the soft ice mixture using a filling machine, and releasing the soft ice mixture to the environment for solidification forming, so as to obtain a cured product, the filling machine being selected from a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump; c) freeze-drying the cured product to obtain a lyophilized preparation. The shape of the lyophilized preparation prepared by the preparation method is controllable and the drug loading is higher; The lyophilized preparation has good preparation strength, fast disintegration rate and good solubility. Test results indicate that: The drug loading of the lyophilized preparation is 0.01-99.9%, with preparation friability being less than 0.1%, preparation disintegration time in water being less than15s, and complete dissolution time being less than 15s.

Description

Lyophilized preparation and preparation method thereof

This application is required to be submitted to the China Patent Office on August 11, 2016, the application number is 201610658872.6, the invention name is “Preparation Method of a Lyophilized Preparation” and submitted to the Chinese Patent Office on August 12, 2016, and the application number is 2016106651950. The title of the invention is “a method and a product for preparing a lyophilized preparation using a single-sided rolling die method” and the Chinese Patent Office submitted to the Chinese Patent Office on August 1, 2017, the application number is 201710647918.9, and the invention name is “a kind of The priority of the Chinese patent application of the lyophilized preparation and its preparation method is hereby incorporated by reference in its entirety.

Technical field

The invention relates to the technical field of lyophilized preparations, in particular to a lyophilized preparation and a preparation method thereof.

Background technique

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, medical equipment, health care products and other fields.

Most of the freeze-dried shaped preparations on the market are single in shape and single in addition, and the molding die used is a mold in the traditional sense, that is, a common groove type mold, the conventional freeze-dried shaped preparation and preparation method thereof The following disadvantages exist:

(1) Must be molded by means of a molding die.

(2) The shape of the preparation is single, because the shape of the mold is fixed, and it can only be released from the mold or released from the single direction. The mold release means that the mold is directly formed in a certain shape of the packaging material, so that the shape is rare. Special shapes such as ellipsoidal shape, irregular three-dimensional shape, etc., due to the conventional preparation method, it is difficult to obtain a specially shaped freeze-dried shaped preparation.

(3) The preparation structure is single, because the single-direction filling is difficult to become a multi-layer structure.

(4) The composition of the preparation is single, because the first step of the conventional preparation process is to configure the aqueous solution, so that some functional substances which are difficult to store under normal temperature and under water conditions cannot be added, such as superoxide dismutase, lysozyme, volatile substances and the like. The type of functional ingredients of the formulation is extremely limited.

(5) The adhesion between the material and the mold is large, which causes the mold wall to adhere to a large amount of materials, is difficult to demould, and the production cost is improved.

(6) The drug loading amount has a certain limit, because the solubility of many components has a certain limit, and the active ingredient is used to prepare an aqueous solution for lyophilization, and the amount of the active ingredient carried thereon is limited.

Summary of the invention

In view of the above, an object of the present invention is to provide a method for preparing a lyophilized preparation, which has a controllable shape and a high drug loading amount.

The invention provides a preparation method of a lyophilized preparation, comprising the following steps:

a) mixing the preparation raw materials, freezing, to obtain a soft ice mixture, the preparation raw material comprising an active ingredient, a binder and water; the mass ratio of the active ingredient to the binder is 0 to 100: 0 to 100, and they When the content is different, it is 0;

b) using a filling machine to release the soft ice mixture to the environment for solidification molding, the filling machine being selected from the group consisting of a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain a cured product;

c) The cured product is freeze-dried to obtain a lyophilized preparation.

Preferably, the soft ice mixture is released into a one-side rolling die for solidification molding;

The single-side rolling die includes a rolling die and a flat die; the rolling die is provided with a first concave die, and the flat die is provided with a second concave die;

Filling the soft ice mixture into the second die of the flat die through the filling head, the filling amount is the sum of the volumes of the first die and the second die, and simultaneously rotating the die while horizontally moving the die, the first When a concave die and the second female die are opposed to each other, a sealed state is formed, and the soft ice mixture is solidified to obtain a cured product.

Preferably, the step a) specifically includes:

Mixing some of the prepared raw materials to obtain a part of the soft ice mixture.

If the remaining part of the raw materials are mixed and liquid, the remaining part of the raw materials are mixed and frozen, and then mixed with a part of the soft ice mixture to obtain a soft ice mixture;

If the remaining portion of the raw material is solid after mixing, the remaining portion of the raw material and a portion of the soft ice mixture are uniformly mixed to obtain a soft ice mixture.

Preferably, the preparation method specifically includes:

A, the active ingredient, the binder and water are all mixed or partially mixed, and then formulated into a solution, suspension or emulsion to obtain a liquid 1;

B, the liquid 1 is frozen, and fully stirred during the freezing process to form a soft ice mixture to obtain component 2;

C, after obtaining liquid 1 in step A, if there is residual material 11, it is thoroughly mixed with component 2 to obtain component 4;

If the remaining material 11 is mixed and then in a liquid state, the remaining material is also uniformly frozen by freezing, forming a soft ice mixture component 3, and then thoroughly mixing components 2 and 3 to obtain component 4;

If the remaining material 11 is in a solid state, the remaining material is thoroughly mixed, component 2 is added, and the stirring is continued to obtain component 4;

D, pre-cooling the roller die 51 and the flat die 52, and the pre-cooling temperature is lower than the component eutectic point temperature of the component 2 or the component 4;

E, the surface of the roller die 51 has a concave die 511 and the surface of the flat die 52 has a concave die 521; when the flat die 52 moves horizontally, the roller die 51 rotates at the same time, so that the concave die 511 of the roller die 51 and the die 521 of the flat die 52 In a relative height, a gap is formed to form a sealed state of not more than 10 mm; and component 2 or component 4 is filled onto the concave mold 521, and the filling amount is the sum of the volume of the concave mold 511 and the concave mold 521 or Close to the sum of its volume; while horizontally moving the flat die 52, the roller die 51 is rotated, the female die 511 and the female die 521 are sequentially butted, and the component 2 or the component 4 in the female die is fixed to a certain specification;

F, the pre-cooled roller die 51 and flat mold 52 to further freeze the component 2 or component 4, forming a quantitative component 6;

G, using zero adhesion technology, the quantitative component 6 temperature continues to decrease below the material eutectic point to completely freeze;

H, continue to rotate the roller mold 51, while horizontally moving the flat mold 52, when the concave mold 511, the concave mold 521 is rotated, the frozen solidified component 6 is obtained;

I. The freeze-cured component 6 is freeze-dried to obtain a lyophilized preparation.

Preferably, the active ingredient is selected from the group consisting of a chemical drug, a traditional Chinese medicine, a natural extract, a biologically active ingredient, One or more of skin care benefit ingredients, sanitizers, oral food supplements, and cosmetic medications.

Preferably, the binder is selected from a single binder and/or a combination binder;

The single binder is selected from the group consisting of edible water-soluble polymer materials and/or pharmaceutically acceptable water-soluble polymer materials;

The combined binder is composed of a low temperature binder having a mass ratio of 1:100 to 100:1 and a lyophilized binder selected from the group consisting of C1 to C16 alcohols, greases, and surfactants. And one or more combination of a high molecular weight polymer having a molecular weight of 1 to 80 million g/mol; the lyophilized binder is an artificial high molecular polymer, a natural high molecular polymer, an inorganic gelling agent, Cellulose ethers, modified starches, hyaluronic acid, albumin, dextran, chitosan and their different molecular weight products, sodium alginate, PVP, PVA, polyethylene glycol, agar, polyamino acids and glycans One or more.

Preferably, the single binder is selected from the group consisting of gelatins, cellulose ethers, modified starches, hyaluronic acid, albumin, dextran, chitosan and their different molecular weight products, sodium alginate, polyvinylpyrrolidone, One or more of polyvinyl alcohol, polyethylene glycol, gum arabic, guar gum, xanthan gum, konjac gum, carrageenan, carbomer, agar, carrageenan and pectin.

Preferably, the preparation raw material of the lyophilized preparation further comprises one or more of a skeleton support agent, an antioxidant, a flavoring agent, a fragrance, a transmucosa and a pH adjuster.

Preferably, the skeleton support agent is selected from one or more of a sugar, a sugar alcohol, a C1-C12 amino acid, and an inorganic salt;

The antioxidant is selected from one or more of vitamin C, vitamin C derivatives, anthocyanins, resveratrol, and plant-derived polyphenolic compounds;

The pH adjusting agent includes, but is not limited to, one or more of citric acid, tartaric acid, sodium hydrogencarbonate, carbonate, sodium carbonate, and phosphate.

Preferably, the freezing temperature is from 0 to -100 °C.

Preferably, the shape of the cured product is spherical, ellipsoidal or spheroidal.

Preferably, the soft ice mixture is mixed with air such that the expansion ratio of the soft ice mixture is from 0.1% to 1000%.

Preferably, the shape of the cured product is a tablet shape, a capsule shape, a soft capsule shape, a spherical shape, an ellipsoid shape, a spheroidal shape, various characters, animals, plants, foods, graphic logos or cartoon characters.

Preferably, the surface of the one-side rolling die is processed; the manner of the treatment is selected from the group consisting of coating Layer, plating, oxidation, acid-base washing, polishing, wire drawing, electrophoresis or physical vapor deposition.

Preferably, the solid content in the solution 1 is from 1% by weight to 99% by weight;

The content of the solid matter in the remaining substance 11 is from 1% by weight to 99% by weight.

Preferably, the preparation material of the single-sided mold is selected from materials having a press-in hardness of 0.1 N or more and a thermal conductivity of 0.01 W/(m.k) or more.

Preferably, the lyophilized formulation has no sharp edges.

The present invention provides a lyophilized preparation prepared by the preparation method described in the above technical scheme.

The invention provides a preparation method of a lyophilized preparation, comprising the steps of: a) mixing and preparing a raw material to obtain a soft ice mixture, the preparation raw material comprising an active ingredient, a binder and water; and the active ingredient and the active ingredient The mass ratio of the binder is 0 to 100:0 to 100, and their contents are different at 0; b) the soft ice mixture is used in a filling machine to release the soft ice mixture to the environment for solidification molding, The filling machine is selected from a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain a cured product; c) freeze-drying the cured product to obtain a lyophilized preparation. The lyophilized preparation prepared by the preparation method provided by the invention has the shape controllable and the drug loading amount is high. In addition, the lyophilized preparation prepared by the method has good preparation strength, fast disintegration speed and good solubility. The experimental results show that the drug loading of the lyophilized preparation is 0.01% to 99.9%; the friability of the preparation is <0.1%, the disintegration time of the preparation in water is <15s, and the complete dissolution time is <15s.

DRAWINGS

Figure 1 is a schematic view of a filling head filling a soft ice mixture into a flat mold;

Figure 2 is a schematic view of a soft ice mixture after completion of the filling process;

Figure 3 is a schematic view of the rolling down of the rolling die;

Fig. 4 is a schematic view showing the soft ice mixture being filled into a flat mold while the rolling mold is pressed down.

detailed description

The technical solutions in the embodiments of the present invention are clearly and completely described below. It is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments obtained by those skilled in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.

The invention provides a preparation method of a lyophilized preparation, comprising the following steps:

a) mixing the preparation raw materials, freezing, to obtain a soft ice mixture, the preparation raw material comprising an active ingredient, a binder and water; the mass ratio of the active ingredient to the binder is 0 to 100: 0 to 100, and they When the content is different, it is 0;

b) using a filling machine to release the soft ice mixture to the environment for solidification molding, the filling machine being selected from the group consisting of a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain a cured product;

c) The cured product is freeze-dried to obtain a lyophilized preparation.

The lyophilized preparation prepared by the preparation method provided by the invention has the shape controllable and the drug loading amount is high. In addition, the lyophilized preparation prepared by the method has good preparation strength, fast disintegration speed and good solubility. The invention solves the problems that the lyophilized preparation has a single form, a single type of lyophilized preparation, a difficult mold release, and a small drug loading amount, and the filling head can be designed according to requirements, and the lyophilized preparation is prepared into various three-dimensional shapes required. The lyophilized formulation is presented in a more diverse form and the production cost is controlled to a controlled range.

The preparation of the raw material is mixed and frozen to obtain a soft ice mixture, the preparation raw material comprises an active ingredient, a binder and water; the mass ratio of the active ingredient to the binder is 0-100:0-100, and they The content is 0 when it is not the same.

In the present invention, the active ingredient is preferably selected from one or more of a chemical drug, a traditional Chinese medicine, a natural extract, a biologically active ingredient, a skin care benefit component, a disinfectant, an oral food supplement, and a cosmetic drug. The active ingredient may be a substance that is soluble in water or a substance that is insoluble in water.

The chemical drug, that is, the pharmaceutically active ingredient, is preferably selected from the group consisting of an antipyretic analgesic anti-inflammatory drug, a central stimulant drug, a migraine drug, an analgesic drug, an anti-Parkinson's disease, and an anti-psychotic drug, an antipsychotic drug, and an anti-psychotic drug. Epilepsy and anticonvulsants, sedative hypnotics, cholinesterase inhibitors, antiarrhythmic drugs, anti-angina and anti-atherosclerosis drugs, antihypertensive drugs, adrenal receptor blockers, corticosteroids, Antidiabetic drugs, antithyroid drugs, antihistamines, autologous active substances, digestive system drugs, blood system drugs, urinary system drugs, reproductive system drugs, antiparasitic drugs, antitumor drugs, antimicrobial drugs and antibiotic drugs One or more. The antipyretic analgesic anti-inflammatory drug is preferably selected from the group consisting of aspirin, diflunisal, salsalate, acetaminophen, indomethacin, ibuprofen, naproxen, ketoprofen, pirfen, One or more of suflupron, flurbiprofen, piroxicam, meloxicam, nimesulide, and benzbromarone; the central stimulant is preferably selected from the group consisting of pemoline, aprefini, and piracetam One or more of the treatment; the therapeutic migraine drug is preferably selected from the group consisting of sumatriptan succinate; the analgesic is preferably selected from the group consisting of rotundine, buprenorphine, pentazocine and naloxone. One or more; the anti-Parkinson's disease and the treatment of senile dementia drugs are preferred One or more of levodopa, compound carbidopa, compound benserazide, amantadine hydrochloride, piracetil, profenamide, donepezil and huperzine; the antipsychotic One or more selected from the group consisting of chlorpromazine, promethazine, meperidine, thioridazine, cloprofen, clozapine, sulpiride, tiapride, penfluridol and risperidone; The anti-epileptic and anticonvulsant is preferably selected from one or more of phenytoin, carbamazepine, primidone, gabapentin, lamotrigine, sodium valproate, and clonazepam; the sedation The hypnotic agent is preferably selected from one or more of diazepam, nitrazepam, oxazepam, lorazepam and phenobarbital; the cholinesterase inhibitor is preferably selected from the group consisting of scopolamine; The antiarrhythmic agent is preferably selected from one or more of the group consisting of propionate, tonicani, mexiletine, ethyl thiazide, phenytoin, propafenone, and amiodarone; the anti-angina and anti-atherosclerosis The atherosclerating agent is preferably selected from the group consisting of propranolol, nifedipine, gemfibrozil, bezafibrate, lovastatin, simvastatin and pravastatin. One or more; the antihypertensive agent is preferably selected from one or more of enalapril, captopril, hydrochlorothiazide and amlodipine; the adrenal receptor blocker is preferably selected from the group consisting of acebutolol And/or aplol; the corticosteroid is preferably selected from the group consisting of betamethasone and/or cortisone acetate; the antidiabetic agent is preferably selected from the group consisting of repaglinide; the antithyroid drug is preferably selected from the group consisting of propylthiouracil, One or more of carbimazole and methimazole; the antihistamine is preferably selected from the group consisting of cetirizine hydrochloride and/or loratadine; the autoactive substance is preferably selected from the group consisting of dinoprostone and the forefront One or more of diltiazem and betahistine; the digestive system administration is preferably selected from the group consisting of butyl bromide and/or granisetron hydrochloride; the blood system drug is preferably selected from the group consisting of EPO and/or adenosine cobalamin The urinary system drug is preferably selected from the group consisting of azosemide and/or furosemide; the reproductive system drug is preferably selected from the group consisting of estrogen and/or norronilone; the antiparasitic agent is preferably selected from the group consisting of albendazole and/or Campidazole; the antineoplastic agent is preferably selected from the group consisting of aminoglutethimide and/or amsacrine; the antimicrobial agent is preferably selected from the group consisting of ampicillin And/or sulficillin sodium and an antibiotic drug are preferably selected from one or more of amoxicillin, cephalexin, cefprozil, cefuroxime axetil, roxithromycin, erythromycin ethylsuccinate, and josamycin. Kind.

The traditional Chinese medicine is preferably selected from the group consisting of a traditional Chinese medicine active ingredient monomer or a single Chinese herbal medicine extract and a compound Chinese medicine extract; the traditional Chinese medicine active ingredient monomer is selected from the group consisting of breviscapine, artemisinin, Huperzine A, and Tetrahydropalmatine; The single-flavor Chinese herbal medicine extract and the compound Chinese medicine extract are selected from the group consisting of 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 and ginkgo One or more of the leaf extracts.

The natural extract is preferably selected from the group consisting of 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 and paeonol extract One or more of them.

The bioactive component is preferably selected from the group consisting of EGF, bFGF, aFGF, KGF, IGF, NGF, TGF, HGH, EPO, G-CSF, GM-CSF, various antibody drugs, various vaccines, toxoids, antitoxins, various Enzyme

The skin care benefit component is preferably selected from the group consisting of vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, vitamin K, coenzyme, superoxide dismutase, protease, One or more of metallothionein, pearls and their hydrolysates, cow's milk and its extracts, pollen and its extracts, royal jelly and propolis.

The disinfectant is preferably selected from the group consisting of liquid chlorine, potassium permanganate, ozone, hydrogen peroxide, chloramine, chlorine dioxide, peracetic acid, 84 disinfectant, ethanol, lysul, phenol, cresol, and flu. One or more of malin, red mercury, glutaraldehyde, bleaching powder and quaternary ammonium disinfectant. The quaternary ammonium salt disinfectant is selected from the group consisting of neostigmine and/or chlorhexidine.

The oral food supplement is preferably selected from one or more of the group consisting of amino acids, polyunsaturated fatty acids, minerals, vitamins, dietary ingredients, herbs, and other botanical ingredients.

The cosmetic drug is preferably selected from one or more cosmetically effective substances in the list of cosmetic raw materials issued by the State Food and Drug Administration.

In a specific embodiment of the present invention, the active ingredient comprises vitamin C, bilberry fruit extract, blueberry fruit extract, grape seed extract, orange fruit extract, Dendrobium candidum extract, Morinda officinalis extract, One or more of ibuprofen and racecadot.

In the present invention, the binder is preferably selected from a single binder and/or a combination binder.

The single binder is preferably selected from edible water-soluble polymer materials and/or pharmaceutically acceptable water-soluble polymer materials; the single binder is more preferably selected from the group consisting of gelatins, cellulose ethers, and modifications. Starch, hyaluronic acid, albumin, dextran, chitosan and their different molecular weight products, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, gum arabic, guar gum, xanthan gum, One or more of konjac gum, carrageenan, carbomer, agar, carrageenan and pectin; the gelatin is selected from the group consisting of One or more of gum, fish gelatin, bird gelatin and hydrolyzed gelatin; the cellulose ethers being selected from the group consisting of methylcellulose, carboxymethylcellulose, hydroxypropylmethylcellulose, and carboxyethylmethyl One or more of cellulose; the modified starch is selected from the group consisting of pullulan and/or methylol starch.

The combination binder preferably consists of a low temperature binder having a mass ratio of 1:100 to 100:1 and a lyophilized binder, preferably selected from the group consisting of C1 to C16 alcohols, greases, and surfaces. One or more combinations of an active agent and a high molecular polymer having a molecular weight of from 1 to 80 million g/mol; the lyophilized binder is an artificial high molecular polymer, a natural high molecular polymer, an inorganic gel Agents, cellulose ethers, modified starches, hyaluronic acid, albumin, dextran, chitosan and their different molecular weight products, sodium alginate, PVP, PVA, polyethylene glycol, agar, polyamino acids and poly One or more of the sugars. The volume ratio of the binder to the lyophilized preparation is (0.1 to 5000) mg: 1 cm ³ .

The C1-C16 alcohol is selected from the group consisting of propylene glycol, butanediol, glycerin, 1,2-butanediol, 1,2-propanediol, 1,3-butanediol, pentanediol, polyethylene glycol, One or more of polyglycerol and diglycerin;

The oil or fat is selected from the group consisting of polydimethylsiloxane, polyglyceryl-6 octarate, caprylic/capric triglyceride, tris(ethylhexanoate), diisostearyl malate, Polyglycerol-2 triisostearate, dipentaerythritol tris-polyhydroxystearate, phytosterol oleate, petrolatum, xanthan gum, glycerol (behenic acid/isostearic acid/twenty Alkanoic acid esters, lecithin, hydrogenated lecithin, hydrogenated polydecene, ethylhexyl methoxycinnamate, butter, oyster sauce, goose oil, shark liver oil, almond oil, almond oil, olive oil, sesame oil, One or more of tea seed oil, ethylhexyl palmitate, avocado, hexyl laurate, dioctyl carbonate, GTCC, propyl heptyl octyl ester, oleyl alcohol, and triglyceride;

The surfactant is selected from the group consisting of a Tween component, a Span component, PEG-20 glyceryl triisostearate, polyglyceryl-10 distearate, polyglycerol-2 oleate, cocoyl glycine One or more of potassium, potassium lauroyl glycinate, and the like.

The high molecular polymer is sodium alginate, lanolin, agar, polyvinyl alcohol methyl acrylate graft copolymer, carbomer, carbomer resin, sodium hyaluronate, hyaluronic acid, polyvinylpyrrolidone, polyethylene One or more of an alcohol, polyethylene glycol, polyethylene oxide, modified paraffin, polyacrylamide, sodium polyacrylate, polyacrylate, and polyacrylic acid and derivatives thereof.

The inorganic gelling agent is preferably selected from one or more of diatomaceous earth, bentonite, montmorillonite, lithium montmorillonite, and silicone gel.

The gum-based binder is preferably selected from the group consisting of collagen, gelatin, hydrolyzed gelatin, gum arabic, xanthan gum, large One or more of bean protein gum, small nucleocapsid gum, bio-sugar gum, carrageenan, guar gum, gellan gum, pectin, konjac gum, carrageenan, locust bean gum, gum and locust bean gum Kind.

The cellulose ether-based binder is preferably selected from one of microcrystalline cellulose, carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethyl methyl cellulose, and hydroxypropyl methyl cellulose. A variety.

The modified starch-based binder is selected from the group consisting of sodium polyacrylate grafted starch, pullulan, hydroxypropyl starch, hydroxypropyl methyl starch, pregelatinized starch, amylose, carboxymethyl starch, and hydroxy One or more of ethyl starch and hydroxypropyl starch.

The polyamino acid is selected from the group consisting of polyglutamic acid, polyalanine, polyaspartic acid, and polylysine.

The polysaccharide is selected from one or more of fucoidan, inulin and dextran.

In a particular embodiment of the invention, the binder is selected from the group consisting of pullulan, guar gum, pectin, carbomer, glycerin, dextran, sodium alginate, sodium hyaluronate, polyacrylate, and One or more of polyvinylpyrrolidone.

In the present invention, the preparation raw material of the lyophilized preparation further includes one or more of a skeleton supporting agent, an antioxidant, a flavoring agent, a fragrance, a transmucosal film, and a pH adjusting agent.

The skeleton support agent is selected from one or more of a sugar, a sugar alcohol, a C1-C12 amino acid, and an inorganic salt; the sugar is preferably selected from maltose and/or trehalose; and the sugar alcohol is preferably selected from the group consisting of mannitol and/or Sorbitol. The amino acids of C1 to C12 are preferably selected from the group consisting of glycine, alanine, and glutamic acid; and the inorganic salt is preferably selected from the group consisting of sodium phosphate and/or aluminum silicate. In a particular embodiment of the invention, the backbone support agent is selected from the group consisting of mannitol and/or dextran.

The antioxidant is selected from one or more of vitamin C, vitamin C derivatives, anthocyanins, resveratrol, and plant-derived polyphenolic compounds. In a particular embodiment of the invention, the antioxidant is selected from the group consisting of vitamin C.

The flavoring agent is preferably selected from one or more of a mint flavor, a chocolate flavor, a fruit flavor, a vanilla flavor, a coffee flavor, a tea flavor, a corn flavor, a lemon flavor, and a milk flavor.

The transmucosal or transdermal absorption enhancer is preferably selected from one or more of the group consisting of lecithin, saponin, sodium lauryl carbonate, azone, Tween and Span.

The pH adjusting agent is preferably selected from one or more of the group consisting of citric acid, tartaric acid, sodium hydrogencarbonate, carbonate, sodium carbonate, and phosphate.

In the present invention, the freezing temperature is preferably from 0 ° C to -100 ° C, more preferably from 0 to -90 ° C, from -5 to -80 ° C, from -10 to -70 ° C, from -5 to -50 ° C, - 10 to -30 ° C; most preferably -5 to -30 ° C.

In the present invention, the active ingredient may replace the binder in whole or in part. In the present invention, the mass ratio of the active ingredient to the binder is from 0 to 100:0 to 100, and when their contents are different, it is zero. In addition to the active ingredient, the raw materials of the preparation of the lyophilized preparation are referred to as other components; the total mass ratio of the active ingredient to the other components is preferably (1 to 100): (1 to 100); preferably 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 Up 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.

In the present invention, the step a) preferably specifically includes:

Mixing some of the prepared raw materials to obtain a part of the soft ice mixture.

If the remaining part of the raw materials are mixed and liquid, the remaining part of the raw materials are mixed and frozen, and then mixed with a part of the soft ice mixture to obtain a soft ice mixture;

If the remaining portion of the raw material is solid after mixing, the remaining portion of the raw material and a portion of the soft ice mixture are uniformly mixed to obtain a soft ice mixture.

In the present invention, it is preferred to mix air in the soft ice mixture so that the expansion ratio of the soft ice mixture is preferably from 0.1% to 1000%, more preferably from 1% to 900%, from 10% to 800%, from 50% to 600%. 80% to 300% or 100% to 200%; most preferably 50% to 300%.

The soft ice mixture is used in a filling machine to release the soft ice mixture to the environment for solidification molding. The filling machine is selected from a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain curing. Things.

The pipetting device is preferably selected from a precision metering pipette, a pipetting gun or an electronic pipettor.

The present invention preferably releases the soft ice mixture into a one-side rolling die for solidification molding;

The single-side rolling die includes a rolling die and a flat die; the rolling die is provided with a first concave die, and the flat die is provided with a second concave die;

Filling the soft ice mixture into the second die of the flat die through the filling head, the filling amount is the sum of the volumes of the first die and the second die, and simultaneously rotating the die while horizontally moving the die, the first When a concave die and the second female die are opposed to each other, a sealed state is formed, and the soft ice mixture is solidified to obtain a cured product.

The present invention preferably uses a one-side roller die to quantify, shape, and cure the soft ice mixture. It is demolded by zero-adhesion technology, and finally freeze-dried and dehydrated to obtain a preparation method and product of lyophilized preparation containing arbitrarily shaped water, active ingredient and binder. The invention solves the problem that the lyophilized preparation has a single structure and is difficult to demold. The mold can be designed according to the needs, and the lyophilized preparation is prepared into various shapes as needed, so that the lyophilized preparation exhibits more diverse forms, structures and production costs. Control is within a controllable range.

The present invention may have any shape depending on the shape of the mold or the cavity to be enclosed. Preferably, the shape is a tablet shape, a capsule shape, a soft capsule shape, a sphere, an ellipsoid, various characters, animals, plants, food, graphic logos or cartoon characters. The resulting product was prepared using the method of the present invention, and the lyophilized preparations of various shapes did not have sharp edges depending on the shape of the mold.

The preparation material of the single-sided mold is preferably selected from a material having a press-in hardness of 0.1 N or more and a thermal conductivity of 0.01 W/(mk) or more, more preferably one selected from the group consisting of metal, polymer material, ceramic, and glass. Or a variety. The surface of the one-side roll die is preferably treated; the treatment is preferably selected from the group consisting of coating, plating, oxidation, acid-base washing, polishing, wire drawing, electrophoresis or physical vapor deposition.

After obtaining a cured product, the present invention freeze-drys the cured product to obtain a lyophilized preparation. The present invention removes water by freeze drying.

Specifically, the preparation process of the lyophilized preparation comprises the following steps:

A, the active ingredient, the binder and water are all mixed or partially mixed, and then formulated into a solution, suspension or emulsion to obtain a liquid 1;

B, the liquid 1 is frozen, and fully stirred during the freezing process to form a soft ice mixture to obtain component 2;

C, after obtaining liquid 1 in step A, if there is residual material 11, it is thoroughly mixed with component 2 to obtain component 4;

If the remaining material 11 is mixed and then in a liquid state, the remaining material is also uniformly frozen by freezing, forming a soft ice mixture component 3, and then thoroughly mixing components 2 and 3 to obtain component 4;

If the remaining material 11 is in a solid state, the remaining material is thoroughly mixed, component 2 is added, and the stirring is continued to obtain component 4;

D, pre-cooling the roller die 51 and the flat die 52, and the pre-cooling temperature is lower than the component eutectic point temperature of the component 2 or the component 4;

E, the surface of the roller die 51 has a concave die 511 and the surface of the die 52 has a concave die 521; the flat die 52 When moving horizontally, the roller mold 51 is rotated at the same time, so that the concave die 511 of the roller die 51 and the female die 521 of the flat die 52 are closely adhered to each other to form a sealed state in which the slit does not exceed 10 mm; the component 2 or the component 4. Filling onto the die 521, the filling amount is the sum of the volume of the die 511 and the die 521 or the sum of the volumes thereof; while horizontally moving the die 52, the roller die 51 is rotated to make the die 511 and The concave molds 521 are sequentially butted, and the component 2 or the component 4 in the concave mold is shaped and quantified to a certain specification;

F, the pre-cooled roller die 51 and flat mold 52 to further freeze the component 2 or component 4, forming a quantitative component 6;

G, using zero adhesion technology, the quantitative component 6 temperature continues to decrease below the material eutectic point to completely freeze;

H, continue to rotate the roller mold 51, while horizontally moving the flat mold 52, when the concave molds 511, 521 rotate the opening, the frozen solidified component 6 is obtained;

I. The freeze-cured component 6 is freeze-dried to obtain a lyophilized preparation.

The lyophilized preparation is prepared by the one-side rolling method in combination with FIG. 1 to FIG. 4, FIG. 1 is a schematic view of filling the soft ice mixture into the flat mold by the filling head; FIG. 2 is a schematic diagram of the soft ice mixture after the filling process is completed; It is a schematic diagram of the rolling die pressing; Fig. 4 is a schematic diagram of the soft ice mixture being filled into the flat die and the rolling die is pressed down.

In Fig. 1, 52 is a flat mold, 521 is a flat die; the soft ice mixture is extruded from the filling head into a flat die, and the die of the flat die is hemispherical.

As can be seen in Figure 2, the soft ice mixture after filling is not a complete spherical shape, the upper hemisphere is high and the shape is irregular.

In Fig. 3, 51 is a rolling die, and 511 is a rolling die. As shown in Fig. 3, the rolling die is pressed, and the purpose is to extrude the soft ice mixture after filling into a complete spherical shape.

In Fig. 4, 8 is a cured product; as shown in Fig. 4, while filling the soft ice mixture into the flat mold while one side is being squeezed, the squeezed soft ice mixture becomes a complete spherical shape.

When the liquid 1 is prepared in the step A, water may dissolve or disperse part or all of the binder; water may dissolve or disperse part or all of the active ingredient; or may partially dissolve or disperse the binder. Part of the water dissolves or disperses the active ingredient; it may also be water dissolved or dispersed part or all of the active ingredient and binder, or may be a natural substance or extract containing water itself, including but not limited to milk, juice and royal jelly. .

In the present invention, the solid content in the solution 1 is preferably from 1% by weight to 99% by weight; more preferably 5 wt% to 90 wt%, 10 wt% to 80 wt%, 20 wt% to 70 wt%, 30 wt% to 60 wt% or 40 wt% to 50 wt%, most preferably 40 wt% to 50 wt%;

The solid matter content of the remaining substance 11 is preferably from 1 wt% to 99 wt%; more preferably from 5 wt% to 90 wt%, from 10 wt% to 80 wt%, from 20 wt% to 70 wt%, from 30 wt% to 60 wt%, or from 40 wt% to 50 wt%; Most preferably, it is 40% by weight to 50% by weight.

The lyophilized preparation is prepared using the method of the present invention, and has the advantages of:

(1) In the preparation method, the preparation method of the raw material is made into a soft ice mixture, and the other raw materials can be further mixed with solid or liquid, the range of the raw materials and materials suitable for the formulation is increased, and the drug loading amount is also compared with the existing frozen material. The dry formulation product is larger.

(2) Among them, the zero adhesion technology reduces the material loss and production cost caused by the adhesion between the material and the mold; the mold release method can be used to demold the material by flipping the mold and clamping the robot, thereby improving production efficiency and reducing cost.

(3) Text or pattern can be engraved on any part of the mold. Accordingly, text or pattern may appear on any part of the produced product, which may be the product name or trademark, which is the existing freeze-drying shape. Not available in the preparation product.

(4) The obtained product can be designed into any shape that is not easily broken in the package, reducing the loss of the medicine and making the dosage of the medicine accurate.

(5) The method of the invention prepares the lyophilized preparation by adopting a zero adhesion process, so that the preparation can be conveniently and completely demolded, the packaging material does not enter the freeze-drying process, the production efficiency is improved, the production cost is reduced, and energy saving and environmental protection are achieved.

(6) The state of the soft ice mixture can greatly increase the drug loading amount, and when the solid content is very high, the fluidity and formability can be maintained;

(7) Based on the characteristics of the formability of the soft ice mixture, and with the diversification of the filling head, various spherical shapes can be completed.

The present invention provides a lyophilized preparation prepared by the preparation method described in the above technical scheme.

The invention adopts a method for detecting solubility by a friability meter, a disintegration time limit tester and a pharmacopoeia method, and tests the strength, disintegration speed and solubility of the lyophilized preparation described in the above technical scheme.

In order to further illustrate the present invention, a lyophilized preparation provided by the present invention and a method for preparing the same are described in detail below with reference to the examples, but they are not to be construed as limiting the scope of the invention.

Example 1

35g of vitamin C, 10g of pullulan, 25g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -11 ° C while inflating to a swelling ratio of 115% to form a soft ice mixture, which is component 2;

The combination of the roller die 51 and the flat die 52 having the surface of the elliptical die is pre-cooled at -150 ° C; the component 2 is filled into the die 521, the roller die 51 is rotated, and the die 52 is moved in parallel to make the die 511 And the concave mold 521 is sequentially butted, and is closely adhered to form a complete form; the component 2 is frozen and quantified to form a component 6;

The quantitative component 6 and the flat mold 52 are lyophilized together to form a lyophilized oral VC health food, that is, a lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (completely dissolved in water for 15s). The drug loading amount of this example was 3.5%.

Example 2

2 g of guar gum, 8 g of glycerin, 35 g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -8 ° C while inflating to an expansion ratio of 135% to form a soft ice mixture, which is component 2;

Adding vitamin C 55g as a dry powder to component 2, with uniform stirring to form a soft ice mixture, which is component 4;

The combination of the roller die 51 and the flat die 52 having a surface of a spindle-shaped die is pre-cooled at -86 ° C; the component 4 is filled into the die 521, the roller die 51 is rotated, and the die 52 is moved in parallel to make the die 511 The datum 521 is sequentially butted to each other to form a complete form; the component 4 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -145 ° C, leaving the mold;

The flat mold is turned over to release the frozen solidified component 6 from the female mold, and the component 6 which is separated from the mold is freeze-dried to remove the solvent to form a freeze-dried VC external use fine powder.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (brittleness <0.1%), and rapid disintegration rate (<5s). Good solubility (completely dissolved in water for 15s). The drug loading amount of this example was 5.5%.

Example 3

Pectin 6g, glycerol 18g, mannitol 23g, water 500ml, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -9 ° C while inflating to an expansion ratio of 233% to form a soft ice mixture, which is component 2;

Mixing vitamin C 45g, pullulan 7g, water 500 ml, into a mixed solution to form a liquid 2;

The liquid 2 is frozen at -13 ° C while inflating to a swelling ratio of 120% to form a soft ice mixture, which is component 3;

Component 2 and component 3, with uniform stirring to form a soft ice mixture, is component 4;

The combination of the rolling die 51 and the flat die 52 whose surface is a cartoon image die is pre-cooled at -95 ° C; the component 4 is filled into the die 521, the roller die 51 is rotated, and the flat die 52 is moved in parallel to make the die 511 The datum 521 is sequentially butted to each other to form a complete form; the component 4 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -170 ° C, leaving the mold;

The quantitative component 6 and the flat mold 52 were lyophilized together to remove the solvent to form a VC lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (completely dissolved in water for 15s). The drug loading amount of this example was 9%.

Example 4

23g of European bilberry fruit extract, 15g of blueberry fruit extract, 421g of glycerin, 1 liter of water, formulated into a mixed solution 1;

The mixed solution is frozen at -12 ° C, inflated to 155%, forming a soft ice mixture, which is component 2;

The grape seed extract 18g, sweet orange fruit extract 25g, PVPK9g, pullulan 18g, water 1 liter, formulated into a mixed solution 2;

The mixed solution 2 was frozen at -8 ° C and inflated to 180% to form a soft ice mixture, which was component 3.

Component 2 and component 3, with uniform stirring to form a soft ice mixture, is component 4;

The combination of the roll mold 51 and the flat mold 52 whose surface is a female-shaped concave mold is pre-cooled at -105 ° C; the component 4 is filled into the concave mold 521, the rolling mold 51 is rotated, and the flat mold 52 is moved in parallel to make the concave mold 511 With the die 521 Docking in sequence, a high degree of close contact to form a complete form; component 4 is frozen and quantified to form component 6;

The quantitative component 6 temperature is further reduced to -145 ° C, leaving the mold;

The flat mold is turned over to release the frozen solidified component 6 from the female mold, and the component 6 exiting the mold is freeze-dried to remove the solvent to form a composite fruit lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (1 tablet can be dissolved in 15s when dissolved in 250ml water). The drug loading amount of this example was 8.1%.

Example 5

Mixing ibuprofen 16g, glycerol 250g, PVPK18g, water 500ml into a mixed solution 1;

The mixed solution 1 was frozen at -5 ° C, inflated to 260%, forming a soft ice mixture, which is component 2;

The combination of the rolling die 51 and the flat die 52 whose surface is a tablet-shaped concave die is pre-cooled at -102 ° C; the component 2 is filled into the concave die 521, the rolling die 51 is rotated, and the flat die 52 is moved in parallel to make the die 511 and the concave mold 521 are sequentially butted, highly adhered to form a complete form; the component 2 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -199 ° C, leaving the mold;

The quantitative component 6 and the flat mold 52 were lyophilized together to remove the solvent to form an ibuprofen lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (all dissolved within 5s after oral administration). The drug loading amount of this example was 3.2%.

Example 6

30 ml of pullulan, 9 g of sodium alginate, 7 g of mannitol, 1 liter of water, to prepare a mixed solution 1;

The mixed solution 1 is frozen at -13 ° C, inflated to 114%, forming a soft ice mixture, which is component 2;

Add 226g of racecadotril to component 2 in the form of a dry powder, with uniform agitation to form a soft ice mixture, which is component 4;

The combination of the roller die 51 and the flat die 52 having the surface of the capsule-shaped concave die is pre-cooled at -96 ° C; the component 4 is filled into the concave die 521, the roller die 51 is rotated, and the flat die 52 is moved in parallel to make the die 511 The datum 521 is sequentially butted to each other to form a complete form; the component 4 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -126 ° C, leaving the mold;

The flat die is turned over to release the freeze-cured component 6 from the die, and the component 6 exiting the die is freeze-dried to remove the solvent to form a racecaded lyophilized formulation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (all absorption in the 15s orally without residue). The drug loading amount of this example was 22.6%.

Example 7

Carbomer 21g, sodium hyaluronate 14g, dextran 5g, pullulan 12g, dissolved in 1 liter of water to form a liquid 1;

The liquid 1 is frozen at -6 ° C, the inflation rate is 138%, forming a soft ice mixture, which is component 2;

The combination of the roll mold 51 and the flat mold 52 whose surface is a plant-shaped concave mold is pre-cooled at -88 ° C; the component 2 is filled into the concave mold 521, the rolling mold 51 is rotated, and the flat mold 52 is moved in parallel to make the concave mold 511 And the concave mold 521 is sequentially butted, and is closely adhered to form a complete form; the component 2 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -139 ° C, leaving the mold;

The quantitative component 6 and the flat mold 52 were lyophilized together to remove the solvent to form a lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (brittleness <0.1%), good solubility (all dissolved in 5 s) .

This example is a 100% adjuvant formulation.

Example 8

500 g of water, 17 g of polydimethylsiloxane, 18 g of carbomer, and 11 g of polyacrylate were uniformly stirred to form a liquid 1;

The liquid 1 is frozen at -16 ° C, the inflation rate is 89%, forming a soft ice mixture, which is component 2;

500g of water, 29g of Dendrobium candidum, 33g of Morinda officinalis extract, 28g of polyvinylpyrrolidone, 24g of PEG-20 glyceryl triisostearate, 19g of modified corn starch, and 37g of modified PVPK, to form a liquid 2;

The liquid 2 is frozen at -12 ° C, the inflation rate is 146%, forming a soft ice mixture, which is component 3;

Component 2 and component 3, with uniform stirring to form a soft ice mixture, is component 4;

The combination of the rolling die 51 and the flat die 52 having the surface of the Dendrobium shape die is pre-cooled at -96 ° C; the component 4 is filled into the die 521, the roller die 51 is rotated, and the die 52 is moved in parallel to make the die 511 and the concave mold 521 are sequentially butted, highly adhered to form a complete form; the component 4 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -126 ° C, leaving the mold;

The flat die is turned over to release the freeze-cured component 6 from the die, and the component 6 exiting the die is freeze-dried to remove the solvent to form a lyophilized formulation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (brittleness <0.1%), and rapid disintegration rate (<5s). Good solubility (all dissolved within 10s after oral administration). The drug loading amount of this example was 6.2%.

Example 9

30g of vitamin C, 8g of pullulan, 23g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

Liquid 1 was frozen at -12 ° C while aerating to a swelling ratio of 120% to form a soft ice mixture A.

The soft ice mixture A was dropped into a -60 ° C environment using a peristaltic pump at a specification of 0.5 ml/time to rapidly solidify the soft ice mixture A into a spherical shape.

The spherical soft ice mixture A which has been solidified is freeze-dried and the solvent is removed to obtain a VC lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (dissolved in 1ml water for 10s). The drug loading amount of this example was 3%.

Example 10

5 g of guar gum, 5 g of glycerin, 30 g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -10 ° C while inflating to an expansion ratio of 120% to form a soft ice mixture A;

Adding 50 g of vitamin C as a dry powder to the soft ice mixture A, with uniform stirring to form a soft ice mixture B;

The soft ice mixture B was slowly dropped into the -100 ° C environment using a peristaltic pump at a rate of 0.4 ml/time to rapidly solidify the soft ice mixture B to form a body water drop type.

The solidified stereoscopic water-drop type soft ice mixture B was freeze-dried and the solvent was removed to obtain a VC lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (dissolved in 1ml water for 10s). The drug loading amount of this example was 5%.

Example 11

5g of pectin, 15g of glycerin, 20g of mannitol, 500ml of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -5 ° C while inflating to a swelling ratio of 120% to form a soft ice mixture A;

50 g of vitamin C, 5 g of pullulan, 500 ml of water, formulated into a mixed solution to form a liquid 2;

The liquid 1 is frozen at -15 ° C while inflating to an expansion ratio of 120% to form a soft ice mixture B;

Add soft ice mixture B to soft ice mixture A, with uniform stirring to form a soft ice mixture C;

The soft ice mixture C was quickly dropped into a -110 ° C environment using a screw pump at a rate of 1 ml/time to rapidly solidify the soft ice mixture C into an ellipsoidal shape.

The ellipsoidal soft ice mixture C which has been solidified is freeze-dried and the solvent is removed to obtain a VC lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (all dissolved in water for 10s). The drug loading amount of this example was 10%.

Example 12

25g of European bilberry fruit extract, 18g of blueberry fruit extract, 21g of polydimethylsiloxane, 450g of glycerin, 1 liter of water, formulated into a mixed solution 1;

The mixed solution was frozen at -10 ° C and inflated to 195% to form a soft ice mixture A.

15g of grape extract, orange fruit extract 22g, PVPK9g, pullulan 15g, maltose 15g, water 1 liter, formulated into a mixed solution 2;

The mixed solution was frozen at -8 ° C and inflated to 180% to form a soft ice mixture B.

Add soft ice mixture B to soft ice mixture A, with uniform stirring to form a soft ice mixture C;

The soft ice mixture B was dropped into a -90 ° C environment using a plunger pump at a specification of 0.8 ml/time to rapidly solidify the soft ice mixture C into a spherical shape.

The spherical soft ice mixture C which has been solidified is freeze-dried and the solvent is removed to obtain a composite fruit lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (dissolved in 60ml water, all dissolved in 5s). The drug loading amount of this example was 4%.

Example 13

Mixing ibuprofen 14g, propylene glycol 200g, PVPK15g, water 500ml into a mixed solution 1;

The mixed solution 1 was frozen at -3 ° C and inflated to 180% to form a soft ice mixture A.

The soft ice mixture was rapidly solidified into an irregular spherical shape by using an electronic pipette at a dose of 50 mg/time and dropping into a -95 ° C environment.

The irregular spherical soft ice mixture A which has been solidified is freeze-dried and the solvent is removed to obtain an ibuprofen lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (all dissolved within 10s after oral administration). The drug loading amount of this example was 2.8%.

Example 14

50 ml of pullulan, 15 g of sodium alginate, 25 g of mannitol, 1 liter of water, to prepare a mixed solution 1;

The mixed solution 1 is frozen at -8 ° C, inflated to 150%, forming a soft ice mixture A;

Adding 300g of racecaded cardolid into the soft ice mixture A as a dry powder, with uniform stirring to form a soft ice mixture B;

The soft ice mixture B was rapidly solidified into a spherical shape by dropping into a -105 ° C environment using an electronic pipette at a specification of 100 mg/time.

The spherical soft ice mixture B which has been solidified is freeze-dried and the solvent is removed to obtain a racecaded lyophilized preparation.

This example tests the strength and disintegration rate of the lyophilized preparation according to the test method described in the above technical solution. And solubility, the test results are: good preparation strength (fragility <0.1%), rapid disintegration rate (<3s), good solubility (all absorption within 15s without residue). The drug loading amount of this example was 30%.

Example 15

19mg of carbomer, 10g of sodium hyaluronate, 3g of dextran, 8g of pullulan, dissolved in 1 liter of water to form a liquid 1;

The liquid 1 was frozen at -7 ° C and the aeration expansion rate was 135% to form a soft ice mixture.

The soft ice mixture A was rapidly solidified into an irregular spherical shape by using a plunger pump at a rate of 5.0 g/time, dropping into a -120 ° C environment.

The solidified spherical soft ice mixture A is freeze-dried and the solvent is removed to obtain a moisturizing skin care essence lyophilized preparation.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), rapid disintegration rate (<10s), Good solubility (dissolved in 25ml water, all dissolved in 15s). This example is a 100% adjuvant formulation.

Example 16

500g of water, 19g of polydimethylsiloxane, 16g of carbomer, 12g of polyacrylate are stirred uniformly to form liquid 1;

The liquid 1 is frozen at -15 ° C, the inflation rate is 155%, forming a soft ice mixture A;

500g water, Dendrobium candidum extract 27g, Morinda officin extract 31g, polyvinylpyrrolidone 24g, PEG-20 glyceryl triisostearate 22g, modified corn starch 15g, PVPK31g stirred uniformly to form a liquid 2;

The liquid 2 is frozen at -8 ° C, the inflation rate is 125%, forming a soft ice mixture B;

Add soft ice mixture B to the soft ice mixture A, stir well and form a soft ice mixture C;

The soft ice mixture C was injected into the -198 ° C environment using a peristaltic pump at a rate of 3.5 g/time to rapidly solidify the soft ice mixture C into a spherical shape.

The spherical soft ice mixture C which has been solidified is freeze-dried and the solvent is removed to obtain a lyophilized preparation of the traditional Chinese medicine oil control beauty essence.

This example tests the strength and disintegration rate of the lyophilized preparation according to the test method described in the above technical solution. And solubility, the test results are: good preparation strength (brittleness <0.1%), rapid disintegration rate (<5s), good solubility (all dissolved within 10s orally). The drug loading amount of this example was 11.6%.

Example 17

10 g of guar gum, 60 g of glycerin, 40 g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -8 ° C while inflating to an expansion ratio of 135% to form a soft ice mixture, which is component 2;

Adding 900 g of vitamin C as a dry powder to component 2, with uniform stirring to form a soft ice mixture, which is component 4;

The combination of the rolling die 51 and the flat die 52 of the concave mold having the hemispherical surface is pre-cooled at -86 ° C; the component 4 is filled into the concave mold 521, the rolling die 51 is rotated, and the flat die 52 is moved in parallel to make the concave die 511 and the concave mold 521 are sequentially butted, highly adhered to form a complete form; the component 4 is frozen and quantified to form a component 6;

The quantitative component 6 temperature is further reduced to -185 ° C, leaving the mold;

The flat mold is turned over to release the frozen solidified component 6 from the female mold, and the component 6 which is separated from the mold is freeze-dried to remove the solvent to form a freeze-dried VC external use fine powder.

In this embodiment, the strength, disintegration speed and solubility of the lyophilized preparation are tested according to the test method described in the above technical solution. The test results are: good preparation strength (brittleness <0.1%), and rapid disintegration rate (<5s). Good solubility (completely dissolved in 1ml of water for 15s). The drug loading amount of this example was 90%.

Example 18

10 g of guar gum, 50 g of glycerin, 40 g of mannitol, 1 liter of water, formulated into a mixed solution to form a liquid 1;

The liquid 1 is frozen at -10 ° C while inflating to an expansion ratio of 120% to form a soft ice mixture A;

Adding 900 g of vitamin C as a dry powder to the soft ice mixture A, with uniform stirring to form a soft ice mixture B;

The soft ice mixture B was slowly dropped into the -140 ° C environment using a peristaltic pump at a rate of 0.268 ml/time to rapidly solidify the soft ice mixture B to form a body water drop type.

The solidified stereoscopic water-drop type soft ice mixture B was freeze-dried and the solvent was removed to obtain a VC lyophilized preparation.

This example tests the strength, disintegration rate and solubility of the lyophilized preparation according to the test method described in the above technical solution. The test results are: good preparation strength (friability degree <0.1%), and rapid disintegration rate (<3s), Good solubility (dissolved in 1ml water for 10s). The drug loading amount of this example was 90%.

Comparative example

1 liter of water, VC powder 50g, sucralose 5g, pullulan 40g, carrageenan 10g, guar gum 12g, pectin 10g formulated into a solution to form a liquid 1;

The liquid 1 is frozen and thoroughly stirred during the freezing process to form a soft ice mixture, which is component 2;

The surface of the relatively rotating type of roller mold with a five-pointed star shape die is pre-cooled at -60 ° C after filling component 2, the component 2 is solidified quantitatively to form component 6;

The quantitative component 6 temperature is continuously lowered to -150 ° C freezing;

The rotating roller mold removes the freeze-cured component 6 from the die, freezes and freezes the component 6 which is released from the mold, and removes the solvent to form a freeze-dried VC external use powder.

The comparative example tests the strength, disintegration speed and solubility of the lyophilized preparation according to the test method described in the above technical solution, and the test result is: the preparation strength is good (friability degree <0.1%), and the disintegration speed is generally (about 20 s). Good solubility (all dissolved in 1ml of water for 45s). The drug loading amount of this example was 5%.

This comparative example adopts a relatively rotary rolling die, and can only produce a symmetrical shape, and the present invention can produce an asymmetrical and irregular shape; this comparative example is dissolved in 1 ml of water when used, and the solvent contact specific surface area is one side of the same volume. The stereoscopic shape is small, and the dissolution rate will be slower than the formulation of the present invention with the same formulation and volume.

It can be seen that the invention has the advantages of faster dissolution and more morphology under the conditions of the same formulation and dosage.

It can be seen from the above examples that the present invention provides a method for preparing a lyophilized preparation comprising the steps of: a) mixing a raw material, and freezing to obtain a soft ice mixture comprising an active ingredient, a binder and water. The mass ratio of the active ingredient to the binder is from 0 to 100:0 to 100, and their contents are different at 0; b) using a filling machine to release the soft ice mixture to the environment for solidification molding, The filling machine is selected from a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain a cured product; c) freeze-drying the cured product to obtain a lyophilized preparation. The lyophilized preparation prepared by the preparation method provided by the invention has the shape controllable and the drug loading amount is high. In addition, the lyophilized preparation prepared by the method has good preparation strength, fast disintegration speed and good solubility. The experimental results show that the drug loading of the lyophilized preparation is 0.01% to 99.9%; the friability is <0.1%, the disintegration time is <15s, and the dissolution time is <15s.

The above description is only a preferred embodiment of the present invention, and it should be noted that those skilled in the art can also make several improvements and retouchings without departing from the principles of the present invention. It should be considered as the scope of protection of the present invention.

Claims (18)

1. A method for preparing a lyophilized preparation, comprising the steps of:

   a) mixing the preparation raw materials, freezing, to obtain a soft ice mixture, the preparation raw material comprising an active ingredient, a binder and water; the mass ratio of the active ingredient to the binder is 0 to 100: 0 to 100, and they When the content is different, it is 0;

   b) using a filling machine to release the soft ice mixture to the environment for solidification molding, the filling machine being selected from the group consisting of a pipetting device, a plunger pump, a screw pump, a gear pump or a peristaltic pump to obtain a cured product;

   c) The cured product is freeze-dried to obtain a lyophilized preparation.
2. The preparation method according to claim 1, wherein the soft ice mixture is released into a one-side rolling die for solidification molding;

   The single-side rolling die includes a rolling die and a flat die; the rolling die is provided with a first concave die, and the flat die is provided with a second concave die;

   Filling the soft ice mixture into the second die of the flat die through the filling head, the filling amount is the sum of the volumes of the first die and the second die, and simultaneously rotating the die while horizontally moving the die, the first When a concave die and the second female die are opposed to each other, a sealed state is formed, and the soft ice mixture is solidified to obtain a cured product.
3. The preparation method according to claim 1, wherein the step a) specifically comprises:

   Mixing some of the prepared raw materials to obtain a part of the soft ice mixture.

   If the remaining part of the raw materials are mixed and liquid, the remaining part of the raw materials are mixed and frozen, and then mixed with a part of the soft ice mixture to obtain a soft ice mixture;

   If the remaining portion of the raw material is solid after mixing, the remaining portion of the raw material and a portion of the soft ice mixture are uniformly mixed to obtain a soft ice mixture.
4. The preparation method according to claim 2, wherein the preparation method comprises:

   A, the active ingredient, the binder and water are all mixed or partially mixed, and then formulated into a solution, suspension or emulsion to obtain a liquid 1;

   B, the liquid 1 is frozen, and fully stirred during the freezing process to form a soft ice mixture to obtain component 2;

   C. After liquid 1 is obtained in step A, if there is residual substance 11, it is thoroughly mixed with component 2. Obtaining component 4;

   If the remaining material 11 is mixed and then in a liquid state, the remaining material is also uniformly frozen by freezing, forming a soft ice mixture component 3, and then thoroughly mixing components 2 and 3 to obtain component 4;

   If the remaining material 11 is in a solid state, the remaining material is thoroughly mixed, component 2 is added, and the stirring is continued to obtain component 4;

   D, pre-cooling the roller die 51 and the flat die 52, and the pre-cooling temperature is lower than the component eutectic point temperature of the component 2 or the component 4;

   E, the surface of the roller die 51 has a concave die 511 and the surface of the flat die 52 has a concave die 521; when the flat die 52 moves horizontally, the roller die 51 rotates at the same time, so that the concave die 511 of the roller die 51 and the die 521 of the flat die 52 In a relative height, a gap is formed to form a sealed state of not more than 10 mm; and component 2 or component 4 is filled onto the concave mold 521, and the filling amount is the sum of the volume of the concave mold 511 and the concave mold 521 or Close to the sum of its volume; while horizontally moving the flat die 52, the roller die 51 is rotated, the female die 511 and the female die 521 are sequentially butted, and the component 2 or the component 4 in the female die is fixed to a certain specification;

   F, the pre-cooled roller die 51 and flat mold 52 to further freeze the component 2 or component 4, forming a quantitative component 6;

   G, using zero adhesion technology, the quantitative component 6 temperature continues to decrease below the material eutectic point to completely freeze;

   H, continue to rotate the roller mold 51, while horizontally moving the flat mold 52, when the concave mold 511, the concave mold 521 is rotated, the frozen solidified component 6 is obtained;

   I. The freeze-cured component 6 is freeze-dried to obtain a lyophilized preparation.
5. The preparation method according to claim 1, wherein the active ingredient is selected from the group consisting of a chemical drug, a traditional Chinese medicine, a natural extract, a biologically active ingredient, a skin care benefit component, a disinfectant, an oral food supplement, and a cosmetic drug. One or several.
6. The preparation method according to claim 1, wherein the binder is selected from the group consisting of a single binder and/or a combination binder;

   The single binder is selected from the group consisting of edible water-soluble polymer materials and/or pharmaceutically acceptable water-soluble polymer materials;

   The combined binder is composed of a low temperature binder having a mass ratio of 1:100 to 100:1 and a lyophilized binder selected from the group consisting of C1 to C16 alcohols, greases, and surfactants. And molecular weight is 1~8000 One or more combinations of 10,000 g/mol of high molecular weight polymer; the lyophilized binder is an artificial high molecular polymer, a natural high molecular polymer, an inorganic gelling agent, a cellulose ether, and a modified One or more of amylopectin, hyaluronic acid, albumin, dextran, chitosan and its different molecular weight products, sodium alginate, PVP, PVA, polyethylene glycol, agar, polyamino acid and glycan .
7. The preparation method according to claim 6, wherein the single binder is selected from the group consisting of gelatin, cellulose ether, modified starch, hyaluronic acid, albumin, dextran, chitosan and the like. Molecular weight products, sodium alginate, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, gum arabic, guar gum, xanthan gum, konjac gum, carrageenan, carbomer, agar, carrageenan and fruit One or more of the gums.
8. The preparation method according to claim 1, wherein the preparation raw material of the lyophilized preparation further comprises one or more of a skeleton supporting agent, an antioxidant, a flavoring agent, a fragrance, a transmucosal film, and a pH adjusting agent. Kind.
9. The preparation method according to claim 8, wherein the skeleton supporting agent is one or more selected from the group consisting of a sugar, a sugar alcohol, a C1-C12 amino acid, and an inorganic salt;

   The antioxidant is selected from one or more of vitamin C, vitamin C derivatives, anthocyanins, resveratrol, and plant-derived polyphenolic compounds;

   The pH adjusting agent includes, but is not limited to, one or more of citric acid, tartaric acid, sodium hydrogencarbonate, carbonate, sodium carbonate, and phosphate.
10. The preparation method according to claim 1, wherein the freezing temperature is 0 to -100 °C.
11. The preparation method according to claim 1, wherein the cured product has a spherical shape, an ellipsoidal shape or a spheroidal shape.
12. The preparation method according to claim 1, wherein the soft ice mixture is mixed with air so that the expansion ratio of the soft ice mixture is from 0.1% to 1000%.
13. The preparation method according to claim 2, wherein the shape of the cured product is a tablet shape, a capsule shape, a soft capsule shape, a spherical shape, an ellipsoid shape, a spheroid shape, various characters, animals, plants, foods. , graphic logo or cartoon image.
14. The preparation method according to claim 2, wherein the surface of the one-side rolling die is processed; the treatment is selected from the group consisting of coating, electroplating, oxidation, acid-base washing, polishing, Drawing, electrophoresis or physical vapor deposition.
15. The preparation method according to claim 4, wherein the solid content in the solution 1 is from 1% by weight to 99% by weight;

    The content of the solid matter in the remaining substance 11 is from 1% by weight to 99% by weight.
16. The preparation method according to claim 2, wherein the preparation material of the one-side mold is selected from materials having a press-in hardness of 0.1 N or more and a thermal conductivity of 0.01 W/(m.k) or more.
17. The preparation method according to claim 2, wherein the lyophilized preparation has no sharp edges.
18. A lyophilized preparation obtained by the production method according to any one of claims 1 to 17.

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