CN101816630B - Uricase lipid nanoparticle and preparation method thereof - Google Patents
Uricase lipid nanoparticle and preparation method thereof Download PDFInfo
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- CN101816630B CN101816630B CN2009101032691A CN200910103269A CN101816630B CN 101816630 B CN101816630 B CN 101816630B CN 2009101032691 A CN2009101032691 A CN 2009101032691A CN 200910103269 A CN200910103269 A CN 200910103269A CN 101816630 B CN101816630 B CN 101816630B
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Abstract
The invention belongs to the technical field of medicinal preparation. The invention discloses a formula of an uricase lipid nanoparticle and a preparation method thereof. The content of the uricase is 0.1U/ml-1U/ml, and other materials are the medical auxiliary material or the additive of the lipid nanoparticle. The uricase lipid nanoparticle can be used for curing different diseases which are characterized in the increase of the level of the circulated uric acid, wherein the diseases comprise but are not limited to the hyperuricemia and the tumor disintegration syndrome.
Description
Technical field
The invention belongs to field of medicaments, relate to Uricase lipid nanoparticle and preparation method thereof.
Background technology
The purine that is generated in intracellular nucleic acid and the nucleotide catabolic process is transformed into uric acid under the xanthine oxidase effect.(Uricase, but UC) catalysis uric acid oxidation generate hydrogen peroxide (H202) and allantoin (allantion) and excrete uricase.But because human body lacks UC, purine catabolism can only generate uric acid through RE.When uricopoiesis surpasses RE, will cause hyperuricemia (uric acid concentration is higher than 0.42mmol/L in the blood).Hyperuricemia can cause or aggravate multiple disease: the hyperuricemia that causes owing to a large amount of cracking of tumor cell during malignant tumor chemotherapy can cause metabolism disorder and renal failure even death, i.e. tumor lysis syndrome; Uric acid is deposited on intraarticular and causes gout, is deposited on renal tubules and causes renal dysfunction, injury of renal tubular, IgA nephropathy inflammation; Uric acid stimulated vascular smooth muscle cell propagation can cause endothelial dysfunction; Hyperuricemia is the important risk factor of cardiovascular disease such as atherosclerosis.
The scheme of preventing and treating commonly used of present hyperuricemia gives xanthine oxidase inhibitor (allopurinol) and has drawback: (1) allopurinol can block uricopoiesis; But can increase the load of RE uric acid precursor (hypoxanthine and in urine than the uric acid xanthine of indissoluble more); For the patient who follows hyperuricemia generation high concentration haemoxanthine, make the matter worse; (2) uric acid to having retained in the patient body is failed to respond to any medical treatment with allopurinol; (3) allopurinol and probenecid class medicine all have obvious Liver and kidney toxicity, also are prone to cause allergic reaction.
The good water solublity of allantoin and kidney make UC might become the ideal medicament of treatment hyperuricemia to the efficient discharge capacity of allantoin.Clinical research shows that UC can rapidly and efficiently reduce blood uric acid, and specificity is high, and when the treatment tumor lysis syndrome, UC is more safer and more effective than allopurinol.The hyperuricemia that France and Italy approval Aspergillus flavus UC (Uricozyme) before more than 20 year, the beginning of this century, the U.S. and the approval gene recombinaton UC of European Union (Rasburicase) produced when being used to prevent and treat chemotherapy of tumors.UC also can be used for treating gout.There is great demand in UC as the medicine that reduces the blood plasma uric acid.
But all there is latent defect in all natural UC: (1) external environment pH value is very big to the influence of UC catalytic capability.The optimum pH meta-alkalescence (8.5～9.2) of UC, catalytic capability low (when UC is merely optimum pH in the bacillus fastidiosus born of the same parents active 20%) during pH 7.4 (in blood plasma), catalytic capability is lower during pH 5 (in renal tubules).This causes UC, and activity is lower in vivo, and required dosage is bigger during treatment, and the treatment cost is higher, and safety is low.(2) the body-internal-circulation half-life is shorter.UC is unstable in vivo, is easy to lost activity by protease hydrolysis.(3) be prone to bring out organism immune response, produce immunogenicity and antigen-reactive.The severe allergic reaction incidence rate of Uricozyme is 5%, uses UC vomiting (～50%), fever (～46%), the untoward reaction such as (～27%) of feeling sick also often to occur.
Defective to native enzyme; Following research is arranged: with UC absorption, be covalently bonded in chitosan or glucosan, UC is embedded in carboxy methyl amylose or is encapsulated in the erythrocyte, UC and albumin is crosslinked; PEGization UC is encapsulated in the liposome; UC is encapsulated in the alginate microcapsule, UC is fixed in metal-chelating pearl (150～200 μ m) surface, UC is covalently bind in immunoliposome or conventional liposome surface etc.But above variety of way all can not make UC the righttest or near optimum pH environment performance catalytic activity, and mostly exist enzyme to be prone to come off, biocompatibility is lower, be prone to cause shortcomings such as blood coagulation, stability and specificity be undesirable.
In recent years, people modify UC with PEG and have obtained some progress, and the Puricase that is just carrying out the III clinical trial phase at present in the North America is the most successful example of PEGization UC research.Though PEGization UC is having certain advantage than native enzyme aspect prolongation half life of enzyme, reduction immunogenicity and the antigen reactivity; But still have some shortcomings: (1) remains at pH 7.4 but not the optimum pH (8.5～9.2) of UC plays a role; The UC activity is lower, PEGization back activity lower (specific activity of reservation is 10%～40%).(2) though optimized Puricase, the bioavailability behind the quiet notes is also than native enzyme low (partly cause is that the molecular weight of enzyme-PEG polymer is very big).(3) as long as there is a spot of macromole aggregation, PEGization UC will produce immunogenicity.(4) PEGization UC specification requirement is high, complex process, and cost is higher.
Up to now; The research of the little response system of semipermeability of mediation enzyme mainly concentrates on PEGization polylactic acid/hydroxy acetic acid (PLGA) nanoparticle, PLGA microsphere, Polyisobutyl cyanoacrylate (PIBCA) nanoparticle and lipid nanoparticle; The microenvironment of the enzyme that makes up is neutrality or slant acidity mostly, is not suitable for the UC (see figure 1).
Warp inquiry patent and document, all unmanned little response system of semipermeability meta-alkalescence that structure is mediated uricase with the buffering of meta-alkalescence (pH8～9).And the mentality of designing of this patent, prescription, method for preparing, the preparation that obtains and characteristic thereof and former research are all inequality.
Summary of the invention
Technical problem to be solved by this invention provides a kind of Uricase lipid nanoparticle and preparation method thereof.Said preparation can overcome the shortcoming of other uricase preparation of research and development up to now to clinical definite needs.The Uricase lipid nanoparticle that this research makes can obviously improve the activity of uricase when body fluid pH7.4, prolong half-life, and non-immunogenicity reduces dosage, improves stability.The dosage form that prepared preparation can be used as intravenously administrable is applied to clinical.
Uricase lipid nanoparticle of the present invention is a kind of colloidal drug delivery system, comprises uricase, phospholipid, the cholesterol of treating effective dose, regulates the buffer of pH, the stabilizing agent bovine serum albumin, and lipid nanoparticle prepares required other additives.The particle diameter of lipid nanoparticle is 100～1000nm, and preferred prescription is: 1 part in lecithin, 1 part in cholesterol; Contain the long-acting lipid of polyethylene glycol type such as DSPE-PEG20000.05 part; Uricase is 0.3U/ml, bovine serum albumin 0.05mg/ml, and 50mM boric acid-borate buffer solution pH is 8.5.Optimizing the lipid nanoparticle particle diameter that makes is about 200nm.Uricase lipid nanoparticle method for preparing of the present invention is: formula ratio lecithin and cholesterol are dissolved in an amount of organic solvent, and the Rotary Evaporators decompression volatilizes organic solvent, adds an amount of organic solvent; Add the 50mmol/L boric acid-borate buffer solution buffer (pH is 8～9) that contains UC and BSA,, water-bath is ultrasonic is with opalescent dispersion uniformly to forming; Continue reduction vaporization, subsiding to gel when being with opalescent uniform liquid, adds the right amount of boron acid buffer for milky; Continue the decompression rotation; The gained suspension is crossed the microporous filter membrane of 0.22 μ m after 4 ℃ in refrigerator is placed 24 hours, promptly get.The lipid nanoparticle particle diameter of gained of the present invention must not be lower than 95% less than the sum of 1 μ m, must not surpass 3% greater than the sum of 1 μ m, must not detect the nanoparticle greater than 5 μ m.The lipid nanoparticle of gained of the present invention can pass through the Sephadex column chromatography, separates and removes the resolvase that is un-encapsulated in the lipid nanometer intragranular.The mean diameter of the uricase nanoparticle that prescription of optimizing and technology obtain about 200nm, Zeta potential＜-30mV, envelop rate＞88%.The lipid nanoparticle of gained of the present invention can quiet notes be used for clinically, perhaps adopts art-recognized method to be prepared into powder and lyophilized preparation administration.
Under medium pH7.4 condition; The UC of the same dosage of the lipid nanoparticle that the present invention makes (use pH is 8.5 borate buffer during preparation) mediation reduces to normal level (0.24mM) with uric acid from high concentration (0.6mM); The used time, more natural UC obviously reduced; It is low-level to reduce to other uric acid, and the UC required time of lipid nanoparticle mediation also is starkly lower than natural UC.The Uricase lipid nanoparticle that this research makes can obviously improve activity (when activity that the UC of preparation mediation keep can reach native enzyme in optimum pH active 80～150% of uricase at body fluid pH7.4; When UC is merely optimum pH in the bacillus fastidiosus born of the same parents 20%; The activity that PEGization UC keeps when body fluid pH7.4 is 10%～40%); Non-immunogenicity (adopts subcutaneous injection to contain the complete Freund's adjuvant emulsion preparation rabbit anti-serum of UC; After hatching 30min under 37 ℃ of Uricase lipid nanoparticle and the not commensurability antiserum liquid, investigate antigenicity, Uricase lipid nanoparticle and antiserum do not react, and the native enzyme immunogenicity of dosage is stronger equally).Add the Uricase lipid nanoparticle of the long-acting lipid preparation of polyethylene glycol type, can obviously prolong the uricase half-life (extending to 18.5 hours in 4 hours from native enzyme) in vivo.Uricase lipid nanoparticle is to blood vessel nonirritant (select 20 of healthy Kunming mouses, tail vein injection 0.2ml Uricase lipid nanoparticle, after the administration 1 hour, the administration mice did not have any Deviant Behavior, the nonirritant reaction, mice is movable and diet is unaffected).Uricase lipid nanoparticle does not have blood coagulation, no erythroagglutination (one of white big ear rabbit; Heart extracting blood; Be prepared into 2% red cell suspension in each test tube, add not commensurability reagent liquid and the normal saline of receiving again respectively and do that sample cell, positive control pipe only add normal saline, the positive control pipe only adds deionized water, place in 37 ℃ of calorstats; Whenever observed once at a distance from 20 minutes, observed altogether 6 hours.Each pipe that adds lipid nanoparticle transparent red normal complexion rufous flocky precipitate, the complete hemolysis of positive control pipe all do not occur with the supernatant of negative control pipe).
This patent uses the buffer of meta-alkalescence (pH8～9) to make up the little response system of semipermeability lipid nanoparticle of mediation uricase first; Measure the microenvironment meta-alkalescence of this nanoparticle mediation uricase with fluorescent probe, be different from the microenvironment slant acidity or the neutrality of conventional lipid nanoparticle.The Uricase lipid nanoparticle for preparing can fine reservation uricase activity, non-immunogenicity reduces dosage, improves stability, the lipid nanoparticle that adds long-acting lipid preparation obviously prolongs the half-life in the uroxisome.
Description of drawings:
Fig. 1 under medium pH7.4 condition, the situation of Uricase lipid nanoparticle of the present invention and native enzyme uric acid reducing (uric acid concentration that system begins is 0.60mmol/L).The situation of the Uricase lipid nanoparticle preparation that preparation 1 makes for the present invention (using pH during preparation is boric acid-borate buffer solution of 9) uric acid reducing (uric acid concentration that system begins is 0.60mmol/L); Preparation 2 is the situation of the PBS buffer formulation of natural uricase (pH is 7.4) uric acid reducing (uric acid concentration that system begins is 0.60mmol/L); Preparation 3 is the borate buffer liquid formulation of natural uricase (pH is 9) (the situation assay method of uric acid reducing (uric acid concentration that system begins is 0.60mmol/L): the uric acid PBS (pH is 7.4) that adds 6mL0.60mmol/L in the 60 μ L samples (preparation); Mixing; 37 ℃ of constant-temperature shaking, the different time points sampling.Time point: 0,0.083h, 0.167h, 15min-0.25h, 0.5h, 0.75h, 1h, 2h, 4h, 8h, 12h, 16h, 24h.Measuring the concentration of uric acid, is abscissa with time, and the percent of residue uric acid is the vertical coordinate mapping in the system.)
Fig. 2 is the electromicroscopic photograph of Uricase lipid nanoparticle of the present invention
Fig. 3 is the particle size distribution of Uricase lipid nanoparticle of the present invention
Fig. 4 is the Zeta potential of Uricase lipid nanoparticle of the present invention
Fig. 5 is FITC fluorescent probe standard curve (emission wavelength is 522nm).Record pH and be the fluorescence intensity F of the lipid nanoparticle that boric acid-borate buffer solution of 8.5 makes up
EMRatio (λ 495/409) be 12.76, can know that from FITC fluorescent probe standard curve the Uricase lipid nanoparticle microenvironment that the present invention makes up is about 8.0, is meta-alkalescence.
In order to further specify the present invention and advantage thereof, provided following certain embodiments, should understand these embodiment only has in specifying rather than as the restriction of the scope of the invention.
Embodiment 1:
Prescription: 0.8 part in lecithin, 0.8 part in cholesterol, 0.07 part of DSPE-PEG2000, uricase, bovine serum albumin an amount of (make make content is 0.3U/ml in the preparation, bovine serum albumin 0.05mg/ml), the 50mMTris pH of buffer is 8.Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 10ml ether, and the Rotary Evaporators decompression volatilizes chloroform, adds the 15ml ether; Add the 50mmol/L boric acid-borate buffer solution buffer that contains UC and BSA,, water-bath is ultrasonic is with opalescent dispersion uniformly to forming; Continue reduction vaporization, subsiding to gel when being with opalescent uniform liquid, adds the right amount of boron acid buffer for milky; Continue the decompression rotation; The gained suspension is crossed the microporous filter membrane of 0.22 μ m after 4 ℃ in refrigerator is placed 24 hours, promptly get.
Embodiment 2:
Prescription: 1.5 parts in lecithin, 1 part in cholesterol, 0.05 part of DSPE-PEG5000, uricase, bovine serum albumin an amount of (make make content is 0.2U/ml in the preparation, bovine serum albumin 0.08mg/ml), 10mM boric acid-borate buffer solution (pH is 8.5).Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 20ml chloroform, and the Rotary Evaporators decompression volatilizes chloroform, adds the 30ml ether, adds the 50mmol/L boric acid-borate buffer solution that contains UC and BSA, and all the other are operated with embodiment 1.
Embodiment 3:
Prescription: 2 parts in lecithin, 2 parts in cholesterol, 0.05 part of DSPE-PEG2000, uricase, bovine serum albumin an amount of (make make content is 0.1U/ml in the preparation, bovine serum albumin 0.1mg/ml), 100mMBicine buffer (pH is 9).Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 30ml ether, and the Rotary Evaporators decompression volatilizes, and adds an amount of ether, adds the 100mmol/LBicine buffer that contains UC and BSA, and all the other are operated with embodiment 1.
Embodiment 4:
Prescription: 1 part in lecithin, 1 part in cholesterol, 0.06 part of DSPE-PEG5000, uricase, bovine serum albumin an amount of (make make content is 0.5U/ml in the preparation, bovine serum albumin 0.15mg/ml), 50mMTris buffer (pH is 8.5).Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 50ml chloroform, and the Rotary Evaporators decompression volatilizes chloroform, adds an amount of ether, adds the 50mmol/LTris buffer that contains UC and BSA, and all the other are operated with embodiment 1.
Embodiment 5:
Prescription: 1.2 parts in lecithin, 2.8 parts in cholesterol, 0.05 part of DSPE-PEG2000, uricase, bovine serum albumin an amount of (make make content is 0.8U/ml in the preparation, bovine serum albumin 0.15mg/ml), 50mM boric acid-borate buffer solution (pH is 8.5).Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 50ml chloroform, and the Rotary Evaporators decompression volatilizes chloroform, adds an amount of ether, adds the 50mmol/L boric acid-borate buffer solution that contains UC and BSA, and all the other are operated with embodiment 1.
Embodiment 6:
Prescription: 3 parts in lecithin, 1.5 parts in cholesterol, uricase, bovine serum albumin an amount of (make make content is 1U/ml in the preparation, bovine serum albumin 0.1mg/ml), 30mMBicine buffer (pH is 8.5).Method for preparing is: formula ratio lecithin and cholesterol are dissolved in the 15ml chloroform, and the Rotary Evaporators decompression volatilizes chloroform, adds the 8ml ether, adds the 30mmol/LBicine buffer that contains UC and BSA, and all the other are operated with embodiment 1.
Claims (4)
1. Uricase lipid nanoparticle; It is characterized in that uricase content is 0.1～1U/mL in the preparation; Bovine serum albumin is 0.02～0.15mg/ml, and the used pH of buffer of preparation preparation is 8～9, and ionic strength is 10～100mM; All the other composition weight proportionings are: phospholipid composition is 1～3 part, and cholesterol is 1～3 part.
2. Uricase lipid nanoparticle according to claim 1, it is characterized in that preparing the used buffer of preparation is boric acid-borate buffer solution, Tris buffer, Bicine buffer, and ionic strength is 10～100mM, and the pH value scope is 8～9.
3. Uricase lipid nanoparticle according to claim 1 is characterized in that preparing the used phospholipid of preparation and is one or more of injection lecithin, fabaceous lecithin, the long-acting lipid of polyethylene glycol type.
4. Uricase lipid nanoparticle according to claim 1 is characterized in that: mean diameter is less than 1 μ m, and Zeta potential is less than-20; The microenvironment meta-alkalescence of lipid nanoparticle mediation enzyme; During body fluid pH 7.4, be compared to natural uricase, the catalytic activity of Uricase lipid nanoparticle increases; Half-life prolongs, and immunogenicity descends.
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| CN104013576B (en) * | 2014-06-06 | 2017-03-01 | 重庆医科大学 | Uricase multivesicular liposome and preparation method thereof |
| CN109223707B (en) * | 2018-09-13 | 2020-12-08 | 中国药科大学 | Uricase external gel preparation, preparation method and application thereof |
| CN110075073B (en) * | 2019-06-03 | 2021-09-07 | 深圳市健开医药有限公司 | Cabazitaxel protein nano injection and preparation method thereof |
| CN115444834B (en) * | 2022-09-24 | 2023-07-14 | 重庆医科大学 | Fusion cell membrane coated uricase and superparamagnetism ferric oxide nano enzyme lipid nanoparticle and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864744A (en) * | 2005-05-18 | 2006-11-22 | 杭州北斗生物技术有限公司 | Pharmaceutical preparation containing urate oxidase |
| CN101168052A (en) * | 2007-10-26 | 2008-04-30 | 西安交通大学 | Enteric coated preparation for preventing and treating hyperuricemia and gout |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1864744A (en) * | 2005-05-18 | 2006-11-22 | 杭州北斗生物技术有限公司 | Pharmaceutical preparation containing urate oxidase |
| CN101168052A (en) * | 2007-10-26 | 2008-04-30 | 西安交通大学 | Enteric coated preparation for preventing and treating hyperuricemia and gout |
Non-Patent Citations (2)
| Title |
|---|
| Nishida Y.等."Hypouricemic effect after oral administration in chickens of polyethylene glycol-modified uricase entrapped in liposomes"， Nishida |
| Nishida, Y.等."Hypouricemic effect after oral administration in chickens of polyethylene glycol-modified uricase entrapped in liposomes", Nishida, Y.等,J. Pharm. Pharmacol.,第36卷第5期,第354-355页,1984年.《J. Pharm. Pharmacol.》.1984,第36卷(第5期),第354-355. * |
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