CN105434365A - Preparation method and application of oral micelle microspheres - Google Patents
Preparation method and application of oral micelle microspheres Download PDFInfo
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- CN105434365A CN105434365A CN201510893235.2A CN201510893235A CN105434365A CN 105434365 A CN105434365 A CN 105434365A CN 201510893235 A CN201510893235 A CN 201510893235A CN 105434365 A CN105434365 A CN 105434365A
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- 239000004005 microsphere Substances 0.000 title claims abstract description 72
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- 239000000243 solution Substances 0.000 claims abstract description 54
- 229920001661 Chitosan Polymers 0.000 claims abstract description 36
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims abstract description 36
- 239000004925 Acrylic resin Substances 0.000 claims abstract description 34
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 33
- 239000003814 drug Substances 0.000 claims abstract description 32
- 239000000725 suspension Substances 0.000 claims abstract description 32
- 239000000463 material Substances 0.000 claims abstract description 26
- 239000011259 mixed solution Substances 0.000 claims abstract description 22
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 17
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 229940079593 drug Drugs 0.000 claims description 21
- 239000008346 aqueous phase Substances 0.000 claims description 20
- 238000003756 stirring Methods 0.000 claims description 20
- JLPULHDHAOZNQI-ZTIMHPMXSA-N 1-hexadecanoyl-2-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phosphocholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCC\C=C/C\C=C/CCCCC JLPULHDHAOZNQI-ZTIMHPMXSA-N 0.000 claims description 11
- 239000008347 soybean phospholipid Substances 0.000 claims description 11
- 238000004090 dissolution Methods 0.000 claims description 10
- 238000003760 magnetic stirring Methods 0.000 claims description 10
- 239000012528 membrane Substances 0.000 claims description 10
- 239000008363 phosphate buffer Substances 0.000 claims description 10
- 238000004321 preservation Methods 0.000 claims description 10
- 230000001105 regulatory effect Effects 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 9
- 238000002347 injection Methods 0.000 claims description 6
- 239000007924 injection Substances 0.000 claims description 6
- WTJKGGKOPKCXLL-RRHRGVEJSA-N phosphatidylcholine Chemical compound CCCCCCCCCCCCCCCC(=O)OC[C@H](COP([O-])(=O)OCC[N+](C)(C)C)OC(=O)CCCCCCCC=CCCCCCCCC WTJKGGKOPKCXLL-RRHRGVEJSA-N 0.000 claims description 6
- 238000011275 oncology therapy Methods 0.000 claims description 4
- 238000010790 dilution Methods 0.000 claims description 2
- 239000012895 dilution Substances 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 18
- 238000010521 absorption reaction Methods 0.000 abstract description 5
- 239000000203 mixture Substances 0.000 abstract description 5
- 231100000331 toxic Toxicity 0.000 abstract description 3
- 230000002588 toxic effect Effects 0.000 abstract description 3
- 210000000936 intestine Anatomy 0.000 abstract 2
- 206010000059 abdominal discomfort Diseases 0.000 abstract 1
- 239000008055 phosphate buffer solution Substances 0.000 abstract 1
- 230000002035 prolonged effect Effects 0.000 abstract 1
- 210000000813 small intestine Anatomy 0.000 abstract 1
- 238000001179 sorption measurement Methods 0.000 abstract 1
- 238000001694 spray drying Methods 0.000 abstract 1
- 206010028980 Neoplasm Diseases 0.000 description 12
- 230000000259 anti-tumor effect Effects 0.000 description 7
- 230000031891 intestinal absorption Effects 0.000 description 6
- 206010006187 Breast cancer Diseases 0.000 description 5
- 208000026310 Breast neoplasm Diseases 0.000 description 5
- 201000008275 breast carcinoma Diseases 0.000 description 5
- 201000001514 prostate carcinoma Diseases 0.000 description 5
- 229920006395 saturated elastomer Polymers 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 239000008280 blood Substances 0.000 description 4
- 210000004369 blood Anatomy 0.000 description 4
- 238000010579 first pass effect Methods 0.000 description 4
- 230000000968 intestinal effect Effects 0.000 description 4
- 238000012360 testing method Methods 0.000 description 4
- 241000699670 Mus sp. Species 0.000 description 3
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 3
- 239000003005 anticarcinogenic agent Substances 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 230000002496 gastric effect Effects 0.000 description 3
- 239000013642 negative control Substances 0.000 description 3
- 238000007920 subcutaneous administration Methods 0.000 description 3
- 238000002835 absorbance Methods 0.000 description 2
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- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 229940126701 oral medication Drugs 0.000 description 2
- 230000035945 sensitivity Effects 0.000 description 2
- 208000024891 symptom Diseases 0.000 description 2
- 210000001519 tissue Anatomy 0.000 description 2
- 238000011282 treatment Methods 0.000 description 2
- 230000004614 tumor growth Effects 0.000 description 2
- VEEGZPWAAPPXRB-BJMVGYQFSA-N (3e)-3-(1h-imidazol-5-ylmethylidene)-1h-indol-2-one Chemical compound O=C1NC2=CC=CC=C2\C1=C/C1=CN=CN1 VEEGZPWAAPPXRB-BJMVGYQFSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- STHUIDFAVZVDLW-RLOHNOFUSA-N COC1[C@@]2(C(CC[C@H]2[C@@H]2CCC3=C([C@H]2C1)C=CC(=C3)O)O)C Chemical compound COC1[C@@]2(C(CC[C@H]2[C@@H]2CCC3=C([C@H]2C1)C=CC(=C3)O)O)C STHUIDFAVZVDLW-RLOHNOFUSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N EtOH Substances CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 210000001015 abdomen Anatomy 0.000 description 1
- 238000009825 accumulation Methods 0.000 description 1
- 239000004037 angiogenesis inhibitor Substances 0.000 description 1
- 229940121369 angiogenesis inhibitor Drugs 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 230000000118 anti-neoplastic effect Effects 0.000 description 1
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- 210000004204 blood vessel Anatomy 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 208000030270 breast disease Diseases 0.000 description 1
- 238000010835 comparative analysis Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
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- 238000002474 experimental method Methods 0.000 description 1
- 238000002637 fluid replacement therapy Methods 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000002513 implantation Methods 0.000 description 1
- 238000011081 inoculation Methods 0.000 description 1
- 238000007689 inspection Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000011806 microball Substances 0.000 description 1
- 210000000865 mononuclear phagocyte system Anatomy 0.000 description 1
- 210000002445 nipple Anatomy 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
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- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000002861 polymer material Substances 0.000 description 1
- 239000013641 positive control Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
Classifications
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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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/565—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
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- Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
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Abstract
The invention relates to a preparation method and application of oral micelle microspheres. The problems that existing medicine is low in bioavailability when taken orally, poor in adsorption and large in toxic and side effect and causes stomach discomfort due to burst release of the medicine can be effectively solved. The preparation method includes the steps that PEG5000-PLGA5000 and granulesten are dissolved to serve as the water phase, 2-ME is ultrasonically dissolved in methyl alcohol, and the mixture is added into the water phase dropwise to obtain micelle suspension; carboxymethyl chitosan is prepared into a carboxymethyl chitosan solution with ultrapure water, polyacrylic resin is prepared into a polyacrylic resin solution with a phosphate buffer solution, and the carboxymethyl chitosan solution and the polyacrylic resin solution are mixed to obtain a microsphere material mixed solution; the micelle suspension and the microsphere material mixed solution are magnetically stirred and diluted in a 1-3 fold mode with the ultrapure water, and the micelle microspheres are obtained through spray drying. Intestine targeted control release of medicine carrying micelles can be realized, the intestine absorption time of the micelles is prolonged, the absorptivity to the medicine carrying micelles of the small intestine is improved, oral bioavailability of the medicine is obviously improved, and the medicine efficacy is improved.
Description
Technical field
The present invention relates to field of medicaments, particularly a kind of preparation method of oral micelle microsphere and application thereof.
Background technology
In some water, insoluble drug such as most of anticarcinogen can only adopt intravenous administration mode to carry out the treatment of disease because oral administration biaavailability is low clinically.Intravenously administrable needs to inject frequently, and the compliance of patient is poor, and blood concentration fluctuation causes more greatly obvious toxic and side effects.Oral administration patient can medication voluntarily, and patient compliance is high.These drug oral artifact availabilities low mainly because the unstable or metabolism of obvious first pass effect of hepar, gastrointestinal may be there is, intestinal absorption arranges outward or absorbs the obstacles such as saturated.The ordinary preparation (medicine carries out gastrointestinal absorption with molecularity) of these medicines, is difficult to overcome these obstacles and causes bioavailability very low after oral at present.Along with development and the growth in the living standard of society, the exploitation of oral drugs must become development trend.
2ME2 (2-ME) is a kind of slightly water-soluble anticarcinogen, generates effect be used for the treatment of breast carcinoma, the diseases such as carcinoma of prostate mainly through angiogenesis inhibitor effect and anti-tumor.There is obvious first pass effect of hepar and the saturated mechanism of intestinal absorption in oral administration.Its oral preparation drug administration is invalid at present.Therefore, how to solve 2ME2 slightly water-soluble, the oral curative effect improving 2ME2 is the technical problem needing conscientiously to solve.
Summary of the invention
For above-mentioned situation, for overcoming the defect of prior art, the object of the present invention is just to provide a kind of preparation method and application thereof of oral micelle microsphere, effectively can solve existing drug oral bioavailability low, absorption difference, toxic and side effects is comparatively large, and burst drug release causes the problem of gastric discomfort.
The technical scheme that the inventive method solves is realized by following steps:
(1) micelle suspension, is prepared:
Under 35-50 DEG C of water-bath, by 80-100mgPEG5000-PLGA5000,5-10mg soybean phospholipid (PC-80, phosphatidylcholine content >80%, injection stage) be dissolved in 2-4ml water, as aqueous phase, by 2-5mg2-ME ultrasonic dissolution in 400-600 μ L methanol, then dropwise join in aqueous phase, 700-1000rpm stirs 9-12h, crosses 0.45 μm of filter membrane, obtain micelle suspension, 4 DEG C of preservations;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan (viscosity-average molecular weight is 2.5 × 100000) is made the carboxymethyl chitosan solution of mass concentration 1-2%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 1-2% polyacrylic resin solution, the pH to 5-7 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 1-3, stir, obtain micro-sphere material mixed solution; The micelle suspension getting step (1) obtained is mixed homogeneously according to volume ratio 1 ︰ 1-2 under magnetic stirring with micro-sphere material mixed solution, with ultra-pure water dilution 1-3 doubly, spray-dried must micelle microsphere.
The application in cancer therapy drug prepared by micelle microsphere prepared by described method.
The present invention can realize the intestinal target slow-release of carrier micelle, extend the intestinal absorption time of micelle, the corresponding prolongation carrier micelle holdup time in blood, and it is saturated and absorb the obstacles such as outer row to overcome first pass effect of hepar, intestinal absorption to a certain extent, improve small intestinal to the absorbance of carrier micelle, overcome the obstacle of the oral absorption of poorly water soluble drugs to a certain extent, the oral administration biaavailability of these medicines can be significantly improved, thus play due pharmacological action, improve drug effect, have significant economic and social benefit.
Detailed description of the invention
Below in conjunction with embodiment, the specific embodiment of the present invention is elaborated.
Embodiment 1
A preparation method for micelle microsphere, is realized by following methods:
(1) micelle suspension, is prepared:
Under 35 DEG C of water-baths, by 80mgPEG5000-PLGA5000,10mg soybean phospholipid (PC-80, phosphatidylcholine content >80%, injection stage) be dissolved in 4ml water, as aqueous phase, by 5mg2-ME ultrasonic dissolution in 500 μ L methanol, then dropwise add in the middle of aqueous phase, 900r/min stirs 9h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan (viscosity-average molecular weight is 2.5 × 100000) is made the carboxymethyl chitosan solution of mass concentration 1%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 2% polyacrylic resin solution, and the pH to 6 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin (EudragitL100) solution are mixed according to volume ratio 1 ︰ 3 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 2 with micro-sphere material mixed solution, 2 times are diluted with ultra-pure water, spray-dried micelle microsphere.
Embodiment 2
A preparation method for micelle microsphere, is realized by following methods:
(1) micelle suspension, is prepared:
Under 45 DEG C of water-baths, by 80mgPEG5000-PLGA5000,10mg soybean phospholipid (PC-80, phosphatidylcholine content >80%, injection stage) be dissolved in 2ml water, as aqueous phase, by 2mg2-ME ultrasonic dissolution in 400 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 10h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan (viscosity-average molecular weight is 2.5 × 100000) is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 2% polyacrylic resin solution, and the pH to 6.5 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin (EudragitL100) solution are mixed according to volume ratio 1 ︰ 1 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 1.5 times are diluted with ultra-pure water, spray-dried micelle microsphere.
Embodiment 3
A preparation method for micelle microsphere, is realized by following methods:
(1) micelle suspension, is prepared:
Under 40 DEG C of water-baths, by 100mgPEG5000-PLGA5000,10mg soybean phospholipid (PC-80, phosphatidylcholine content >80%, injection stage) be dissolved in 3ml water, as aqueous phase, by 4mg2-ME ultrasonic dissolution in 500 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 12h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan (viscosity-average molecular weight is 2.5 × 100000) is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 1% polyacrylic resin solution, and the pH to 5 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin (EudragitL100) solution are mixed according to volume ratio 1 ︰ 1 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 1 times is diluted with ultra-pure water, spray-dried micelle microsphere.
Embodiment 4
A preparation method for micelle microsphere, is realized by following methods:
(1) micelle suspension, is prepared:
Under 50 DEG C of water-baths, by 90mgPEG5000-PLGA5000,8mg soybean phospholipid (PC-80, phosphatidylcholine content >80%, injection stage) be dissolved in 3ml water, as aqueous phase, by 3mg2-ME ultrasonic dissolution in 400 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 10h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan (viscosity-average molecular weight is 2.5 × 100000) is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 1% polyacrylic resin solution, and the pH to 7 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin (EudragitL100) solution are mixed according to volume ratio 1 ︰ 2 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 3 times are diluted with ultra-pure water, spray-dried micelle microsphere.
Micelle microsphere prepared by the inventive method can be effective to prepare cancer therapy drug, realizes micelle microsphere and is preparing the application in cancer therapy drug.
The method of the invention, through repeated tests, all draws identical or close result, and related experiment data is as follows:
The test data of micelle microball preparation of the present invention anti-Subcutaneous tumor activity is specific as follows:
1. animal: SPF level Balb/c mice, female, 42 scholar 2 ages in days, body weight 19 ± 2g, by Hunan, Si Laike Jing Da laboratory animal company limited provides.The quality certification is numbered: SCXK (Hunan) 2011-0003.Every treated animal number: negative control group 10, administration group often organizes 10.
2. transplanted tumor: mouse mastopathy cell (4T1)
3. anti-tumor activity in body: get frozen 4T1 cell strain, in 37 DEG C, 5%C0 after rapid fluid resuscitation
2and under saturated humidity condition, cultivate after 24h and change liquid, continue to cultivate, when cell to cover with bottom culture bottle 70 ~ 80%, go down to posterity 1 time, later every 2 ~ 3d goes down to posterity 1 time, after reaching for 4 ~ 5 generations, starts mass propgation.
By exponential phase 4T1 cell good for growth conditions, trypsinization, centrifugal collecting cell, is adjusted to 5 × 10 with normal saline by cell concentration
6individual ml
-1cell suspension, in aseptic superclean bench, be inoculated in around Balb/C right side of mice subcutaneous abdomen nipple by every 0.2ml cell suspension amount, totally 30.Random packet after inoculation 10d, according to grouping different dosing.Negative control group and every day oral 1 normal saline, successive administration 21 days; Positive controls 2ME2 (2-ME) oral administration every day (po) once, totally 21 times.Within 21st day, put to death animal, to weigh, tumor weight, calculate each group of average tumor weight, obtain tumor control rate and carry out t inspection, optimizing optimal treatment group, the results are shown in Table 1.
The oral Graft Versus Tumor of table 12-methoxyestradiol micelle microsphere
The research of tumor pharmacodynamics in Mice is carried by subcutaneous implantation 4T1, take oral normal saline as negative control group, as shown in Table 1, the test group of 2-ME micelle microsphere oral formulations under two dosage all has significant antitumous effect, inhibition rate of tumor growth is all higher than 80%, and the curative effect of high dose group is apparently higher than the curative effect of low dose group.And other 2-ME preparation comprises quiet injecting glue bundle group and oral micelle group, oral crude drug microsphere group inhibition rate of tumor growth is all lower than 50%, and antitumous effect is undesirable.Visible, independent oral micelle or separately oral microsphere group antitumous effect are all poor, and 2-ME micelle microsphere oral formulations has antitumous effect desirable significantly, illustrate that the biphase delivery system micelle microsphere of combining preparation of micelle and microsphere is an effective oral formulations of antitumor for 2-ME.
Poorly water soluble drugs is encapsulated in micelle by the present invention, again carrier micelle and the drying of pH Sensitive Polymer Materials mixed atomizing are prepared into pH sensitivity micelle microsphere, oral administration, overcomes the obstacle of these medicine oral absorption to a certain extent, significantly improves the oral administration biaavailability of its these medicines.The present invention adopts polyethylene glycol-polylactic acid ethanol copolymer material (wherein the mol ratio of the lactic acid/glycolic of PLGA material is 1/1-3/1) to prepare carrier micelle, then itself and macromolecular material aqueous solution are spray dried to microsphere.Macromolecular material is the mixture of carboxymethyl chitosan and acrylic resin, and wherein the mass percent of carboxymethyl chitosan is 10-40%.
The oral micelle microsphere of the present invention is used for some poorly water soluble drugs as the oral administration of anticarcinogen, carrier micelle can significantly improve the dissolubility of insoluble drug, the nano-scale of micelle and hydrophilic shell absorbed by reticulo-endothelial system identification in human body after can prevent micelle from entering blood, the holdup time of prolong drug in blood circulation, simultaneously, because tumor blood vessels has high osmosis and high anelasticity, the small particle diameter of polymer micelle is conducive to medicine in the delay of tumor tissues and accumulation, gives the passive target effect to tumor tissues.The micelle microsphere of pH sensitivity, the impact of gastric juice on micelle stability can be reduced, reduce the loss of carrier micelle at gastric juice, the intestinal target slow-release of carrier micelle can be realized, extend the intestinal absorption time of micelle, the corresponding prolongation carrier micelle holdup time in blood, and overcome first pass effect of hepar to a certain extent, intestinal absorption is saturated and absorb the obstacles such as outer row, improve small intestinal to the absorbance of carrier micelle, the oral administration biaavailability of these medicines can be significantly improved, change the oral invalid present situation of ordinary preparation prepared by original crude drug, make it effectively oral, and through clinical trial, achieve very satisfied curative effect, interrelated data is as follows:
Clinical on probation to 108 routine tumor patients, wherein breast carcinoma 58 people, carcinoma of prostate 50 people, undertaken by original same series antineoplastic medicament therapeutic scheme, warm boiled water, takes after 6 months and adds up curative effect, adopts the single factor test variance comparative analysis of SPSS11.5 statistical software, P<0.01, improve curative effect more than 40% than similar drugs, have pole significant difference, concrete outcome is as follows:
Symptom obvious improver 58 people, wherein breast carcinoma 32 people, carcinoma of prostate 26 people, account for 53.7%;
Symptom improver 40 people, wherein breast carcinoma 22 people, carcinoma of prostate 18 people, account for 37%;
Invalid 10 people, wherein breast carcinoma 4 people, carcinoma of prostate 6 people, account for 9.3%, continuous use more than 5 years, average life is survived more than 5 years person 70 people, 2-4 person 21 people, about 1 year person 17 people, visible nano mciroball of the present invention effectively changes the problem that former similar slightly solubility oral drug bioavailability is low, curative effect is low, has opened up the new way of tumor, there is very strong practicality, have significant economic and social benefit.
Claims (6)
1. a preparation method for oral micelle microsphere, is characterized in that, realized by following steps:
(1) micelle suspension, is prepared:
Under 35-50 DEG C of water-bath, 80-100mgPEG5000-PLGA5000,5-10mg soybean phospholipid is dissolved in 2-4ml water, as aqueous phase, by 2-5mg2-ME ultrasonic dissolution in 400-600 μ L methanol, then dropwise join in aqueous phase, 700-1000rpm stirs 9-12h, crosses 0.45 μm of filter membrane, obtain micelle suspension, 4 DEG C of preservations; Described soybean phospholipid is PC-80, phosphatidylcholine content >80%, injection stage;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan is made the carboxymethyl chitosan solution of mass concentration 1-2%, with the phosphate buffer of pH7.4, polyacrylic resin (EudragitL100) is made mass concentration 1-2% polyacrylic resin solution, the pH to 5-7 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 1-3, stir, obtain micro-sphere material mixed solution; The micelle suspension getting step (1) obtained is mixed homogeneously according to volume ratio 1 ︰ 1-2 under magnetic stirring with micro-sphere material mixed solution, with ultra-pure water dilution 1-3 doubly, spray-dried must micelle microsphere; Described carboxymethyl chitosan viscosity-average molecular weight is 2.5 × 100000.
2. the preparation method of oral micelle microsphere according to claim 1, is characterized in that, realized by following steps:
(1) micelle suspension, is prepared:
Under 35 DEG C of water-baths, 80mgPEG5000-PLGA5000,10mg soybean phospholipid is dissolved in 4ml water, as aqueous phase, by 5mg2-ME ultrasonic dissolution in 500 μ L methanol, then dropwise add in the middle of aqueous phase, 900r/min stirs 9h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan is made the carboxymethyl chitosan solution of mass concentration 1%, with the phosphate buffer of pH7.4, polyacrylic resin is made mass concentration 2% polyacrylic resin solution, and the pH to 6 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 3 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 2 with micro-sphere material mixed solution, 2 times are diluted with ultra-pure water, spray-dried micelle microsphere.
3. the preparation method of oral micelle microsphere according to claim 1, is characterized in that, realized by following steps:
(1) micelle suspension, is prepared:
Under 45 DEG C of water-baths, 80mgPEG5000-PLGA5000,10mg soybean phospholipid is dissolved in 2ml water, as aqueous phase, by 2mg2-ME ultrasonic dissolution in 400 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 10h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin is made mass concentration 2% polyacrylic resin solution, and the pH to 6.5 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 1 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 1.5 times are diluted with ultra-pure water, spray-dried micelle microsphere.
4. the preparation method of oral micelle microsphere according to claim 1, is characterized in that, realized by following steps:
(1) micelle suspension, is prepared:
Under 40 DEG C of water-baths, 100mgPEG5000-PLGA5000,10mg soybean phospholipid is dissolved in 3ml water, as aqueous phase, by 4mg2-ME ultrasonic dissolution in 500 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 12h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin is made mass concentration 1% polyacrylic resin solution, and the pH to 5 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 1 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 1 times is diluted with ultra-pure water, spray-dried micelle microsphere.
5. the preparation method of oral micelle microsphere according to claim 1, is characterized in that, realized by following steps:
(1) micelle suspension, is prepared:
Under 50 DEG C of water-baths, 90mgPEG5000-PLGA5000,8mg soybean phospholipid is dissolved in 3ml water, as aqueous phase, by 3mg2-ME ultrasonic dissolution in 400 μ L methanol, then dropwise add in the middle of aqueous phase, 1000r/min stirs 10h, crosses 0.45 μm of filter membrane, obtain micelle suspension, the preservation of 4 DEG C, refrigerator;
(2) micelle microsphere, is prepared:
With ultra-pure water, carboxymethyl chitosan is made the carboxymethyl chitosan solution of mass concentration 2%, with the phosphate buffer of pH7.4, polyacrylic resin is made mass concentration 1% polyacrylic resin solution, and the pH to 7 of solution is regulated with the NaOH of 1mol/L, carboxymethyl chitosan solution and polyacrylic resin solution are mixed according to volume ratio 1 ︰ 2 and stir, obtain micro-sphere material mixed solution, get step (1) gained micelle suspension to mix homogeneously under magnetic stirring according to volume ratio 1 ︰ 1 with micro-sphere material mixed solution, 3 times are diluted with ultra-pure water, spray-dried micelle microsphere.
6. the application in cancer therapy drug prepared by the oral micelle microsphere that prepared by method described in claim 1 or any one of 2-5.
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| CN101953775A (en) * | 2010-09-17 | 2011-01-26 | 郑州大学 | Hydrogel nanoparticles used as injectable subcutaneous implant agent |
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| CN101953775A (en) * | 2010-09-17 | 2011-01-26 | 郑州大学 | Hydrogel nanoparticles used as injectable subcutaneous implant agent |
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