CN101658494B - Huperzine A solid lipid nano particle and preparation method thereof - Google Patents
Huperzine A solid lipid nano particle and preparation method thereof Download PDFInfo
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Abstract
The invention relates to the field of pharmaceutical preparations, which discloses a huperzine A solid lipid nano particle and a preparation method thereof. The huperzine A solid lipid nano particle is prepared from the following components in weight percent: 0.05-1% of huperzine A, 3-10% of lipid material, 2-10% of emulsifying agent and the balance water. The preparation method adopts a high-pressure even emulsification method to coat the huperzine A into a solid lipid nano particle so as to prepare the huperzine A solid lipid nano particle. The particle diameter of the huperzine A solid lipid nano particle prepared by the invention is 10-100nm, the medicine envelopment rate and the medicine-carrying quantity are high, and the stability is good; simultaneously, the use of an addition agent and an organic solvent which are harmful to a human body is avoided; and the bioavailability is enhanced, the brain targeting property is increased, and the dose and the toxic or side effect are small.
Description
Technical field
The present invention relates to field of pharmaceutical preparations, be specifically related to solid lipid nanoparticle of a kind of Chinese medicine huperzine A and preparation method thereof.
Background technology
Huperzine A (Huperzine A, C
15H
18N
2O), be that China medical research person separates the new construction alkaloid that obtains from Huperziaceae phytobezoar China fir herb, pharmacological experiments shows that huperzine A is a kind of efficient, reversible cholinesterase inhibitor, has very strong inhibitory action to true property choline enzyme (AChE).Drugs approved by FDA listing in 1993, China's approval in 1996 is two kind new medicines, is used for treatment and prevention alzheimer disease and improves the juvenile intelligence memory.Clinical trial confirms that it can prevent the decomposition of acetylcholine in the cerebral tissue, improves mental activity efficient, directly improves memory.Characteristics such as have the selectivity height, toxicity is low and EDD is long.Be to treat the comparatively ideal prospect of senile dementia up to now in the world.
The formulation products that relates to huperzine A at present has tablet, capsule and injection.But the huperzine A biological half-life is shorter; The blood drug level peak valley phenomenon that can cause when huperzine A oral or drug administration by injection produces tinnitus, dizziness, fasciculation, perspiration stomachache, vomiting, stool increase, blurred vision, alteration in heart rate, sialorrhea, untoward reaction such as drowsy thus.Influenced the therapeutic effect of this medicine.
At present, the patent of relevant huperzine A has: huperzine A sustained-release micro-spheres, huperzine A sustained-release matrix tablets, huperzine dropping pills, huperzine A implant etc.These preparations are increasing drug absorption, improve the therapeutic effect aspect and compare with ordinary preparation, have remarkable advantage.But further improve the bioavailability of huperzine A, reduce untoward reaction, the targeting aspect that especially improves specific part remains the problem that the research of huperzine A memory needs solution.
(lipid Solid nanoparticles SLN) is the new colloidal drug-supplying system of a kind of alternative Emulsion that grows up the nineties in 20th century, liposome, polymer/nanometer grain to solid lipid nanoparticle.It is a carrier with the good solid-state natural or synthetic lipoid of physiological compatibility, pharmaceutical pack is wrapped in the lipoid nuclear processes solid-state micelle.Because of its carrier material that uses in the preparation at room temperature is a solid; Make it both have that the physical stability of polymer nanocomposite ball and nanocapsule is high, medicine is revealed less, have slow-releasing and targeting property, characteristics such as can sterilize, have to have the advantage that liposome toxicity is low, be easy to large-scale production concurrently.Laboratory adopts methods such as microemulsion method, solvent evaporated method, the sedimentation method and injection to prepare SLN more at present.But above-mentioned system method all will be used organic solvent, is impossible and will eliminate deleterious organic solvent fully, thereby has limited the application of SLN pharmaceutical carrier.At present, existing do not have the high pressure of employing not see the report that huperzine A solid lipid nano particle is arranged newborn sparing in the technology preparation as yet.
Summary of the invention
The objective of the invention is to remedy the deficiency of prior art, a kind of have higher bioavailability, strong huperzine A solid lipid nano particle brain targeting, that dosage is little, toxic and side effects is little are provided.
Another object of the present invention provides the method for preparing of above-mentioned huperzine A solid lipid nano particle.
The present invention realizes above-mentioned purpose through following technical scheme:
A kind of huperzine A solid lipid nano particle, process by following components in weight percentage:
Huperzine A 0.05～1%,
Matrix material 3～10%,
Emulsifying agent 2～10%,
Surplus is a water.
Any or two or more mixture in the preferred glyceryl monostearate of said matrix material, glycerol distearate, glyceryl tristearate, Compritol 888 ATO, tripalmitin, LAURIN DYNASAN 112, myristin, decanoyl/octanoyl glycerides, stearic acid, Palmic acid, capric acid, the oleic acid.
Any or two or more mixture in the preferred soybean phospholipid of said emulsifying agent, egg yolk lecithin, poloxamer 188, poloxamer 407, tween 80, tween 20, Arlacel-20, Myrij, the Brij.
The method for preparing of huperzine A solid lipid nano particle of the present invention may further comprise the steps:
Step 1:, process water with emulsifying agent and an amount of distilled water or the dissolving extremely fully of deionized water ultra-sonic dispersion; With huperzine A, matrix material mixed melting, process oil phase;
Step 2: water and oil phase are heated to 65～85 ℃ respectively, treat oil phase clarification after, under stirring condition, water is added drop-wise in the oil phase, keep constant temperature to stir 10～30 minutes, stop heating then and continue to be stirred to room temperature, form colostrum;
Step 3: will make colostrum after breast is even, and make huperzine A solid lipid nano particle.
The preferred heating in water bath of mode of heating described in the step 2; The preferred constant temperature magnetic agitation of said stirring, mixing speed is 800～1500rpm; Said colostrum is a milky emulsion.
Even 2～7 times of the even preferred high pressure homogenizer 500～1200bar breast of breast described in the step 3.
The said huperzine A solid lipid nano particle that makes is the huperzine A solid lipid nano particle aqueous dispersion that is dispersed in the water, preserves 3～5 ℃ of sealings.
After said huperzine A solid lipid nano particle aqueous dispersion carries out filtering with microporous membrane, add the freeze drying protectant lyophilization again and promptly get lyophilized formulations.Freeze drying protectant can be chosen wantonly, like sucrose, lactose etc.
Compared with prior art, the present invention has following beneficial effect:
The present invention adopts the solid lipid nanoparticle technology to seal huperzine A; The huperzine A solid lipid nano particle that makes has strengthened stability of drug; Improved bioavailability of medicament; Improve the therapeutic index of medicine, reduced dosage and toxic and side effects, also increased brain targeting simultaneously.
Compare with existing liposome; The present invention adopts the even legal system of high pressure breast to be equipped with huperzine A solid lipid nano particle; Prepare solid lipid nanoparticle with other drug and compare, the present invention need not with an organic solvent, can prepare envelop rate height, good stability and the solid lipid nanoparticle carrier system of certain slow-releasing and controlled-releasing action is arranged; The nanoparticle particle diameter is between 10～100nm, and envelop rate is greater than 50%.
The method for preparing of huperzine A solid lipid nano particle provided by the invention---the even method of high pressure breast is to utilize pushed at high pressure liquid through a narrow pipeline, and liquid obtains very big speed through very short distance, splits into nano level small-particle.This law can avoid the use of harmful additives and organic solvent; Be particularly useful for heat-labile medicine; Also relatively be fit to industrialized great production; The present invention simultaneously also combines fusion method and lyophilization to make huperzine A solid lipid nano particle and lyophilized formulations, has filled up the blank in this technical field.
Description of drawings
Fig. 1 is huperzine A solid lipid nano particle particle size distribution figure.
Fig. 2 is huperzine A solid lipid nano particle Zeta potential figure.
The specific embodiment
Below through specific embodiment the present invention is described further, evaluation of indexes test methods such as the form of the huperzine A solid lipid nano particle of being addressed, particle diameter, zeta potential, envelop rate, drug loading are following:
1, morphologic observation
Get in right amount and be added on the copper mesh that is coated with carbon film through water-reducible huperzine A solid lipid nano particle aqueous dispersion drop, the Salkowski's solution negative staining with 2% after drying naturally, is observed its form under transmission electron microscope.
2, the mensuration of particle diameter and zeta potential
Get the huperzine A solid lipid nano particle aqueous dispersion and dilute in right amount, measure the particle diameter and the zeta potential of nanoparticle with laser particle analyzer with distilled water.
3, the mensuration of envelop rate
Precision pipettes 2mL huperzine A solid lipid nano particle aqueous dispersion, adds to ultrafiltration in the ultra-filtration centrifuge tube, discards filtrating just, collects subsequent filtrate.Precision pipettes the 1mL subsequent filtrate and places the 10mL volumetric flask, adds 80% methanol aqueous solution dilution standardize solution, through 0.22 μ m filtering with microporous membrane, injects chromatograph of liquid then and measures, and calculates the amount (W of free drug
f).Simultaneously precision pipettes 1mL huperzine A solid lipid nano particle aqueous dispersion and adds 80% methanol aqueous solution breakdown of emulsion and be settled to 10mL, with 0.22 μ m filtering with microporous membrane, injects chromatograph of liquid and measures after the centrifugal treating, calculating SLN Chinese medicine total content (W
t).By following formula computational envelope rate.
4, the mensuration of drug loading
After the packing of huperzine A solid lipid nano particle aqueous dispersion, lyophilization gets freeze dried powder.Calculate drug loading by following formula.
Preparation huperzine A solid lipid nano particle (percentage ratio in the prescription is this component shared percentage by weight in whole prescription, and following each embodiment is identical):
Prescription: huperzine A 30mg
Glyceryl monostearate 1.5g
Poloxamer 188 0.5g
Tween 80 0.5g
Distilled water 50mL
Method for preparing:
Step 1: take by weighing poloxamer 188, tween 80, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate mixed melting, constitute oil phase;
Step 2: water and oil phase water-bath are heated to 65 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed 1500rpm keeps constant temperature to stir 10 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 7 times, and make the huperzine A solid lipid nano particle aqueous dispersion, and preserve about 3～5 ℃ of sealings through high pressure homogenizer 500bar breast.
Detect: the mean diameter of huperzine A solid lipid nano particle is 58.1nm, and envelop rate is 57.6%.
Embodiment 2
The preparation huperzine A solid lipid nano particle:
Prescription: huperzine A 80mg
Glyceryl monostearate 2g
Poloxamer 188 1g
Egg yolk lecithin 0.5g
Distilled water 50mL
Step 1: take by weighing poloxamer 188, egg yolk lecithin, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 85 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 800rpm, keeps constant temperature to stir 30 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 2 times through high pressure homogenizer 1200bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, about 3～5 ℃ of sealings are preserved.
Detect: the mean diameter of huperzine A solid lipid nano particle is 34.6nm, and envelop rate is 53.7%.
Embodiment 3
The preparation huperzine A solid lipid nano particle:
Prescription: huperzine A 180mg
Glyceryl monostearate 3g
Poloxamer 188 1.5g
Tween 80 1.5g
Distilled water 50mL
Method for preparing:
Step 1: take by weighing poloxamer 188, tween 80, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 70 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 1000rpm, keeps constant temperature to stir 18 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 5 times through high pressure homogenizer 700bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, about 3～5 ℃ of sealings are preserved.
Detect: the mean diameter of huperzine A solid lipid nano particle is 62.2nm, and envelop rate is 55.1%.
Embodiment 4
The preparation huperzine A solid lipid nano particle:
Prescription: huperzine A 350mg
Glyceryl monostearate 3g
Oleic acid 1g
Poloxamer 188 3.5g
Distilled water 50mL
Method for preparing:
Step 1: take by weighing poloxamer 188, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate, oleic acid mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 75 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 1200rpm, keeps constant temperature to stir 25 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 4 times through high pressure homogenizer 900bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, about 3～5 ℃ of sealings are preserved.
Detect: the mean diameter of huperzine A solid lipid nano particle is 29.6nm, and envelop rate is 54.3%.
Prescription: huperzine A 500mg
Glyceryl monostearate 3.8g
Oleic acid 1.2g
Poloxamer 188 4g
Distilled water 50mL
Method for preparing:
Step 1: take by weighing poloxamer 188, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate, oleic acid mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 80 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 1200rpm, keeps constant temperature to stir 25 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 3 times through high pressure homogenizer 900bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, about 3～5 ℃ of sealings are preserved.
Detect: the mean diameter of huperzine A solid lipid nano particle is 75.9nm, and envelop rate is 52.9%.
Claims (2)
1. huperzine A solid lipid nano particle is characterized in that prescription is:
Obtain by following method:
Step 1: take by weighing poloxamer 188, egg yolk lecithin, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 85 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 800rpm, keeps constant temperature to stir 30 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 2 times through high pressure homogenizer 1200 bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, 3～5 ℃ of sealings are preserved.
2. huperzine A solid lipid nano particle is characterized in that prescription is:
Obtain by following method:
Step 1: take by weighing poloxamer 188, add an amount of distilled water ultra-sonic dispersion, constitute water to dissolving fully; With huperzine A, glyceryl monostearate, oleic acid mixed melting, constitute oil phase;
Step 2: with water and oil phase heating in water bath to 75 ℃ respectively, treat that oil phase is dissolved as the clarification hot body fully after, under constant temperature magnetic agitation condition, water is added drop-wise in the oil phase, mixing speed is 1200rpm, keeps constant temperature to stir 25 minutes; Remove water-bath then and continue to be stirred to room temperature, make it become milky emulsion, form colostrum;
Step 3: will make colostrum and spare 4 times through high pressure homogenizer 900 bar breast, and make the huperzine A solid lipid nano particle aqueous dispersion, 3～5 ℃ of sealings are preserved.
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| CN102813653B (en) * | 2012-08-22 | 2015-12-16 | 郭涛 | A kind ofly treat medicine of cerebral ischemia dementia and preparation method thereof |
| CN104958267A (en) * | 2015-06-12 | 2015-10-07 | 海南灵康制药有限公司 | Huperzine-a lipid micro-sphere preparation |
| CN105168182A (en) * | 2015-10-10 | 2015-12-23 | 莆田学院附属医院 | Methylprednisolone solid lipid nanoparticles and preparing method thereof |
| CN106924172B (en) * | 2017-03-10 | 2020-03-31 | 武汉百纳礼康生物制药有限公司 | Huperzine A lyotropic liquid crystal preparation and preparation method thereof |
| CN109589367A (en) * | 2018-11-22 | 2019-04-09 | 福建中医药大学 | A kind of vine tea general flavone solid lipid nano granule and preparation method |
| CN110237037B (en) * | 2019-07-22 | 2021-12-03 | 王盟 | Rhynchophylline solid lipid nanoparticle, preparation method thereof and freeze-dried powder preparation |
| CN110585171A (en) * | 2019-10-18 | 2019-12-20 | 武汉布润脑医学科技有限责任公司 | Temozolomide solid lipid nanoparticle and preparation method thereof |
| CN112691044B (en) * | 2019-10-22 | 2023-10-17 | 上海家化联合股份有限公司 | Positive charge modified solid lipid nanoparticle and preparation method thereof |
| CN113304109A (en) * | 2021-06-08 | 2021-08-27 | 内蒙古大唐药业股份有限公司 | A flavone acetylsalicylate solid lipid nanoparticle dispersion and its preparation method |
| CN113786387B (en) * | 2021-10-22 | 2022-03-08 | 中国人民解放军联勤保障部队第九八八医院 | Huperzine A liposome and application thereof in medicine for treating Alzheimer disease |
| CN114711288A (en) * | 2022-03-01 | 2022-07-08 | 珠海科技学院 | Cinnamyl aldehyde solid lipid nanoparticle with high stability and preparation method thereof |
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| CN101264058A (en) * | 2007-03-13 | 2008-09-17 | 中国科学院上海药物研究所 | Huperzine A and its derivative or salts sustained-release nanometer granule and preparing method thereof |
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