CN107260688A

CN107260688A - A kind of formula of lyophilized formulations and preparation method thereof

Info

Publication number: CN107260688A
Application number: CN201610219250.3A
Authority: CN
Inventors: 董玲
Original assignee: Individual
Current assignee: Individual
Priority date: 2016-04-08
Filing date: 2016-04-08
Publication date: 2017-10-20

Abstract

The invention discloses a kind of formula of lyophilized formulations and preparation method thereof, more particularly to a kind of formula for lyophilized preparation using graft starch class binding agent as primary raw material.Its preparation process is that formula supplementary material material is configured into solution, freezes rear physical crushing, is freeze-dried after loading quantitative mould, forms freeze-drying prods.

Description

A kind of formula of lyophilized formulations and preparation method thereof

Technical field

The invention discloses a kind of formula of lyophilized formulations and preparation method thereof, it is more particularly to a kind of using graft starch class binding agent be main The formula for lyophilized preparation of raw material.Its preparation process is that formula supplementary material material is configured into solution, freezes rear physical crushing, loads quantitative It is freeze-dried after mould, forms freeze-drying prods.

Background technology

Lyophilized figuration technology refer in the active component of flowable liquid, semisolid or solid addition skeleton supporting agent, binding agent etc. into Point, or itself, containing compositions such as binding agent, skeleton supporting agents, is then filled into the flowable liquid, semisolid or solid In mould, the preparation prepared by freezing figuration technology is referred to as lyophilized excipient.

Its technical process of lyophilized figuration technology, is that wet stock or solution are frozen into solid-state at relatively low temperature (- 10 DEG C~-50 DEG C), Then moisture therein is directly sublimed into gaseous state without liquid under vacuum (1.3~13 handkerchief), finally make material dewatering.

Because such preparation uses freeze drying process, thermally sensitive composition can be protected not to be destroyed, while being produced by water sublimed a large amount of Micropore and duct, can have disintegration and dissolution velocity quickly, therefore receive extensive use, can apply to oral disnitegration tablet, speed Release the multiple fields such as piece, chewable tablets, novel cosmetic, health products, solid beverage, medicine, medicine equipment.

Lyophilized excipient currently on the market is big polymorphic single, and used mould is traditional mould, i.e., common Fluted body mould, this traditional lyophilized excipient and preparation method thereof has the following disadvantages：

(1) preparation shape is single, and reason is that mold shape is all fixed, and can not only be stripped or be stripped from one direction, wherein not taking off Mould refers to directly be molded in the packaging material of definite shape, therefore the special shape such as rare spherical, elliposoidal, irregular ball-shape, It is difficult to the lyophilized excipient that special shape is made.

(2) there are tablet made from the numerous tablets with sharp edge obtained after sharp edge, the demoulding together to enter acute angle after same packaging Easily worn and torn between side, cause the inaccurate of drug dose.

(3) because one direction is filling, it is difficult to which, as sandwich construction, therefore, preparation structure is single.

Inventor is dedicated itself to innovation, and has carried out a large amount of in-depth studies and experiment work, and the principle based on lyophilized excipient preparation manufacturing process is carried out Process optimization is there is provided a kind of method of lyophilized formulations that can prepare arbitrary shape and its according to product made from this method, particularly A kind of formula of lyophilized formulations and preparation method thereof, more particularly to a kind of lyophilized formulations using graft starch class binding agent as primary raw material are matched somebody with somebody Side.Its preparation process is that formula supplementary material material is configured into solution, freezes rear physical crushing, loads to freeze after quantitative mould and does It is dry, the arbitrary shape of formation, the lyophilized formulations product of main active composition and binding agent.

The present invention solves the problem of lyophilized formulations form is single, and mould can be designed as needed, and lyophilized formulations are prepared into each of needs Shape is planted, allows lyophilized formulations to show more various form, structure (double-layer tablets, multilayer tablet) and control production cost at one In controlled range.

The content of the invention

The invention provides a kind of formula of lyophilized formulations, it is made up of the active component and binding agent of effective dose, binding agent is to account for tablet weight It is 0.1mg/cm to measure the ratio between the graft starch class that percentage is 0.1%-99.9%, and weight and volume of lyophilized formulations³-5000mg/cm³。

The graft starch class includes but is not limited to Sodium Polyacrylate graft starch -7, Sodium Polyacrylate graft starch -12, Sodium Polyacrylate and connect One or more in the models such as branch starch -25, polyacrylic acid grafted starch, polyvinyl alcohol/methyl acrylate graft copolymer.

The binding agent to account for tablet weight percentage 0.1%-99.9%, can further be optimized for 0.5%-50%, 1%-50%, 0.5%-30%, 1%-30%, 0.5%-20%, 1%-20%, 0.5%-10%, 1%-10%, most preferably 1%-20%.

The ratio between weight and volume of the lyophilized formulations are 0.1mg/cm³-5000mg/cm³, can further be optimized for 1mg/cm³-500 mg/cm³、10mg/cm³-50mg/cm³、100mg/cm³-50mg/cm³、1000mg/cm³-5mg/cm³, most preferably 100mg/cm³-50mg/cm³。

The formula of described lyophilized formulations, can also further add additional adhesive, account for tablet weight percentage for 0.1%-99.9%, enter One step can be optimized for 0.5%-50%, 1%-50%, 0.5%-30%, 1%-30%, 0.5%-20%, 1%-20%, 0.5%-10%, 1%-10%, Most preferably 1%-20%.

Described additional adhesive is selected from native starch, modified starch series, cellulose ethers, polyvinyl alcohol copolymer class, polyacrylic acid and connect Branch starch, glue class, PVP, carbomer, PVA, hyalomitome acids, albumin, chitosan, dextran, agar, polyaminoacid, Glycan or combinations thereof.

The native starch class includes tapioca, farina, cornstarch, rice starch, wheaten starch, oat starch, open country One or more combinations in amylum marantae；The modified starch include modified corn starch, modified potato starch, modified tapioca starch, Hydrogenated starch, hydrogenated starch hydrolysate, Sodium Polyacrylate graft starch, polyacrylic acid grafted starch, hydroxypropul starch, hydroxypropul starch Phosphate, amylose, amylopectin, CMS, sodium carboxymethyl starch, cornstarch/acrylamide/sodium Acrylate copolymer In one or more combinations；It is carboxymethyl cellulose, carboxyethyl cellulose, hydroxyl that the cellulose ethers, which includes cellulose ethers binding agent, One or more combinations in ethylmethylcellulose, hydroxypropyl methyl cellulose；The polyvinyl alcohol copolymer class is handed over including polyvinyl alcohol One or more groups in linked polymer, polyvinyl alcohol/methyl acrylate graft copolymer, polyving alcohol/polylactic acid co-glycolic acid Close；The glue class include pectin, carragheen, xanthan gum, collagen, hydrolytic collagen, gelatin, gelatin hydrolysate, Arabic gum, konjac glucomannan, Carrageenan, locust bean gum, natural gum, locust bean gum etc.；Described polyaminoacid is selected from polyglutamic acid, polyalanine, polylysine etc.； Affiliated glycan is selected from fucoidin, synanthrin etc..

The active component, which can be dissolved in water, can also be insoluble in the material of water, and the active component is selected from chemicals composition, Chinese medicine One or more kinds of combinations in composition, natural extract, bioactive ingredients, skin nursing beneficiating ingredient.

There is no particular limitation for the active component, can be selected from, but not limited to, the composition of following one or more of compositions.

Chemicals (active constituents of medicine)：

Antipyretic-antalgic anti-inflammatory agent, such as aspirin, Diflunisal, salsalate, paracetamol, Indomethacin, brufen, Naproxen, Ketoprofen, pirprofen, suprofen, Flurbiprofen, piroxicam, Meloxicam, aulin, Benzbromarone etc.；

Central stimulant, such as pemoline, adrafinil, Piracetam；

Treat migraine agent, such as Sumatriptan succinate；

Antalgesic, such as rotundin, buprenorphine, pentazocine, naloxone；

Anti-parkinson and treatment senile dementia medicine, for example levodopa, compound carbidopa, compound benserazide, amantadine hydrochloride, Piribedil, phenolicamine, donepezil, huperzine are first-class；

Psychotolytic, such as chlorpromazine, fenazil, pethidine, thioridazine, Chlorprothixene, Clozapine, Sulpiride, Thailand must Profit, penfluridol, Risperidone etc.；

Antiepileptic and anticonvulsive drug, such as dilantin sodium, carbamazepine, Primidone, Gabapentin, Lamotrigine, sodium vedproate, Clonazepam etc..

Hypnotic sedative agent, such as diazepam, nitrazepam, Oxazepam, Lorazepam, phenobarbital；

Cholinesterase inhibitor, such as hyoscine；

Antiarrhymic, such as third pyridine, tocainide, mexiletine, aetmozine, dilantin sodium, Propafenone, amiodarone；

Antianginal and antiatherosclerotic, such as Propranolol, nifedipine, Gemfibrozil, Bezafibrate, Lovastatin, Simvastatin, Pravastatin etc.；

Antihypertensive, such as Enalapril, captopril, Hydrochioro, Amlodipine；

Adrenoceptor blocking agents, such as acebutolol, alprenolol；

Corticosteroid medicine, such as betamethasone, cortisone acetate；

Antidiabetic, such as Repaglinide；

Antithyroid drug, such as propylthiouracil (PTU), Carbimazole, methimazole；

Antithistamine, such as Cetirizine Hydrochloride, Loratadine；

Autacoid, such as dinoprostone, Alprostadil, Betahistine；

Digestive system surgical procedures, such as scopolamine butylbromide, Granisetron Hydrochloride；

Hematological system medicine, such as EPO, cobamamide；

Urinary system medicine, such as azosemide, frusemide；

Reproductive system medicine, such as estrogen, Nandrolone Phenylpropionate；

Antiparasitic agent, such as albendazole, cambendazole；

Antineoplastic, such as aminoglutethimide, amsacrine；

Antimicrobial, such as ampicillin, sulbenicillin sodium；

Tri-Biocin, such as Amoxicillin, cefalexin, Cefprozil, CEFUROXIME AXETIL, ROX, Erythromycin Ethylsuccinate, friendship Arenomycin etc..

Traditional Chinese medicine ingredients：

Effective component of chinese medicine monomer, such as：Breviscapinun, qinghaosu, huperzine, tetrahydropalmatine etc.；

Single medicinal material material extract and compound Chinese medicine extract, such as：Tanshinone extract, salvianolic acid extract, compound danshen dripping pills Extract, cow-bezoar bolus compound extract, ginseng stem and leave general saponin, asiatic moonseed extract, general ginsenoside, American ginseng total saponins, Breviscapinun, Glabrous Sarcandra Herb medicinal extract, arasaponin, capillary extract, extractum rhei, andrographolide, hawthorne leaf P.E, accumulated snow Careless total glycosides, ginkgo biloba p.e etc..

Natural plant extracts：

Such as aloe extract, yam extract, Bilberry fruit P.E, Bitter Melon P.E, Echinacea Purpurea Herb P.E, Feverfew P.E, mangosteen Extract, pine needle and Pine Bark, Brazilian blackberry extract, mulberries extract, elderberry extract, Cranberry extract, Astaxanthin, lycopene, green-tea extract, grape pip and grape skin extract, glabridin, Paeoniflorin, licoflavone, the root bark of tree peony are carried Take thing etc..

Bioactive ingredients：

EGF, bFGF, aFGF, KGF, IGF, NGF, TGF, HGH, EPO, G-CSF, GM-CSF, various antibody Medicine, various vaccines, toxoid, antitoxin, various biology enzymes etc..

Skin nursing beneficiating ingredient：

Vitamin A, vitamin B1, vitamin B2, vitamin B3, vitamin B6, vitamin B12, vitamin C, vitamin D, Vitamin E, vitamin K, coenzyme class, protease, metallothionein, pearl and its hydrolysate, cow's milk and its extract, pollen and Its extract, royal jelly, propolis etc..

A kind of formula of described lyophilized formulations, can also further contain other auxiliary materials, and other auxiliary materials include skeleton agent, anti-oxidant One or more in agent, flavouring and essence, skin penetration enhancer, PH conditioning agents, disintegrant.

A kind of formula of described lyophilized formulations, the skeleton agent is (such as sweet comprising sugar (such as maltose, trehalose), sugar alcohol is not limited to Reveal alcohol, sorbierite), the amino acid (such as glycine, alanine, glutamic acid) of 2-12 carbon atoms and inorganic salts (such as sodium phosphate, Alumina silicate etc.) etc. material；The antioxidant is selected from vitamin C, anthocyanidin, resveratrol, the polyhydric phenols of plant origin In one or several kinds of mixtures；The flavouring and essence are selected from mint flavored, chocolate flavoured, vanilla flavored, caf, tea flavour, jade The mixture of the one or more of fragrance of the essence such as rice taste, lemon, milk flavor or more；The skin penetration enhancer be selected from lecithin, Any of tween, sapn or several mixtures；The PH conditioning agents are in citric acid, tartaric acid, sodium acid carbonate, sodium carbonate Any or several mixture；The disintegrant include but is not limited to starch (wheaten starch, cornstarch, green starch, Sweet potato starch, farina, tapioca etc.), modified starch series (α, β, cyclooctaamylose, maltodextrin, amylose, Crosslinked starch and its esters, esterification starch, etherification starch, graft starch, oxidative crosslinked starch, esterified and cross-linked starch and its esters, phosphorus Acid esters starch, acidified starch, cationic starch, CMS and its esters etc.), cellulose family (microcrystalline cellulose etc.), cellulose Ethers (methylcellulose, carboxymethyl cellulose, sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl methyl cellulose, carboxylic second Ylmethyl cellulose, low substitution carboxy-propyl cellulose etc.), insoluble polymer (PVPP, grafting starch copolymer etc.) is sliding Stone flour, gelatin, silica, superfine silica gel powder etc..

Any one described formula, the lyophilized formulations being made up of freeze drying process, it is characterised in that preparation method uses ice powder pressure Piece method, comprises the following steps：

A. after the mixing of supplementary material material whole will be formulated or partly mixed, wiring solution-forming, suspension or emulsion, formation liquid 1； Or water individualism, form liquid 1；

B. liquid 1 is freezed, in refrigerating process or freezing after, by physical method by liquid 1 freeze and be ground into ice pellets or Person's ice powder, is for component 2；

C. prepare after liquid 1, if surplus materials, it is sufficiently mixed with component 2 in technical process A, form component 3；Such as Fruit component 2 is the ice pellets or ice powder of pure water formation, then the ice pellets or ice powder formed binding agent and active material with the pure water is abundant Mixing, or the ice pellets that is formed with the pure water of solution or ice powder of binding agent and active material are sufficiently mixed, formation component 3；

D. component 2 or component 3, are fitted into mould 11 quantitative；Form quantitative component 4；

E. the component 4 after will be quantitative is freeze-dried, and forms freeze-drying prods 12.

Described preparation method, compression step is added between step D and E, and quantitative component 4 is compressed into certain shape and density, Component 5 is formed, afterwards component 5 is freeze-dried, freeze-drying prods 12 are formed.

Described lyophilized formulations product, product can have any shape.Selected from square, rectangle, spherical, heart-shaped, lobate, animal One kind in shape, cartoon character shape, drop shape, fruit shape etc..

A kind of described lyophilized formulations product, can apply to cosmetics, health products, food, human drugs, animal-use drug product, medical treatment Instrument field.

Embodiment

The present invention is further illustrated by the following examples, but the present invention is not restricted to this.

Embodiment 1：

By cherry extract：Sodium Polyacrylate graft starch=5:The raw material of 2 ratios, be configured to 2% mixed solution；Mixing liquid is freezed, Mixing liquid is freezed by physical method and ice powder is ground into；Ice fen-ting amount is fitted into heart, packed after freeze-drying, is formed Lyophilized formulations product.

Embodiment 2：

1g oligopeptides -6,3g angelica extracts, 2g Sodium Polyacrylates graft starch -12 are sufficiently mixed, 2.5% mixed solution is configured to； Mixing liquid is freezed, the mixed solution freezed is ground into ice powder using pulverizer after freezing；1g Propirams are sufficiently mixed with ice powder, Quantitatively it is fitted into spherical die；- 150 DEG C of freeze-dryings are carried out, are packed, lyophilized formulations product is formed.

Embodiment 3：

Pure water is freezed, using ice crusher physical crushing into ice pellets；With 1.5g Sodium Polyacrylates graft starch -7,3g Ganodenna Lucidum P.Es, 2g safflowers, 4g Notogineng Extracts, 0.5g modified corn starch, 0.5g xanthans are sufficiently mixed；Fill this blend into water-drop-shaped mould In it is quantitative；Mixture freeze-drying after will be quantitative, packs, forms lyophilized formulations product.

Embodiment 4：

Pure water is freezed, using ice crusher physical crushing into ice pellets；3g aloe vera extracts, 1g Scutellaria baicalensis extracts, 2h is saturating The sour sodium of bright matter, 1g Sodium Polyacrylates graft starch -25, be configured to 5% mixed solution；Pure water ice pellets and mixed solution are sufficiently mixed, It is quantitative to load oval mould；It is freeze-dried, is formed after lyophilized formulations and carry out double alumiseal packagings.

Embodiment 5：

Pure water is freezed, using ice crusher physical crushing into ice pellets；By 3g Gotu Kola P.Es, 1g chrysanthemum extracts, 2g white fungus Entity extraction thing, 1g Sodium Polyacrylates graft starch, 0.3g cornstarch, 0.5g modified potato starch, 0.2g konjac glucomannans, are prepared Into 5% mixed solution；Pure water ice pellets and mixed solution are sufficiently mixed, load the mould that capacity is 4ml；Volume of mixture is compressed To 2ml, it is shaped as being freeze-dried after ellipse, is formed after lyophilized formulations and carry out double alumiseal packagings.

The occupation mode of the present invention is not limited to form cited in embodiment, and embodiment is only presently preferred embodiments of the present invention, no Protection domain can be limited with this.All simple or equivalent changes and modification with described in scope of the presently claimed invention, come under this hair Bright protection domain.

Claims

1. a kind of formula of lyophilized formulations and preparation method thereof, it is characterised in that the lyophilized formulations are made up of the active component and binding agent of effective dose, Binding agent is to account for the graft starch class that tablet weight percentage is 0.1%-99.9%, and the ratio between weight and the volume of lyophilized formulations are 0.1mg/cm³ -5000mg/cm³。

2. a kind of formula of lyophilized formulations as claimed in claim 1, it is characterised in that graft starch class includes but is not limited to Sodium Polyacrylate grafting shallow lake Powder -7, Sodium Polyacrylate graft starch -12, Sodium Polyacrylate graft starch -25, polyacrylic acid grafted starch, polyvinyl alcohol/methyl acrylate grafting One or more in the models such as copolymer.

3. the formula of a kind of lyophilized formulations as described in claim 1-2, it is characterised in that additional adhesive can also be further added in formula, piece is accounted for Agent percentage by weight is 0.1%-99.9%.

4. additional adhesive as claimed in claim 3, it is characterised in that the binding agent be selected from native starch, modified starch series, cellulose ethers, Polyvinyl alcohol copolymer class, glue class, PVP, carbomer, PVA, hyalomitome acids, albumin, chitosan, dextran, agar, poly- amino Acid, glycan or combinations thereof.

5. a kind of formula of lyophilized formulations as described in claim 1-4, it is characterised in that the native starch class include tapioca, farina, One or more combinations in cornstarch, rice starch, wheaten starch, oat starch, elegant jessamine starch；The modified starch includes modified corn Starch, modified potato starch, modified tapioca starch, hydrogenated starch, hydrogenated starch hydrolysate, Sodium Polyacrylate graft starch, polyacrylic acid connect Branch starch, hydroxypropul starch, hydroxypropyl starch phosphate, amylose, amylopectin, CMS, sodium carboxymethyl starch, cornstarch One or more combinations in/acrylamide/sodium Acrylate copolymer；It is carboxymethyl cellulose that the cellulose ethers, which includes cellulose ethers binding agent, One or more combinations in carboxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl methyl cellulose；The polyvinyl alcohol copolymer class includes Polyvinyl alcohol crosslinked polymer, polyvinyl alcohol/methyl acrylate graft copolymer, one kind in polyving alcohol/polylactic acid co-glycolic acid or many Plant combination；The glue class include pectin, carragheen, xanthan gum, collagen, hydrolytic collagen, gelatin, gelatin hydrolysate, Arabic gum, konjac glucomannan, Carrageenan, locust bean gum, natural gum, locust bean gum etc.；Described polyaminoacid is selected from polyglutamic acid, polyalanine, polylysine etc.；It is affiliated poly- Sugar is selected from fucoidin, synanthrin etc..

6. a kind of formula of lyophilized formulations as described in claim 1-5, it is characterised in that the active component be selected from chemicals composition, traditional Chinese medicine ingredients, One or more kinds of combinations in natural extract, bioactive ingredients, skin nursing beneficiating ingredient.

7. the formula of a kind of lyophilized formulations as described in claim 1-6, it is characterised in that wherein can also further contain other auxiliary materials, described other Auxiliary material includes the one or more in skeleton agent, antioxidant, flavouring and essence, skin penetration enhancer, PH conditioning agents, disintegrant.

8. the formula of a kind of lyophilized formulations as described in claim 1-7, it is characterised in that the skeleton agent, which is included, is not limited to sugared (such as maltose, sea Algae sugar etc.), sugar alcohol (such as mannitol, sorbierite), the amino acid (such as glycine, alanine, glutamic acid) and inorganic salts of 2-12 carbon atoms Materials such as (such as sodium phosphates, alumina silicate)；The antioxidant is selected from vitamin C, anthocyanidin, resveratrol, the polyatomic phenol of plant origin One or several kinds of mixtures in compound；The flavouring and essence are selected from mint flavored, chocolate flavoured, vanilla flavored, caf, tea flavour, jade The mixture of the one or more of fragrance of the essence such as rice taste, lemon, milk flavor or more；The skin penetration enhancer be selected from lecithin, tween, Any of sapn or several mixtures；The PH conditioning agents are selected from any one of citric acid, tartaric acid, sodium acid carbonate, sodium carbonate Or several mixtures；The disintegrant includes but is not limited to starch (wheaten starch, cornstarch, green starch, sweet potato starch, potato Starch, tapioca etc.), modified starch series (α, β, cyclooctaamylose, maltodextrin, amylose, crosslinked starch and its esters, ester Change starch, etherification starch, graft starch, oxidative crosslinked starch, esterified and cross-linked starch and its esters, phosphate ester starch, acidified starch, cation Starch, CMS and its esters etc.), cellulose family (microcrystalline cellulose etc.), cellulose ethers (methylcellulose, carboxymethyl cellulose, Sodium carboxymethylcellulose, calcium carboxymethylcellulose, hydroxypropyl methyl cellulose, carboxyethylmethylcellulose, low substitution carboxy-propyl cellulose etc.), Insoluble polymer (PVPP, grafting starch copolymer etc.), talcum powder, gelatin, silica, superfine silica gel powder etc..

9. any one formula, the lyophilized formulations being made up of freeze drying process as described in claim 1-8, it is characterised in that preparation method is used Ice powder pressed disc method, comprises the following steps：

A. after the mixing of supplementary material whole will be formulated or partly mixed, wiring solution-forming, suspension or emulsion, formation liquid 1；Or water is independent In the presence of formation liquid 1；

B. liquid 1 is freezed, in refrigerating process or after freezing, liquid 1 is freezed by physical method and ice pellets is ground into or ice powder, It is for component 2；

C. prepare after liquid 1, if surplus materials, it is sufficiently mixed with component 2 in technical process A, form component 3；Such as fruit component 2 be the ice pellets or ice powder of pure water formation, then the ice pellets or ice powder formed binding agent and active material with the pure water is sufficiently mixed, or is bonded The ice pellets or ice powder that the solution of agent and active material is formed with the pure water are sufficiently mixed, and form component 3；

10. preparation method as claimed in claim 9, it is characterised in that：Compression step is added between step D and E, quantitative component 4 is compressed Into certain shape and density, component 5 is formed, afterwards component 5 is freeze-dried, form freeze-drying prods 12.

11. the lyophilized formulations product as described in claim 1-10, it is characterised in that product can have any shape.Selected from square, rectangle, ball One kind in shape, heart, lobate, animals shaped, cartoon character shape, drop shape, fruit shape etc..

12. a kind of lyophilized formulations product as described in claim 1-11, it is characterised in that can apply to cosmetics, health products, food, people's medication Product, animal-use drug product, medical instruments field.