CN103893133A

CN103893133A - Formula and preparing method of freeze-dried excipient preparation

Info

Publication number: CN103893133A
Application number: CN201210572673.5A
Authority: CN
Inventors: 李和伟
Original assignee: Individual
Current assignee: Changzhou Youdun Industrial Investment Co ltd
Priority date: 2012-12-26
Filing date: 2012-12-26
Publication date: 2014-07-02
Anticipated expiration: 2032-12-26
Also published as: CN103893133B

Abstract

The invention relates to a formula and a preparing method of a freeze-dried excipient preparation. The formula is new and simplified. By controlling the ratio of an adhesive and the ratio of active components in the freeze-dried excipient preparation, the freeze-dried excipient preparation can be free of a skeleton supporting agent system and only contains the adhesive and the active components. The skeleton supporting agent comprises, but not limited to, sugar, sugar alcohol, amino acids having 2-12 carbon atoms, inorganic salts, and the like. Based on this, an antioxidant, a corrigent, essence, a skin penetration enhancer, a pH modifier, and other auxiliary materials can be added into the preparation. By avoiding the use of the skeleton supporting agent, technical effects of reducing the moisture adsorption risk, simplifying the preparing process, reducing the cost and increasing the drug loading capacity per unit are achieved.

Description

Formula of a kind of lyophilizing excipient preparation and preparation method thereof

Technical field

The present invention relates to a kind of formula and preparation method of lyophilizing excipient preparation, particularly a kind of by the proportioning of binding agent and active component in control lyophilizing excipient preparation, can make not contain skeleton proppant system in lyophilizing excipient pharmaceutical formulation material, only contain formula and the preparation method of the lyophilizing excipient preparation of binding agent and active component.

Background technology

Lyophilizing excipient technology refers to and in the active component of flowable liquid, semisolid or solid, adds skeleton proppant and binding agent, or in described flowable liquid, semisolid or solid, itself contain binding agent and skeleton proppant, then be filled in mould, be able to the technology of molding by freeze drying process, the preparation of preparing by lyophilizing excipient technology is called lyophilizing excipient preparation.Because such preparation adopts freeze drying process; can protect thermally sensitive composition not to be destroyed; produce a large amount of micropores and duct by water sublimed simultaneously; can there is very fast disintegrate and dissolution velocity; therefore be subject to extensive use, can be applied to multiple fields such as oral cavity disintegration tablet, fast-release tablet, chewable tablet, special cosmetics.

Traditional lyophilized excipient substrate comprises skeleton proppant and binding agent, and skeleton proppant is selected from aminoacid and the inorganic salt (as sodium phosphate, aluminium silicate etc.) etc. (referring to Chinese patent CN200580013010.8) of sugar, a sugar alcohol and 2-12 carbon atom mostly.

Sugar, sugar alcohol, inorganic salt (as sodium phosphate, aluminium silicate etc.) are during as skeleton proppant, due to the hygroscopicity of sugar, sugar alcohol and inorganic salt (as sodium phosphate, aluminium silicate etc.), be very easy in process of production absorb airborne moisture and cause the framing structure composition of preparation to subside or cave in completely, or stick to your hands to wait and bring the bad impact of experiencing using due to what moisture absorption rapidly brought when user is unpacked, also there is many defects such as the disintegrating procedue of making prolongation simultaneously; Though and aminoacid has reduced hygroscopic this problem during as skeleton agent, can not address this problem, and the Cost Problems of production technology also there is no good solution at all.

Therefore, in this area, there is the demand that does not use skeleton proppant in lyophilized excipient.But due to technical limitations and traditional view, and only use active component and binding agent can make lyophilized excipient there are no bibliographical information.Patent: 200580013010 and patent 200410038822 have in this respect clear and definite explanation.

Summary of the invention

Technical problem to be solved by this invention is to provide a kind of new simplification formula, in formula, only contain binding agent and active component, it is not added into the skeleton proppant in process system, and described skeleton proppant is including but not limited to the material such as aminoacid (as glycine, alanine, glutamic acid etc.) and inorganic salt (as sodium phosphate, aluminium silicate etc.) of sugar (as maltose, trehalose etc.), sugar alcohol (as mannitol, sorbitol), 2-12 carbon atom.

Inventor dedicates itself to innovation, a large amount of deep research and experiment work are carried out, the proportioning of binding agent and active component in discovery control lyophilizing excipient preparation, can make not contain skeleton proppant system in lyophilizing excipient pharmaceutical formulation material, and only form the lyophilizing excipient preparation that can obtain conforming to quality requirements by binding agent and active component two parts.On this basis, can add other adjuvants such as antioxidant, correctives and essence, Percutaneous absorption enhancer, PH regulator.By avoiding using skeleton proppant, can reach and reduce moisture absorption risk, simplify preparation technology, reduce costs, improve the technique effect of unit drug loading.

Below, the present invention will be described in detail.

Lyophilizing excipient preparation provided by the present invention is only made up of binding agent and active component two parts, and wherein the weight proportion of binding agent and active component is binding agent: active component=1: 100 to 100: 1.Experiment shows, exceeds this ratio range and cannot prepare the lyophilizing excipient preparation conforming to quality requirements.The weight proportion of binding agent and active component can be further preferably 1: 90 to 90: 1, and 1: 80 to 80: 1,1: 70 to 70: 1,1: 60 to 60: 1,1: 50 to 50: 1,1: 40 to 40: 1,1: 30 to 30: 1, more preferably 1: 20 to 20: 1,1: 10 to 10: 1,1: 9 to 9: 1,1: 8 to 8: 1,1: 7 to 7: 1, most preferably 1: 6 to 6: 1,1: 5 to 5: 1.Lyophilizing excipient preparation provided by the present invention also can further comprise other adjuvant, such as antioxidant, correctives and essence, Percutaneous absorption enhancer, PH regulator etc., the content range of these other adjuvants can be the 0.1-5% that accounts for the total content of the lyophilizing excipient preparation preparing, preferably 0.1-3%..

Active component can be water-soluble can be also water-fast material, described active component can be selected from one or more the combination in chemicals composition, Chinese medicine ingredients, natural extract, bioactive ingredients, skin nursing beneficiating ingredient.

There is no particular limitation for active component involved in the present invention, can be selected from but be not limited to the compositions of following one or more compositions.Chemicals (active constituents of medicine):

Antipyretic-antalgic anti-inflammatory agent, such as aspirin, diflunisal, salsalate, acetaminophen, indomethacin, ibuprofen, naproxen, ketoprofen, pirprofen, suprofen, flurbiprofen, piroxicam, meloxicam, nimesulide, benzbromarone etc.;

Central stimulants, such as pemoline, adrafinil, piracetam etc.;

Treatment migraine agent, for example Sumatriptan Succinate;

Analgesic, such as rotundine, buprenorphine, pentazocine, naloxone etc.;

Anti-parkinson and treatment senile dementia medicine, for example levodopa, compound recipe carbidopa, compound recipe benserazide, amantadine hydrochloride, piribedil, general sieve phenol amine, donepezil, huperzine are first-class;

Psychotolytic, such as chlorpromazine, promethazine, Pethidine, thioridazine, chlorprothixene, clozapine, sulpiride, Tai Bili, penfluridol, risperidone etc.;

Epilepsy disease and anticonvulsant, such as phenytoin Sodium, carbamazepine, primidone, gabapentin, lamotrigine, sodium valproate, clonazepam etc.Sedative hypnotic, such as diazepam, nitrazepam, oxazepam, lorazepam, phenobarbital etc.;

Cholinesterase inhibitor, such as scopolamine etc.;

Anti-arrhythmic, for example the third pyridine, tocainide, mexiletine, aetmozine, phenytoin Sodium, Propafenone, amiodarone etc.;

Antianginal and antiatherosclerotic, such as Propranolol, nifedipine, gemfibrozil, bezafibrate, lovastatin, simvastatin, pravastatin etc.;

Antihypertensive, such as Enalapril, captopril, hydrochlorothiazide, amlodipine etc.;

Adrenoreceptor blocker, such as acebutolol, alprenolol etc.;

Corticosteroid medicine, such as betamethasone, cortisone acetate etc.;

Antidiabetic drug, such as repaglinide etc.;

Antithyroid drug, such as propylthiouracil, carbimazole, thiamazole etc.;

Antihistaminic, such as cetirizine hydrochloride, loratadine etc.;

Autologous active substance, such as dinoprostone, Alprostadil, betahistine etc.;

Digestive system medication, such as scopolamine butylbromide, Granisetron Hydrochloride etc.;

Blood system medicine, such as EPO, cobamamide etc.;

Urinary system medicine, such as azosemide, furosemide etc.;

Reproductive system medicine, such as estrogen, nandrolone phenylpropionate etc.;

Antiparasitic, such as albendazole, cambendazole etc.;

Antineoplastic agent, such as aminoglutethimide, amsacrine etc.;

Antimicrobial drug, such as ampicillin, sulbenicillin disodium etc.;

Tri-Biocin, such as amoxicillin, cefalexin, cefprozil, CEFUROXIME AXETIL, Roxithromycin, erythromycin ethylsuccinate, josamycin etc.

Chinese medicine ingredients:

Effective Component of Chinese Medicine monomer, as: breviscapine, arteannuin, huperzine A, tetrahydropalmatine etc.;

Single medicinal material material extract and compound Chinese medicine extract, as: tanshinone extract, Radix Salviae Miltiorrhizae total phenolic acids extract, composite salvia dropping extract of bolus, cow-bezoar bolus for clearing away heat of the upper part of the body compound extract, stem and leaf of Radix Ginseng total saponins, Rhizoma Menispermi extract, Radix Ginseng total saponins, American ginseng total saponins, breviscapine, Herba Sarcandrae extractum, Radix Notoginseng total arasaponins, Herba Artemisiae Scopariae extract, extractum rhei, andrographolide, Folium Crataegi extract, Herba Centellae total glycosides, Folium Ginkgo extract etc.Natural plant extracts: as Aloe extract, Rhizoma Dioscoreae extract, Pericarpium Citri tangerinae extract, Fructus Momordicae charantiae extract, Echinacea extract, Feverfew P.E, mangosteen extract, Folium Pini and Cortex Pini Massonianae extract, Brazilian blackberry extract, Fructus Mori extract, fruit of Ramulus Sambuci Williamsii extract, cranberry extract, astaxanthin, lycopene, green tea extract, Semen Vitis viniferae and Pericarpium Vitis viniferae extract, glabridin, peoniflorin, licoflavone, Cortex Moutan extract etc.Bioactive ingredients: EGF, bFGF, aFGF, KGF, IGF, NGF, TGF, HGH 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, Margarita and hydrolysate, Lac Bovis seu Bubali and extract thereof, pollen and extract thereof, Lac regis apis, propolis etc.

Described binding agent is edible or pharmaceutically useful a kind of water-soluble high-molecular material, can be polysaccharide, polypeptide, protein, also may be artificial polymerization macromolecule, or through natural macromolecular material or its mixture of remodeling.Conventional binding agent includes but not limited to, glue class (collagen, gelatin, gelatin hydrolysate, arabic gum, xanthan gum, carrageenan, pectin, Konjac glucomannan, carrageenin, locust bean gum, natural gum, locust bean gum etc.), cellulose ethers (carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose etc.), modified starch series (pulullan, hydroxypropyl starch etc., referring to R.P.Scherer US4305502A), PVP, PVA, hyalomitome acids, albumin, chitosan, dextran, agar, , polyamino acid, polysaccharide and their combination etc. thereof, , it is characterized in that described glue class binding agent is gelatin, gelatin hydrolysate, arabic gum, xanthan gum, carrageenan, pectin, Konjac glucomannan, carrageenin, locust bean gum, natural gum, locust bean gum, described cellulose ethers binding agent is carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose etc., described modified starch series binding agent is selected from pulullan, hydroxypropyl starch, hydroxypropyl methyl starch, pregelatinized Starch, amylose, carboxymethyl starch, hetastarch, hydroxypropyl starch etc., described polyamino acid is selected from polyglutamic acid, polyalanine, polylysine etc., affiliated polysaccharide is selected from fucoidin, inulin etc.。

Described antioxidant includes but not limited to one or several the mixture in the polyhydric phenols of vitamin C and derivant thereof, anthocyanidin, resveratrol, plant origin;

Described correctives and essence include but not limited to the mixture of the essence such as mint flavored, chocolate flavoured, fruity, vanilla flavored, caf, tea flavour, Semen Maydis taste, lemon, milk taste or above one or more fragrance;

Described Percutaneous absorption enhancer includes but not limited to any or several the mixture in lecithin, saponin, Laurel alkyd sodium, azone, tween, span;

Described PH regulator includes but not limited to any in citric acid, tartaric acid, carbonate, sodium carbonate, phosphate or several mixture.

What the present invention related on the other hand is the method for the above-mentioned lyophilizing excipient preparation of preparation, and the method comprises:

I. do not contain the preparation method of the lyophilizing excipient preparation of other adjuvant:

(a) solution or the suspension injection molding that active component, water and binding agent are formed; Or by solid active agent and/or binding agent injection molding, then add water to be made into suspension;

(b) solution (a) being obtained or suspension carry out degassed in quantitative mould;

(c) (b) obtained degassed after suspension or without degassed direct by freezing at low temperatures to (a);

(d) preparation (c) being obtained lyophilization in quantitative mould, obtains lyophilizing excipient preparation.

II. contain the preparation method of the lyophilizing excipient preparation of other adjuvant:

(a) active component, water, binding agent and other adjuvant are formed to suspension injection molding; Or by solid active agent and/or binding agent and/or other adjuvant injection molding, then add water to be made into suspension;

(c) (b) obtained degassed after solution or suspension or without degassed direct by freezing at low temperatures to (a);

(d) preparation (c) being obtained lyophilization in quantitative mould, except desolventizing, obtain lyophilizing excipient preparation.

In above two kinds of methods, the weight proportion of active component and binding agent and water is 100: 1 to 1: 100, can be further 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 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.

Wherein liquid injection molding can adopt the liquid-transfering devices such as accurate quantification pipet, liquid-transfering gun, electronic liquor-transferring rifle, also can adopt plunger displacement pump, gear pump, peristaltic pump etc., the solution configuring, suspension or suspension are injected to quantitative mould, solid injection molding can adopt accurate solid measurer, vibrations capillary tube flow of powder controller;

Wherein degas method can adopt centrifugal degassing method, vacuum outgas method and ultrasonic degas method etc.;

The wherein freezing mode that can adopt liquid nitrogen or liquid, drikold spray refrigeration or sleeve pipe cooling back installation, turbine expander refrigeration mode or cascade refrigeration mode, at-20 DEG C--at 196 DEG C of temperature, rapidly by freezing to solution, suspension or the suspension solid that becomes;

Wherein lyophilizing adopts the vacuum of 0.01-20 millibar, temperature lyophilizing between-70 DEG C to 50 DEG C scopes;

Detailed description of the invention

Further illustrate by the following examples the present invention, but the present invention is not restricted to this.

In following examples and comparative example, the evaluation methodology of lyophilizing excipient preparation is as follows:

1) disintegration time:

Preparation is dropped in the test tube that 2 milliliter of 37 degree water Celsius is housed, the time of 20 mesh sieves is also spent in the complete disintegrate of observation preparation;

2) friability:

By preparation from one meter of high position in freely falling body mode, drop on rustless steel platform, cast 100, measure the powder body that always comes off, weight be less than total formulation weight amount 3% for qualified.

3) preparation outward appearance:

The lyophilizing excipient preparation of preparation is upwards firmly taken out to preparation from aluminum nest bottom with finger, perusal exterior appearance, smoothness, whether cave in, crackle etc.;

Embodiment 1:

Vitamin C: collagen=100: 1, vitamin C 100mg, accurately fill enters 0.3m1 mould, collagen 1mg, after adding in 0.2ml water and dissolving, pours into into containing in the ascorbic mould of 100mg, stirring makes aqueous dispersion in powder body, and quick-freezing is to-100 degrees Celsius, and lyophilizing becomes solid beverage.

Embodiment 2:

Margarita powder: hyaluronic acid=1: 100, hyaluronic acid 100mg, after wherein 90mg hyaluronic acid mixes with 1mg Margarita fine powder, accurately fill enters in 0.5ml mould, 10mg hyaluronic acid, after 0.3ml water dissolution, pours in the mould that contains 90mg hyaluronic acid and 1mg Margarita powder, stirs and makes aqueous dispersion in powder body, quick-freezing is to-196 degrees Celsius, and lyophilizing becomes skin protection solid elite.

Embodiment 3:

Pericarpium Citri tangerinae extract: Pullulan=5: 1, Pericarpium Citri tangerinae extract 60mg and the Pullulan 12mg 0.4ml that adds water is mixed with solution, and fill enters 0.4 milliliter of mould, and lyophilizing becomes solid beverage.

Embodiment 4:

Radix Notoginseng total arasaponins: PVP=10: 1, Radix Notoginseng total arasaponins 500mg, PVP50mg, wherein the PVP40mg 0.5ml that adds water is mixed with solution, Radix Notoginseng total arasaponins 100mg and PVP10mg enter 0.5 milliliter of mould with powder type perfusion, with the PVP40mg Solution Dispersion that 0.5ml is mixed with that adds water, in mould, lyophilizing becomes buccal tablet afterwards.

Embodiment 5:

Ginkgo total flavones: PVA=1: 1, Ginkgo total flavones 20mg, PVA20mg, the 0.3ml that adds water is mixed with solution, and perfusion enters 0.3 milliliter of mould, and in mould, lyophilizing becomes buccal tablet.

Embodiment 6:

Resveratrol: polylysine=5: 1, resveratrol 100mg, polylysine 20mg, is mixed with suspension, and perfusion enters 0.4 milliliter of mould, and in mould, lyophilizing becomes buccal tablet.

Embodiment 7:

Loratadine: dextran=1: 10, loratadine 10mg, Dextran 100 mg wherein loratadine 10mg and Dextran 5 0mg as powder, disperse to enter 0.2ml mould, 50mg dextran and 0.2ml water are mixed with solution, perfusion enters 0.2ml mould, mixes with powder, and after stirring, in mould, lyophilizing becomes buccal tablet.

Embodiment 8:

Acetaminophen: PVA=25: 1, acetaminophen 500mg and PVA20mg, perfusion enters 1ml mould, mixture is divided into two parts, acetaminophen 500mg powder filling enters 0.6 milliliter of mould, and PVA20mg is with 0.4ml water dissolution, and perfusion enters in 500mg powder, lyophilizing after stirring, becomes acetaminophen medicine.

Embodiment 9:

Cranberry extract: hydroxypropyl emthylcellulose=25: 1, cranberry extract 500mg perfusion enters 0.8ml mould, hydroxypropyl emthylcellulose 20mg, the 1ml that adds water dissolves, and perfusion enters in 500mg powder, and lyophilizing after stirring, becomes cranberry solid beverage.

Embodiment 10:

Selegiline: polyglutamic acid=1: 10, selegiline 1mg, polyglutamic acid 10mg, enters 0.1ml mould with perfusion after 0.1ml aqueous dispersion, and freezing rear lyophilizing, becomes selegiline medicine.

Embodiment 11:

Vitamin B6: hydroxypropyl starch=2: 1, vitamin B6 10mg, hydroxypropyl starch 5mg, enters 0.1ml mould with perfusion after 0.1ml aqueous dispersion, and freezing rear lyophilizing, becomes vitamin B6 medicine.

Embodiment 12:

Aspirin: xanthan gum+Pullulan=10: 1, aspirin 500mg, xanthan gum 10mg, Pullulan 40mg, wherein aspirin 500mg perfusion enters 0.5ml mould, xanthan gum 10mg, after Pullulan 40mg disperses with 0.5ml water dissolution, perfusion enters in 500mg aspirin powder, and lyophilizing after stirring, becomes aspirin medicine.

Table 1: test result

Embodiment 1

Embodiment 2

Embodiment 3

Embodiment 4

Embodiment 5

Embodiment 6

Disintegration time

5S

3S

15S

Outward appearance

Smooth

Friability

＜3％

Embodiment 7

Embodiment 8

Embodiment 9

Embodiment 10

Embodiment 11

Embodiment 12

Disintegration time

5S

15S

5S

3S

15S

Outward appearance

Smooth

Friability

＜3％

It should be noted, can revise arbitrarily for various details of the present invention, but certainly, within these amendments all will fall into protection scope of the present invention.

Claims

1. formula of a lyophilizing excipient preparation and preparation method thereof, is characterized in that being only made up of active component and binding agent and containing skeleton proppant, wherein the weight proportion of binding agent and active component is: binding agent: active component=1: 100 to 100: 1.

2. the formula of lyophilizing excipient preparation claimed in claim 1, is characterized in that described active component is selected from one or more the combination in chemicals composition, Chinese medicine ingredients, natural extract, bioactive ingredients, skin nursing beneficiating ingredient.

3. the formula of lyophilizing excipient preparation claimed in claim 1, is characterized in that described binding agent is glue class, cellulose ethers, modified starch series, PVP, carbomer, PVA, hyalomitome acids, albumin, chitosan, dextran, agar, polyamino acid, polysaccharide or their combination.

4. the formula of lyophilizing excipient preparation claimed in claim 3, is characterized in that described glue class binding agent is collagen, gelatin, gelatin hydrolysate, arabic gum, xanthan gum, carrageenan, pectin, Konjac glucomannan, carrageenin, locust bean gum, natural gum, locust bean gum; Described cellulose ethers binding agent is carboxymethyl cellulose, carboxyethyl cellulose, hydroxyethylmethyl-cellulose, hydroxypropyl emthylcellulose; Described modified starch series binding agent is selected from pulullan, hydroxypropyl starch, hydroxypropyl methyl starch, pregelatinized Starch, amylose, carboxymethyl starch, hetastarch, hydroxypropyl starch etc.; Described polyamino acid is selected from polyglutamic acid, polyalanine, polylysine etc.; Affiliated polysaccharide is selected from fucoidin, inulin etc.

5. the formula of lyophilizing excipient preparation as claimed in claim 1, is characterized in that wherein also containing other adjuvant, and described other adjuvant is one or more in antioxidant, correctives and essence, Percutaneous absorption enhancer, PH regulator.

6. the formula of lyophilizing excipient preparation as claimed in claim 5, is characterized in that described antioxidant is selected from one or several the mixture in the polyhydric phenols of vitamin C, anthocyanidin, resveratrol, plant origin; Described correctives and essence are selected from the mixture of the essence such as mint flavored, chocolate flavoured, vanilla flavored, caf, tea flavour, Semen Maydis taste, lemon, milk taste or above one or more fragrance; Described Percutaneous absorption enhancer is selected from any or several the mixture in lecithin, tween, span; Described PH regulator is selected from any in citric acid, tartaric acid, sodium bicarbonate, sodium carbonate or several mixture.

7. the preparation method of lyophilizing excipient preparation as claimed in claim 1, is characterized in that the method is:

(a) solution or the suspension injection molding that active component, water and binding agent are formed; Or by solid active agent and/or binding agent injection molding, then add water to be made into suspension or suspension;

(b) solution, suspension or the suspension (a) being obtained carries out degassed in quantitative mould;

(c) (a) directly or (b) obtained degassed after solution, suspension or suspension freezing at low temperatures;

8. the preparation method of lyophilizing excipient preparation as claimed in claim 5, is characterized in that the method is:

(a) active component, water, binding agent and other adjuvant are formed to solution or suspension injection molding; Or by solid active agent and/or binding agent and/or other adjuvant injection molding, then add water to be made into suspension or suspension;