CN106389383A - Method for preparing polypeptide nanoparticles used for in-vivo delivery of pharmacological active substances - Google Patents
Method for preparing polypeptide nanoparticles used for in-vivo delivery of pharmacological active substances Download PDFInfo
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- CN106389383A CN106389383A CN201510852627.4A CN201510852627A CN106389383A CN 106389383 A CN106389383 A CN 106389383A CN 201510852627 A CN201510852627 A CN 201510852627A CN 106389383 A CN106389383 A CN 106389383A
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- Prior art keywords
- pharmacological active
- active substance
- gelatin
- polypeptide
- nanoparticle
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5169—Proteins, e.g. albumin, gelatin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
- A61K31/404—Indoles, e.g. pindolol
- A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
Abstract
The invention provides a method for preparing polypeptide nanoparticles used for in-vivo delivery of pharmacological active substances. The method comprises the following steps: (a) preparing common medical gelatin into a gelatin polypeptide solution with the molecular weight being in the specific range by adopting an acid-base hydrolysis method; and (b) dissolving the pharmacological active substances in an appropriate organic solvent, mixing the obtained solution with the gelatin polypeptide solution prepared in the step (a), forming a nanometer microemulsion through a high-pressure homogenizer, meanwhile, enabling polypeptide chains of gelatin to be unfolded and folded under the high pressure, thus a network structure is formed, and enabling nanometer microemulsion particles containing the pharmacological active substances to be dispersed in the network structure formed by gelatin polypeptide without aggregation. According to the method provided by the invention, through the unfolding and folding of gelatin polypeptide, the pharmacological active substance particles are packaged in the grids formed by gelatin polypeptide, then a stable nanoparticle preparation is formed, and compared with the method of providing albumin by adopting the human blood extract in the prior art, the method provided by the invention has the advantages that the resources are rich, the price is low, and the performance is stable.
Description
Technical field
The present invention relates to the delivering in vivo technical field of pharmacological active substance, specifically a kind of method preparing the polypeptide nano grain for delivering in vivo pharmacological active substance.
Background technology
Water insoluble pharmacologically active material is difficult to by intravenous administration, and in order to realize intravenous administration, one of effective method is that pharmacological active substance is made nano level microgranule.On the one hand, intravenous microgranule with slow release pharmacological active substance and can extend half-life of pharmacological active substance；On the other hand, micronized pharmacological active substance can be targeted to lesions position by targeting material.
Relate to the use of in the method that polypeptide prepares pharmacological active substance nano particle preparations existing, United States Patent (USP) US6,749,868, US5,560,933 preparation method, is the conjunction type effect of nano-paclitaxel with human serum albumin as carrier.This preparation method is under having albuminous participation, and under the process of high pressure homogenizer, make albumin that expansion and the refolding of polypeptide chain to occur, the microemulsion grain being dissolved with pharmacological active substance is wrapped in the structure of polypeptide chain lock formation, it is then passed through lyophilization and remove organic solvent, thus obtaining stable pharmacological active substance nanoparticle.Albumin used in this technology typical from human blood liquid extract, resource-constrained and expensive.Therefore find other wide models cheap, that dependable performance, resourceful polypeptide material will be helpful to Nano medication to apply.
Content of the invention
It is an object of the invention to provide a kind of utilizes the method that cheap, resourceful polypeptide material prepares the polypeptide nano grain for delivering in vivo pharmacological active substance, to solve the difficult problem that some pharmacological active substancies lead to not delivering in vivo because its water solublity is low.
A kind of method preparing the polypeptide nano grain for delivering in vivo pharmacological active substance, comprises the steps：
Step (a)：Gelatin solution is made in the dissolving of pharmagel water for injection, the pH value adjusting gelatin solution is 4.5～7.0, it is warming up to 70～100 DEG C, keeping temperature 1～3 hour, stop heating, it is cooled to 25～40 DEG C, the excessive and too small component of molecular weight is removed by membrane filtration, retaining weight average molecular weight is 25,000～45, the part of 000 dalton, add water for injection in the most backward gelatin solution to make the mass volume ratio concentration of gelatin polypeptides is 0.5～1.0g/100ml (with nitrogenous gauge), and solution adjusts pH value to make gelatin polypeptides solution to 3.5～8.5；
Step (b)：Pharmacological active substance is distributed in organic solvent, it is added in the gelatin polypeptides solution described in step (a), mix, proceed to high pressure homogenizer, emulsified in 1000～2000Bar high pressure, form O/W type microemulsion, high pressure makes peptide molecule launch simultaneously, and after high pressure releases, the peptide molecule of expansion occurs refolding or self assembly, interaction is wound network structure, and pharmacological active substance is distributed to wherein formation polypeptide nano grain.
Further, the pharmacological active substance in described step (b) is selected from one of paclitaxel, Docetaxel, Glibenclamide, ibuprofen, irinotecan, 5-fluorouracil, carmustine, amycin, phenesterin, piposulfan, tamoxifen, lomustine, gamlogic acid, rubescensine A, podophyllotoxin, atorvastatin, simvastatin, fenofibrate, nifedipine, indomethacin, Piroxicam diazepam, Risperidone, Ziprasidone, tacrolimuss, rapamycin, indinavir, ritonavir and Lopinavir or a combination thereof.
Further, the organic solvent in described step (b) is selected from one of dichloromethane, chloroform, carbon tetrachloride, DMSO, methanol, ethanol, propanol, isopropanol, formalin, acetone or a combination thereof.
Further, the mean diameter of described polypeptide nano grain is 25nm～500nm.
Further, the mean diameter of described polypeptide nano grain is 50nm～300nm.
Further, the shared weight ratio in nanoparticle of described pharmacological active substance is 1%～20%.
Further, the gelatin polypeptides solution of described step (a) is the pharmagel made by healthy animal bone, through acid and alkali hydrolysis in advance, also cross-linking agent can be added if necessary and carry out the suitable gelatin polypeptides aqueous solution of made molecular weight after cross-linking reaction, the weight average molecular weight of wherein gelatin polypeptides is 25,000-45,000 dalton, described cross-linking agent is formaldehyde, acetaldehyde, glutaraldehyde, succinic anhydrides or combinations thereof.
Further, also include step (c)：Microemulsion prepared by step (b) is passed through the membrane filtration of 0.22 micron pore size.
Further, also include step (d)：Microemulsion prepared by step (c) is prepared into pharmaceutical preparation through dehydration, dewatering includes vacuum distillation or spray drying or lyophilization, gained becomes the moisture of pharmaceutical preparation to be less than 5%.
The present invention launches to wrap in the grid that gelatin polypeptides are constituted with the method for refolding by pharmacological active substance microgranule using gelatin polypeptides, form stable nano particle preparations, albuminous mode is provided to originate more horn of plenty using human blood liquid extract compared to existing technology, and lattice are low more honest and clean, dependable performance.
Specific embodiment
Below in conjunction with the embodiment in the present invention, the technical scheme in the present invention is clearly and completely described.
The preparation of embodiment 1. gelatin polypeptides solution
500g pharmagel water for injection 1.5L dissolves, adjust the pH value 5.2 of gelatin solution, be warming up to 100 DEG C, keeping temperature 2 hours, stop heating, it is cooled to 40 DEG C, the excessive and too small polypeptide fractions of molecular weight are removed by membrane filtration, retaining weight average molecular weight is 25,000～45, the part of 000 dalton, add water for injection in the most backward solution to make the concentration of gelatin polypeptides is 20% (g/100ml), and solution ph is adjusted to 7.5.
The preparation of embodiment 2. gelatin polypeptides solution
500g pharmagel water for injection 1.5L dissolves, the pH value adjusting gelatin solution is 4.5, it is warming up to 120 DEG C, keeping temperature 1.5 hours, stop heating, it is cooled to 40 DEG C, pH value is adjusted to 8.1, plus succinic anhydrides 2.0g, stirs 1.5 hours, the excessive and too small polypeptide fractions of molecular weight are removed by suitable membrane filtration, retain the part that weight average molecular weight is 25,000～45,000 dalton, add water for injection in the most backward solution to make the concentration of gelatin polypeptides is 20% (g/100ml), and solution ph is adjusted to 7.6.
The preparation of embodiment 3. paclitaxels-gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 1 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 240mg paclitaxel is separately taken to be dissolved in 2.4ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1200Bar pressure and repeatedly obtain nano-emulsion, mean diameter 190.6nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 35 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 8.91% (w/w), moisture ＜ 4.1%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 65～152nm.
The preparation of embodiment 4. paclitaxels-gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 2 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 130mg paclitaxel is separately taken to be dissolved in 2.4ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1200Bar pressure and repeatedly obtain nano-emulsion, mean diameter 207.6nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 30 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 5.11% (w/w), moisture ＜ 4.7%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 50～190nm.
The preparation of embodiment 5. paclitaxel gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 1 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 250mg paclitaxel is separately taken to be dissolved in 3.5ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1300Bar pressure and repeatedly obtain nano-emulsion, mean diameter 201.3nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 30 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 9.81% (w/w), moisture ＜ 4.5%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 90～197nm.
The preparation of embodiment 6. paclitaxels-gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 2 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 250mg paclitaxel is separately taken to be dissolved in 2.4ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1300Bar pressure and repeatedly obtain nano-emulsion, mean diameter 167.1nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 35 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 10.01% (w/w), moisture ＜ 4.0%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 50～153nm.
The preparation of embodiment 7. Docetaxels-gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 2 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 250mg Docetaxel is separately taken to be dissolved in 2.4ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1300Bar pressure and repeatedly obtain nano-emulsion, mean diameter 174.2nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 35 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 9.91% (w/w), moisture ＜ 4.1%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 53～163nm.
The preparation of embodiment 8. indomethacins-gelatin polypeptides nanoparticle
Gelatin polypeptides solution 55ml prepared by Example 2 mixes as aqueous phase with 65ml citrate buffer (pH6.5), 200mg Docetaxel is separately taken to be dissolved in 2.4ml chloroform as oil phase, oil phase proceeds to (Germany in high pressure homogenizer after being mixed with water conjunction, APV-2000 type), circulate under 1300Bar pressure and repeatedly obtain nano-emulsion, mean diameter 181.2nm (Brooker Hai Wen instrument company of the U.S., Laser Scattering Particle detector detects).Extremely -30 DEG C of quick freeze, evacuation 48 hours under aseptic condition, are warming up to 35 DEG C and continue evacuation 24 hours.
Bulk sample after obtained freeze-drying contains paclitaxel 10.03% (w/w), moisture ＜ 4.7%, and can easily be redissolved with water or normal saline is original solution, and nanoparticle particle diameter keeps constant, is mainly distributed on 63～180nm.
The above; be only the specific embodiment of the present invention, but protection scope of the present invention is not limited thereto, any belong to those skilled in the art the invention discloses technical scope in; the change or replacement that can readily occur in, all should be included within the scope of the present invention.Therefore, protection scope of the present invention should be defined by scope of the claims.
Claims (9)
1. a kind of method preparing the polypeptide nano grain for delivering in vivo pharmacological active substance,
It is characterized in that comprising the steps：
Step (a)：Gelatin solution is made in the dissolving of pharmagel water for injection, adjusts gelatin molten
The pH value of liquid is 4.5～7.0, is warming up to 70～100 DEG C, keeping temperature 1～3 hour, stops
Heating, is cooled to 25～40 DEG C, removes the excessive and too small component of molecular weight by membrane filtration,
Retain the part that weight average molecular weight is 25,000～45,000 dalton, in the most backward gelatin solution
Plus water for injection make gelatin polypeptides mass volume ratio concentration be 0.5～1.0g/100ml, solution adjust
PH value makes gelatin polypeptides solution to 3.5～8.5；
Step (b)：Pharmacological active substance is distributed in organic solvent, is added to step (a)
Described in gelatin polypeptides solution in, mix, proceed to high pressure homogenizer, in 1000～2000Bar
High pressure is emulsified, forms O/W type microemulsion, and high pressure makes peptide molecule launch simultaneously, works as height
After pressure releases, there is refolding or self assembly in the peptide molecule of expansion, interaction is wound netted
Structure, is distributed to wherein formation polypeptide nano grain pharmacological active substance.
2. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle it is characterised in that：Pharmacological active substance in described step (b) is selected from
Paclitaxel, Docetaxel, Glibenclamide, ibuprofen, irinotecan, 5-fluorouracil,
Carmustine, amycin, phenesterin, piposulfan, tamoxifen, lomustine,
Gamlogic acid, rubescensine A, podophyllotoxin, atorvastatin, simvastatin, fenofibrate,
Nifedipine, indomethacin, Piroxicam diazepam, Risperidone, Ziprasidone, he gram
One of Mo Si, rapamycin, indinavir, ritonavir and Lopinavir or a combination thereof.
3. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle it is characterised in that：Organic solvent in described step (b) is selected from dichloro
Methane, chloroform, carbon tetrachloride, DMSO, methanol, ethanol, propanol, isopropanol, good fortune
One of that Malin, acetone or a combination thereof.
4. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle it is characterised in that：The mean diameter of described polypeptide nano grain be 25nm～
500nm.
5. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 4
The method of nanoparticle it is characterised in that：The mean diameter of described polypeptide nano grain be 50nm～
300nm.
6. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle it is characterised in that：Described pharmacological active substance is shared in nanoparticle
Weight ratio is 1%～20%.
7. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle it is characterised in that：The gelatin polypeptides solution of described step (a) is by health
Pharmagel made by animal bone, through acid and alkali hydrolysis in advance, also can add cross-linking agent if necessary and enter
The suitable gelatin polypeptides aqueous solution of made molecular weight, wherein gelatin polypeptides after row cross-linking reaction
Weight average molecular weight be 25,000-45,000 dalton, described cross-linking agent be formaldehyde, acetaldehyde,
Glutaraldehyde, succinic anhydrides or combinations thereof.
8. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 1
The method of nanoparticle is it is characterised in that also include step (c)：By the microemulsion prepared by step (b)
Liquid passes through the membrane filtration of 0.22 micron pore size.
9. the polypeptide prepared for delivering in vivo pharmacological active substance as claimed in claim 8
The method of nanoparticle is it is characterised in that also include step (d)：By the microemulsion prepared by step (c)
Liquid is prepared into pharmaceutical preparation through dehydration, and dewatering includes vacuum distillation or spray drying
Or lyophilization, gained become pharmaceutical preparation moisture be less than 5%.
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| Application Number | Priority Date | Filing Date | Title |
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| CN201510852627.4A CN106389383A (en) | 2015-11-27 | 2015-11-27 | Method for preparing polypeptide nanoparticles used for in-vivo delivery of pharmacological active substances |
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| CN201510852627.4A CN106389383A (en) | 2015-11-27 | 2015-11-27 | Method for preparing polypeptide nanoparticles used for in-vivo delivery of pharmacological active substances |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309955A (en) * | 2018-04-27 | 2018-07-24 | 武昌理工学院 | A kind of preparation method of Polygeline mating type taxol nanoparticle |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406941A (en) * | 2011-07-29 | 2012-04-11 | 沈阳药科大学 | Nanometer insoluble active component containing modified polyegline and preparation method thereof |
-
2015
- 2015-11-27 CN CN201510852627.4A patent/CN106389383A/en active Pending
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406941A (en) * | 2011-07-29 | 2012-04-11 | 沈阳药科大学 | Nanometer insoluble active component containing modified polyegline and preparation method thereof |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN108309955A (en) * | 2018-04-27 | 2018-07-24 | 武昌理工学院 | A kind of preparation method of Polygeline mating type taxol nanoparticle |
| CN108309955B (en) * | 2018-04-27 | 2020-06-02 | 武昌理工学院 | Preparation method of polygeline-conjugated paclitaxel nanoparticles |
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Inventor after: Zhang Liu Inventor after: Wu Na Inventor after: Xu Lixia Inventor after: Chen Xigao Inventor after: Yao Ping Inventor after: Huang Chuhua Inventor after: Ding Guanjun Inventor before: Zhang Liu Inventor before: Wu Na Inventor before: Xu Lixia Inventor before: Chen Xigao Inventor before: Yao Ping |
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Effective date of registration: 20170414 Address after: 430223 Jiangxia Road, Hubei, Wuhan, No. 16 Applicant after: WUCHANG UNIVERSITY OF TECHNOLOGY Applicant after: Wuhan Hualong Biological Pharmaceutical Co., Ltd. Address before: 430223 Jiangxia Road, Hubei, Wuhan, No. 16 Applicant before: WUCHANG UNIVERSITY OF TECHNOLOGY |
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