CN101829061A - Taxol nanoparticle composition and preparation method thereof - Google Patents
Taxol nanoparticle composition and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a taxol nanoparticle composition and a preparation method thereof, belonging to the technical field of taxol preparations. The invention relates to taxol nanoparticle composition and nanosuspension, the high drug-loading taxol nanoparticle composition and nanosuspension is prepared by taking a surface stabilizer as a carrier, wherein the effective average particle size of the composition is less than 1000 nm; the suspension is subjected to freeze drying or spray drying to obtain the taxol nanoparticle preparation which can be intravenously injected or taken orally. The method of the invention is reliable, easy to operate and low in energy consumption, and avoids interference of organic solvent; meanwhile, the obtained taxol nanoparticle composition has higher bioactivity and can give full play to the curative effect of taxol.
Description
Technical field
The present invention relates to the preparation method of taxol nanoparticle or nanometer suspension liquid; described Nanoparticulate compositions contains paclitaxel and preferred at least a surface stabilizer; have the following effectively mean diameter of 1000nm, the present invention also comprises the method for preparing Nanoparticulate compositions.Belong to technical field of taxol preparations.
Background technology
Paclitaxel (Paclitaxel, trade name Taxol) is the tetracyclic diterpene compounds with active anticancer that extraction separation comes out from Chinese yew genus plants, and its molecular formula is C
47H
51NO
14, molecular weight is 853.9.On December 29th, 1992, and food and drug administration (FDA) approval paclitaxel (trade name taxol) new drug listing is used for the treatment of the invalid ovarian cancer of other anticarcinogens, and this medicine ratified to be used for the treatment of advanced breast cancer again in 1994.Nineteen ninety-five partially synthetic taxinane one Docetaxel (taxotere) goes through to go on the market in Mexico.More than 40 state approvals such as existing so far Britain, France, Japan, Italy, Canada, Germany are used for clinical treatment with paclitaxel.At present paclitaxel is except multiple malignant tumor such as mainly for treating mammary gland cancer, ovarian cancer, nonsmall-cell lung cancer (NSCLC), card ripple network sarcoma clinically and solid tumor, its clinical indication also expands tens kinds of cancers such as uterus carcinoma, pulmonary carcinoma, the esophageal carcinoma, carcinoma of prostate and rectal cancer to, be considered to the human so far the most effective cancer therapy drug of finding, the good reputation of " king of antitumor " is therefore in the industry cycle arranged.
Paclitaxel is injection and venous transfusion as the main dosage form of anticarcinogen.Because traditional taxanes injection in use needs polyoxyethylene castor oil just can inject as solvent, and the anaphylaxis in order to prevent solvent to bring, needs of patients carries out prophylactic before chemotherapy, use medicines such as anti-resistance amine and dexamethasone; In order to increase its curative effect to ovarian cancer, alleviate its untoward reaction, company of U.S. Ah Bolisi life sciences (American Bioscience) has developed albumin bound paclitaxel nano grain injection suspension (paclitaxel, Abraxane), obtain drugs approved by FDA listing, be applicable to the breast carcinoma of recurrence in the metastatic breast cancer of treatment combined chemotherapy failure or the adjuvant chemotherapy 6 months.The data of clinical research show: patient's curative effect of accepting the treatment of this product is to contain 2 times of polyoxyethylene castor oil solvent formulation for paclitaxel, and the orientable tumor cell that is released into improves the curative effect of medicine.Do not use antihistamine drug before the chemotherapy, all patients all finish intravenous drip in 30min, and maximum tolerated dose is 300mg/m
2, per 3 weeks are administered once.Anaphylaxis do not occur in quiet process, the blood system untoward reaction is light and do not have a cumulative bad.Abraxane injection paclitaxel (albumin bound type) utilizes the nanoparticle albumin bound technology of innovation, makes the paclitaxel mesenchyma stroma of tumors that goes directly.This technology combines paclitaxel and albumin (natural protein), so just need not to have used the polyoxyethylene castor oil solvent in medicine.Abraxane injection paclitaxel (albumin bound type) is a kind of novel chemotherapeutics.By utilizing the biomechanism of tumor uptake nutrition, nanoparticle albumin bound technology platform more multiple medicines thing is sent to tumor locus.So for the metastatic breast cancer patient, Abraxane injection paclitaxel (albumin bound type) is a kind ofly not only efficiently but also easily to select.
Albumin nanometer paclitaxel is compared with traditional paclitaxel injection has very big advantage, and that need not to use the oxireme Oleum Ricini exactly, has reduced its toxic and side effects widely.Yet it also has some shortcomings:
(1) need the organic solvent dichloromethane of using toxicity bigger in the production process, though the dichloromethane boiling point is low volatile, always have unavoidably in the medicine residual, thereby cause the toxicity of medicine to increase;
(2) because of dichloromethane belongs to carcinogen, the volatilization of dichloromethane causes environmental pollution in the production procedure;
(3) complex manufacturing, the cost height.
Therefore, in this area, need such paclitaxel nano preparation, can overcome the shortcoming of albumin nanometer paclitaxel, and with traditional paclitaxel injection relatively, have following advantage: 1, improve drug solubility and dissolution rate; 2, make mucous membrane tissue that good adhesiveness be arranged; 3, drug loading height can reduce the administration volume, increases biological safety; 4, can improve the stability of pharmaceutical preparation; 5, can realize target administration; 6, technology is simple, is applicable to large-scale production.
Summary of the invention
The object of the present invention is to provide a kind of taxol nanoparticle composition and nanometer suspension liquid.Said composition comprises paclitaxel and at least a and bonded surface stabilizer in paclitaxel raw material surface.Chemical reaction does not take place with paclitaxel or himself in the surface stabilizer that the present invention uses, and each molecule of surface stabilizer is substantially free of intermolecular cross-linking.Taxol nanometer particle has the effective mean diameter less than 1000nm.
Another object of the present invention provides the pharmaceutical composition that contains taxol nanoparticle composition of the present invention.This pharmaceutical composition preferably contains paclitaxel, at least a surface stabilizer, with one or more nontoxic physiology acceptable carriers, auxiliary agent or excipient, compositions can be mixed with the dosage form that is used for parenteral injection (for example intravenous, intramuscular or subcutaneous), the solid of oral administration, liquid dosage form, or aerosol, form of administration, intraperitoneal form of administration etc. in pulmonary administration dosage form, nose administration dosage form, rectally dosage form, ocular administration dosage form, sheath inner injecting medicine-feeding dosage form, topical dosage form (powder, unguentum or drop), cheek form of administration, the pond.
Taxol nanoparticle composition provided by the invention or nanometer suspension liquid, than the paclitaxel injection of traditional form, described compositions has good mucosal tissue adhesion, stability, the advantage that drug loading height and bioavailability are high.
The invention also discloses the method for preparing taxol nanoparticle composition.Such method comprises paclitaxel raw material and at least a surface stabilizer is contacted certain hour being enough to provide under the condition of nanoscale paclitaxel compositions.Before these one or more surface stabilizers can reduce in the size of paclitaxel, reduce in the process or contact with paclitaxel after reducing.
Technical scheme of the present invention: a kind of taxol nanoparticle composition, contain following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer.
Described a kind of taxol nanoparticle composition, also contain following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer;
(c) one or more additives: pharmaceutical excipient, carrier, buffer, salt, polyhydric alcohol, osmotic pressure regulator, antifreeze or its combination.
Described a kind of taxol nanoparticle composition, also contain following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer;
(c) one or more additives: pharmaceutical excipient, carrier, buffer, salt, polyhydric alcohol, osmotic pressure regulator, antifreeze or its combination;
(d) also contain at least a non-paclitaxel activating agent.
Described taxol nanoparticle composition, wherein:
(a) paclitaxel is present in the compositions with following weight: 99.8%-0.001%;
(b) at least a surface stabilizer is present in the compositions with following weight: 0.2%-99.999%.
Described taxol nanoparticle composition, wherein said surface stabilizer are selected from non-ionic surface stabilizing agent, anionic surface stabilizing agent, cationic surface stabilizing agent or amphion surface stabilizer.
Described taxol nanoparticle composition, wherein at least a surface stabilizer is selected from poloxamer; tyloxapol; tween 80; sodium laurylsulfate; spermol sodium sulfate; stearyl alcohol sodium sulfate; polyvidone; lecithin; arabic gum; gelatin; polyvinyl alcohol; hydroxypropyl cellulose; hydroxypropyl emthylcellulose; methylcellulose; hydroxyethyl-cellulose; cholic acid; deoxycholic acid; polyvinylpyrrolidone; carbopol; potassium oleate; enuatrol; triethanolamine oleate; sucrose ester; carboxymethyl cellulose; Polyethylene Glycol; trehalose; quaternized thing; benzalkonium chloride; acrylamide; organic amine soap; alkaling earth metal base; the aliphatic sulfonic thing; the alkyl aryl sulphonic acid thing; dodecyl sodium sulfate; docusate sodium; dodecylbenzene sodium sulfonate; the dioctyl sodium sulfosuccinate; dioctyl sodium sulfosuccinate; the dihexyl sodium sulfosuccinate; sodium glycocholate; the taurine sodium cholate; glyceryl monostearate; the monostearate propylene diester; distearyl acid second diester; sucrose fatty acid ester; the fatty acid Pyrusussuriensis is smooth; Polysorbate; polyoxyethylene fatty acid ester; polyoxyethylene aliphatic alcohol ether; polyoxyethylene laurate; polyoxy acetic acid monoleate; polyoxyethylene alkylphenol; polyoxyethylene nonyl 2, 2-Oxydiphenol; the Atlas; the polymethyl methacrylate trimethylammonium bromide; polyvinyl pyrrolidone-2-dimethyl amino ethyl methacrylate dimethyl disulfide acid esters; cetab.
Described taxol nanoparticle composition, wherein to be present in the amount in the compositions be 30%-90% to paclitaxel.
Described taxol nanoparticle composition, wherein said non-paclitaxel activating agent is selected from aminoacid, glucose, normal saline, neurotrophic agents, albumen, peptide, nucleotide, the obesity medicine, nutriment, dietary supplement, central nervous system's stimulant, carotenoid, antihistaminic, corticosteroid medication, elastase inhibitor, antifungal, antitumor agent, alkyl-yellow purine, tumor therapeutic agent, the resisting emesis agent, Claritin, antuepileptic, analgesics, opioid, antipyretic, the cardiovascular treatment agent, antiinflammatory, anthelmintic, anti-arrhythmic agents, antibiotic, antidiabetic, hydryllin, hypotensive agent, muscarine antagonist agent, immunosuppressant, blood products, H
2Receptor blocking agent, diuretic, anti-alopecia medicine.
Described taxol nanoparticle composition, wherein the particulate effective mean diameter of paclitaxel crystallinity is 50nm-1000nm.
The preparation method of described taxol nanoparticle composition, with the pick pearl, high-crosslinking-degree poly styrene polymer resin or glass particle are abrasive media, adopt the wet lapping legal system to be equipped with taxol nanoparticle composition.
1, paclitaxel raw material
Paclitaxel (paclitaxel) is to extract the diterpene-kind compound that obtains from the bark of taxaceae Taxus (Taxus) plant.Be that understood at present only a kind of can promote microtubule polymerization and the stable medicine of polymerization microtubule.Isotopic tracing shows that paclitaxel only is attached on the polymeric microtubule, not with unpolymerized tubulin dimer reaction.Can accumulate a large amount of microtubules in cell behind the cells contacting paclitaxel, the various functions of cell have been disturbed in the accumulation of these microtubules, particularly make cell division stop at mitotic phase, have blocked the proper splitting of cell.Paclitaxel has also become a kind of new standard treatment of ovarian cancer first-line treatment with the network platinum medicine.Effect advanced breast cancer second line treatment is first indication that paclitaxel obtains.It is remarkable that paclitaxel adds the effect of present standard chemotherapy Drug therapy breast carcinoma of early stage, is used for the second line treatment of Her-2 overexpression metastatic breast cancer one line medicine and metastatic breast cancer.Shown clinical characters and got permission the indication through confirming except that above-mentioned, paclitaxel now also carrying out its single with and share other antitumor drug and treat cancers such as breast carcinoma, nonsmall-cell lung cancer, small cell lung cancer, the esophageal carcinoma, bladder cancer, tumor of head and neck, cervical cancer and gastric cancer.
2, surfactant
Can use the combination of more than one surface stabilizers in the present invention.Preferred surface stabilizer includes but not limited to hydroxypropyl emthylcellulose, hydroxypropyl cellulose, the random copolymer of polyvinylpyrrolidone, vinyl pyrrolidone and vinylacetate, sodium lauryl sulphate, dioctylsulfosuccinat or its combination.
Can be used for other surface stabilizers of the present invention and comprise nonionic, cationic, anionic and amphoteric ionic surfactant.
The representative example of surface stabilizer also comprises sodium lauryl sulphate, dioctylsulfosuccinat, casein, glucosan, cholesterol, tragacanth gum, stearic acid, calcium stearate, cetostearyl alcohol, cetomacrogol emulsifying wax, Isosorbide Dinitrate, polyethylene oxide alkyl ethers, polyoxyethylene castor oil derivant, polyethylene glycol oxide fatty acid esters of sorbitan; Polyethylene glycol oxide stearate, Hydroxypropyl Methylcellulose Phathalate, noncrystalline cellulose, Magnesiumaluminumsilicate, triethanolamine, sodium cholate, NaTDC, biopolymer, compound of polysaccharide, cellulose, alginate.
3, other medicines excipient
Taxol nanoparticle composition of the present invention can also contain one or more binding agents, filler, lubricant, suspending agent, sweeting agent, flavoring agent, antiseptic, buffer agent, wetting agent, disintegrating agent, effervescent and other excipient.These excipient are known in the art.
Filler comprises lactose, starch; Binding agent comprises polyvinylpyrrolidone, microcrystalline Cellulose; Lubricant comprises stearic acid, magnesium stearate, calcium stearate; Sweeting agent comprises sucrose, xylitol, saccharin sodium; Antiseptic comprises potassium sorbate, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, benzoic acid and salt thereof, other ester of P-hydroxybenzoic acid, butyl p-hydroxybenzoate for example, alcohol is ethanol or benzyl alcohol for example, phenolic compound such as phenol, and quaternary ammonium compound such as benzalkonium chloride; Diluent comprises pharmaceutically useful inert filler, for example microcrystalline Cellulose, lactose, calcium hydrogen phosphate, mannitol, starch, sorbitol, the mixture of saccharide such as sucrose and glucose and/or above-mentioned any material; Disintegrating agent comprises lightly crosslinked polyvinylpyrrolidone, cereal starch, potato starch, corn starch and modified starch, crosslinked sodium carboxymethyl cellulose, crosslinked polyvinylpyrrolidone; Effervescent such as organic acid and carbonate or bicarbonate.Synthetic organic acid comprises citric acid, tartaric acid, malic acid, fumaric acid, adipic acid, succinic acid and alginic acid and anhydride and acid salt.Suitable carbonate and bicarbonate comprise for example sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, magnesium carbonate, sodium glycine carbonate, L-lysine carbonate and arginine carbonate.
Except that above-mentioned required adjuvant; make solid preparation as need; paclitaxel nano suspension by grinding, wet lapping, high pressure homogenization method, emulsion process, microemulsion method or its combined preparation to be used freeze drying protectant glucose, lactose, mannitol, sucrose, trehalose frozen drying or spray drying, improve stability.Freeze drying protectant can be wherein a kind of or any combination.
4, taxol nanoparticle composition or nanometer suspension liquid and surface-stable agent concentration
Paclitaxel purity can be 99.8%-0.001%, 99.5%-0.01%, 99%-0.05%, 95%-0.1% or 90%-0.5%, based on the gross combination weight meter of paclitaxel that does not comprise other additives and at least a surface stabilizer.
The weight 0.2%-99.999% of at least a surface stabilizer, 0.5%-99.99%, 1%-99.95%, 5%-99.9% or 10%-99.5% are based on the gross combination weight meter of paclitaxel that does not comprise other additives and at least a surface stabilizer.
5, preparation taxol nanoparticle composition and nanometer suspension liquid method
5.1 wet grinding
This method needs special media mill machine, is to be made up of grinding house, mill bar and a recirculation chamber.The medium of milling, water, medicine and corresponding above-mentioned described surface stabilizer are housed in the grinding house.The mill high speed shear motion of bar makes between the drug particle and with the medium of milling, grinding house's inwall fierce collision takes place, and obtains nano level drug particle thereby pulverize.The mixture that obtains separates by filter screen, and mill medium and bulky grain medicine are trapped in the grinding house, and the small-particle medicine then enters recirculation chamber.Recirculation chamber Chinese medicine particle diameter then can directly take out as reaching requirement, and remaining carries out a new round and mills.The medium of milling is generally glass particle, Zirconium oxide powder or high-crosslinking-degree polystyrene resin.This method can be in 20～120min be milled into medicine the particle of particle diameter less than 1000nm.Concrete steps are as follows:
(1) one or more surface stabilizers are dissolved in the distilled water as disperse medium with above-mentioned described weight portion, solution A;
The mass content that institute's adding distil water amount is controlled at the total composition that makes paclitaxel and at least a surface stabilizer is 2.5%-10%.
(2) paclitaxel is scattered in the water disperse medium that step (1) makes with above-mentioned described weight portion, suspension B.
(3) suspension B is joined in the ball mill, beginning 10min aerofluxus rotating speed 1500rpm, grinding rate is increased to 3000-5000rpm behind the 10min, 4 ℃ in circulating condensing water, zirconium pearl 50mL, the volume that is used for the suspension B of wet grinding is 1.6-10 a times of zirconium pearl volume, wet grinding 20-120 minute, obtains the paclitaxel nano suspension.
(4) make solid preparation as need, after freezing or spray drying treatment, the granule that obtains is prepared by the conventional method that adds additives and oral or local topical preparation.
5.2 high pressure homogenization method
Earlier the paclitaxel micronization is made suspension, then under the effect of high pressure homogenization machine high-pressure pump by force at a high speed by the slit of homogenize valve, make nano suspension.This law can be finished in a step, also can finish in two steps, and promptly through two placed in-line homogenize valves, the pressure of first homogenize valve falls bigger, mainly plays a part to disperse suspensoid, and the pressure of second homogenize valve is reduced to first, to improve the stability of nanometer suspension liquid.This law also is suitable for preparing the aseptic nano suspension of injection except that the advantage that possesses the medium wet grinding.But must in advance drug micronization be made the microgranule that particle diameter is not more than 25 μ m.
5.3 emulsion process
Emulsion process is paclitaxel to be dissolved in make o/w type Emulsion in the anhydrous ethanol solvent, medicine in the emulsion droplet inner phase becomes nanometer particle, make organic solvent volatilization by modes such as decompressions again, paclitaxel is separated out the formation nano suspension, by ultracentrifugation separate nano-grade medicine or concentrate.Therefore, the size by the control emulsion droplet is with regard to the particle diameter of scalable medicine.Organic solvent is generally selected ethyl acetate, methyl acetate, dehydrated alcohol, chloroform, acetone etc. for use.
5.4 microemulsion method
The microemulsion method is to select for use the organic solvent such as butyl lactate, the glyceryl triacetate etc. that dissolve each other with water section to prepare Emulsion as inner phase, dilute with water then, make the organic solvent of inner phase medicine be separated out, isolate the nanoparticle or the concentrated nano suspension that obtains of medicine then by ultracentrifugation by water dissolution.Can be by the size control diameter of aspirin particle of control emulsion droplet; Do not need special equipment and instrument; Preparation process is simpler, easily prepared in batches.Shortcoming be unsuitable for both water insoluble, also be insoluble to the medicine of organic solvent; Must consider organic solvent residue and safety issue.
6, dosage form of the present invention
Taxol nanoparticle composition of the present invention can be via any conventional route to individual administration.Include but not limited to oral, rectally, parenteral (for example intravenous, intramuscular or subcutaneous), with solid, liquid or aerosol form oral administration, percutaneous dosing, nose administration, rectally, the ear administration, dosing eyes, pulmonary's inhalation, topical, the cheek administration, administration in the pond, intraperitoneal administration; Intravenous administration, sheath inner injecting medicine-feeding.Term used herein " individuality " is meant animal, and preferred mammal comprises the mankind or non-human animal.Term patient and individuality can be used alternatingly.
In addition, taxol nanoparticle composition of the present invention or suspension can be formulated into any suitable dosage form: injection, dispersant, tablet, liposome, gel, sachets, solution, unguentum, aerosol, capsule, cream and composition thereof; Slow releasing preparation, pulmonary's targeting preparation, controlled release preparation, oral fast solubility preparation, lyophilized formulations, delayed release preparation, prolongation delivery formulations, transdermal absorption formulation, pulsation-releasing preparation and blended rapid release and controlled release preparation.
The taxol nanoparticle composition that is suitable for the parenteral injection can comprise the acceptable sterilized water of physiology or non-aqueous solution, dispersion, suspension or Emulsion, and the sterile powder that is used for being mixed with again sterile injectable solution or dispersion.The example of suitable water and nonaqueous carrier, diluent, solvent or excipient comprises for example ethyl oleate of water, ethanol, polyhydric alcohol (propylene glycol, Polyethylene Glycol, glycerol etc.), other suitable mixture, vegetable oil (for example olive oil) and injectable ester.Can keep suitable flowability by for example following means: use coating such as lecithin, keep required particle diameter, and use surfactant for dispersion.
Taxol nanoparticle composition can also contain auxiliary agent for example antiseptic, wetting agent, emulsifying agent and dispersant.Can for example p-Hydroxybenzoate, methaform, phenol, sorbic acid wait and prevent microbial growth by various antibacterial and antifungal.Also might wish to comprise isotonic agent, sodium chloride etc.The prolongation of injectable drug dosage form absorbs and can postpone releasing agent for example aluminum monostearate and gelatin are realized by using.
The solid dosage forms that is used for oral administration includes but not limited to capsule, tablet, pill, micropowder agent and granule, in such solid dosage forms, activating agent is mixed with at least a following component: (a) one or more inert excipients (or carrier), for example sodium citrate or dicalcium phosphate; (b) filler or extender, for example sugar, lactose, sucrose, glucose, mannitol and silicic acid; (c) binding agent, for example starch slurry, methylcellulose, hydroxypropyl cellulose, ethyl cellulose, carboxymethyl cellulose, polyvidone, Polyethylene Glycol, alginate, gelatin, polyvinylpyrrolidone, sucrose and arabic gum; (d) humidizer, for example glycerol; (e) disintegrating agent, for example dried starch, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, cross-linking sodium carboxymethyl cellulose, polyvinylpolypyrrolidone, agar, calcium carbonate, Rhizoma Solani tuber osi or tapioca, alginic acid, some composition silicate and sodium carbonate; (f) dissolving blocker, paraffin for example, (g) absorption enhancer, for example quaternary ammonium compound; (h) wetting agent, for example hexadecanol and glyceryl monostearate; (i) adsorbent, for example Kaolin and bentonite; (j) lubricant, for example Pulvis Talci, calcium stearate, magnesium stearate, sodium laurylsulfate, magnesium laurylsulfate, solid polyethylene glycol, sodium lauryl sulphate or its mixture; (k) diluent, for example starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol, sorbitol.For capsule, tablet and pill, also can contain buffer agent in the dosage form.
The liquid nanometer paclitaxel dosage form that is used for oral administration comprises pharmaceutical acceptable emulsion, solution, suspension, syrup.Except paclitaxel, liquid dosage form can contain this area inert diluent commonly used, for example water or other solvents, solubilizing agent and emulsifying agent.The example of emulsifying agent has ethanol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 one butanediol, dimethyl formamide, oil be Oleum Gossypii semen, Oleum Arachidis hypogaeae semen, maize embryo oil, olive oil, Oleum Ricini and Oleum sesami for example, glycerol, tetrahydrofurfuryl carbinol, Polyethylene Glycol, the fatty acid ester of anhydro sorbitol, or the mixture of these materials etc.
Except inert diluent, compositions can also comprise auxiliary agent for example wetting agent, emulsifying agent and suspending agent, sweeting agent, correctives and aromatic.
7, taxol nanoparticle composition effective dose
The invention provides in individuality and in individuality, reach effective taxol nanoparticle of treatment or suspension dosage with the dosage that is lower than the standard available preparation.According to selected paclitaxel concentration, administration volume or quality that this tolerable is less.Such method comprises the taxol nanoparticle composition to the Orally administered effective dose of individuality.
The treatment effective dose of wherein preferred paclitaxel be selected from the standard paclitaxel injection the treatment effective dose 1/8,1/6,1/5,1/4,1/3 or 1/2.
" treatment effective dose " that this paper uses aspect drug dose is meant such dosage, drug administration in a large amount of individualities of the such treatment of needs, and this dosage provides specific pharmacological reaction.It is emphasized that." the treatment effective dose " that be administered to particular individual under specific circumstances always can not treat disease described herein effectively, even such dosage is thought " treatment effective dose " by those skilled in the art.It is also understood that under specific circumstances.Drug dose is measured as oral dose, or with reference to the levels of drugs as in blood, measuring.
The effective dose that it will be appreciated by those skilled in the art that paclitaxel can determine by rule of thumb, and can be with pure form, perhaps if present, adopts with the form of officinal salt, ester or prodrug.For particular composition and medication, the actual dose level that can change paclitaxel in the taxol nanoparticle composition of the present invention can realize the amount of the paclitaxel of required therapeutic response with acquisition.Therefore, selected dosage level depend on required therapeutical effect, route of administration, effectiveness, required treatment persistent period and other factors of the paclitaxel used.
Dosage unit compositions can contain the secondary multiple dose of such amount, to be used for constituting daily dose.Yet should be clear, for any specific patient, concrete dosage level will depend on multiple factor: the cell that reach or the type of physiological reaction and degree; The concrete medicine that uses or the activity of compositions; Concrete medicine or the compositions used; Patient's age, body weight, general health situation, sex and diet; The drainage rate of administration time, route of administration and medicine; The persistent period of treatment; With associating of concrete medicament or the medicine that uses simultaneously; And well-known similar factor in the medical domain.
Description of drawings
Fig. 1 nano-paclitaxel aqueous dispersions stability.
Fig. 2 wet grinding 20min particle diameter cartogram.
Fig. 3 wet grinding 20min particle size distribution figure.
Fig. 4 wet grinding 30min particle diameter cartogram.
Fig. 5 wet grinding 30min particle size distribution figure.
The specific embodiment
The purpose of present embodiment is to prepare the taxol nanoparticle composition injection with various surface stabilizers.
The 2g paclitaxel is mixed with the following at least a kind of surface stabilizer of 1.25g: the husky nurse of safe pool, poloxamer 188, tween 80, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone-K30, sodium lauryl sulphate, PEG400, NaTDC, lecithin.
Each combination for paclitaxel and surface stabilizer, at first the 1.25g surface stabilizer is dissolved in the 96.75g water for injection, add the 2g paclitaxel then, ultra-sonic dispersion is even, in ball mill, add 50mL zirconium pearl, under the 1500rpm rotating speed, the circulating condensing coolant-temperature gage is controlled at 4 ℃, adds paclitaxel and surface stabilizer mixed solution while stirring, behind the degassing 10min, increase rotating speed to 4000rpm, wet grinding 30min obtains milky paclitaxel suspension altogether, wherein 0.75g poloxamer 188 and 0.5g tween 80 use in conjunction effect are best, mean diameter 444.2nm wherein 93.305% is distributed in 330.9nm-591nm, and drug loading can reach 60%.Wet grinding 20min mean diameter is 538nm, wherein 93.03% is distributed in 417.3nm-663.8nm.
With the 2g paclitaxel is identical amount, with the consumption of different surface stabilizer combination, is that index is investigated three kinds of dispersion liquids 4 ℃ stability with the particle diameter.Sample 1 is 0.9g poloxamer 188 and the combination of 0.6g tween 80, and sample 2 is 0.25g poloxamer 188 and the combination of 0.5g tween 80, and sample 3 is 0.75g poloxamer 188 and the combination of 0.5g tween 80.Experimental result shows that microgranule is highly stable in aqueous dispersions, the results are shown in Figure 1.Add 1% mannitol in this suspension, lyophilization 48h on LABCONCO Freezone2.5 freezer dryer obtains white loose lyophilized powder, after the distilled water dispersion, drug solution stability and redispersibility are good, and mean diameter is 486nm, and drug loading can reach 50%.Be applicable to intravenous injection.The setting of nanometer wet grinding parameter sees Table 1.Wet grinding 20min and 30min particle size determination, cartogram and particle size distribution are seen Fig. 2, Fig. 3, Fig. 4 and Fig. 5.The concrete particle diameter statistical data of wet grinding 20min and 30min sees Table 2, table 3.
Table 1 nanometer wet grinding parameter
The concrete distributed data of table 2 wet grinding 20min particle diameter
| Size (nm) | Average (%) |
| ??371.6 | ??1.24 |
| ??417.3 | ??10.44 |
| ??468.6 | ??25.79 |
| ??526.3 | ??27.92 |
| ??591 | ??17.87 |
| ??663.8 | ??11.01 |
| ??745.4 | ??5.10 |
| ??837.1 | ??0.63 |
The concrete distributed data of table 3 wet grinding 30min particle diameter
| Size (nm) | Average (%) |
| ??294.6 | ??4.31 |
| ??330.9 | ??12.03 |
| ??371.6 | ??14.72 |
| ??417.3 | ??18.45 |
| ??468.6 | ??23.82 |
| Size (nm) | Average (%) |
| ??526.3 | ??17.66 |
| ??591 | ??6.63 |
| ??663.8 | ??1.86 |
| ??745.4 | ??0.52 |
Embodiment 2
The purpose of present embodiment is to prepare the taxol nanoparticle composition oral formulations with various surface stabilizers
2g hydroxymethyl-propyl cellulose and 1g poloxamer 188 are dissolved in the 92g water for injection, be mixed with solution, add the 5g paclitaxel then, said mixture solution ultra-sonic dispersion is even, in ball mill, add 50mL zirconium pearl, under the 1500rpm rotating speed, the circulating condensing coolant-temperature gage is controlled at 4 ℃, adds paclitaxel and surface stabilizer mixed solution while stirring, behind the degassing 10min, increase rotating speed to 4000rpm, wet grinding 30min obtains milky paclitaxel suspension, frozen drying obtains the white solid granule then, cross 80 mesh sieves,, add the appropriate amount of starch slurry and make soft material granule and the appropriate amount of starch mixing that obtains, after the granulation of 14 mesh sieves, put 70 ℃-80 ℃ dry backs in 12 mesh sieve granulate, behind adding dried starch and the magnesium stearate mixing, tabletting promptly.
Claims (10)
1. taxol nanoparticle composition is characterized in that containing following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer.
2. taxol nanoparticle composition is characterized in that containing following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer;
(c) one or more additives: pharmaceutical excipient, carrier, buffer, salt, polyhydric alcohol, osmotic pressure regulator, antifreeze or its combination.
3. taxol nanoparticle composition is characterized in that containing following component:
(a) has taxol nanoparticle less than effective mean diameter of 1000nm;
(b) at least a surface stabilizer;
(c) one or more additives: pharmaceutical excipient, carrier, buffer, salt, polyhydric alcohol, osmotic pressure regulator, antifreeze or its combination;
(d) also contain at least a non-paclitaxel activating agent.
4. according to each taxol nanoparticle composition among the claim 1-3, it is characterized in that wherein:
(a) paclitaxel is present in the compositions with following weight: 99.8%-0.001%;
(b) at least a surface stabilizer is present in the compositions with following weight: 0.2%-99.999%.
5. according to each taxol nanoparticle composition among the claim 1-3, it is characterized in that wherein said surface stabilizer is selected from non-ionic surface stabilizing agent, anionic surface stabilizing agent, cationic surface stabilizing agent or amphion surface stabilizer.
6. according to each taxol nanoparticle composition among the claim 1-5, it is characterized in that wherein at least a surface stabilizer is selected from poloxamer; tyloxapol; tween 80; sodium laurylsulfate; spermol sodium sulfate; stearyl alcohol sodium sulfate; polyvidone; lecithin; arabic gum; gelatin; polyvinyl alcohol; hydroxypropyl cellulose; hydroxypropyl emthylcellulose; methylcellulose; hydroxyethyl-cellulose; cholic acid; deoxycholic acid; polyvinylpyrrolidone; carbopol; potassium oleate; enuatrol; triethanolamine oleate; sucrose ester; carboxymethyl cellulose; Polyethylene Glycol; trehalose; quaternized thing; benzalkonium chloride; acrylamide; organic amine soap; alkaling earth metal base; the aliphatic sulfonic thing; the alkyl aryl sulphonic acid thing; dodecyl sodium sulfate; docusate sodium; dodecylbenzene sodium sulfonate; the dioctyl sodium sulfosuccinate; dioctyl sodium sulfosuccinate; the dihexyl sodium sulfosuccinate; sodium glycocholate; the taurine sodium cholate; glyceryl monostearate; the monostearate propylene diester; distearyl acid second diester; sucrose fatty acid ester; the fatty acid Pyrusussuriensis is smooth; Polysorbate; polyoxyethylene fatty acid ester; polyoxyethylene aliphatic alcohol ether; polyoxyethylene laurate; polyoxy acetic acid monoleate; polyoxyethylene alkylphenol; polyoxyethylene nonyl 2, 2-Oxydiphenol; the Atlas; the polymethyl methacrylate trimethylammonium bromide; polyvinyl pyrrolidone-2-dimethyl amino ethyl methacrylate dimethyl disulfide acid esters; cetab.
7. according to each taxol nanoparticle composition among the claim 1-6, it is characterized in that the amount that paclitaxel wherein is present in the compositions is 30%-90%.
8. taxol nanoparticle composition according to claim 3 is characterized in that wherein said non-paclitaxel activating agent is selected from aminoacid, glucose, normal saline, neurotrophic agents, albumen, peptide, nucleotide, the obesity medicine, nutriment, dietary supplement, central nervous system's stimulant, carotenoid, antihistaminic, corticosteroid medication, elastase inhibitor, antifungal, antitumor agent, alkyl-yellow purine, tumor therapeutic agent, resisting emesis agent, Claritin, antuepileptic, analgesics, opioid, antipyretic, cardiovascular treatment agent, antiinflammatory, anthelmintic, anti-arrhythmic agents, antibiotic, antidiabetic, hydryllin, hypotensive agent, the muscarine antagonist agent, immunosuppressant, blood products, the H2 receptor blocking agent, diuretic, anti-alopecia medicine.
9. according to each taxol nanoparticle composition among the claim 1-8, it is characterized in that wherein the particulate effective mean diameter of paclitaxel crystallinity is 50nm-1000nm.
10. the preparation method of each described taxol nanoparticle composition among the claim 1-3, it is characterized in that with the pick pearl, high-crosslinking-degree poly styrene polymer resin or glass particle are abrasive media, adopt the wet lapping legal system to be equipped with taxol nanoparticle composition.
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| CN103476801A (en) * | 2011-02-02 | 2013-12-25 | 安大略省癌症研究所 | Cellulose-based nanoparticles for drug delivery |
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Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| CN1463969A (en) * | 2002-06-24 | 2003-12-31 | 成都思摩纳米技术有限公司 | Process for the manufacture of pacilitaxel nano granule |
| CN1883266A (en) * | 2006-07-05 | 2006-12-27 | 江苏省血吸虫病防治研究所 | A snail-killing medicine-nano suspension concentrate of niclosamide ethanolamine and method for preparing same |
-
2010
- 2010-05-14 CN CN 201010177980 patent/CN101829061A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030054042A1 (en) * | 2001-09-14 | 2003-03-20 | Elaine Liversidge | Stabilization of chemical compounds using nanoparticulate formulations |
| CN1463969A (en) * | 2002-06-24 | 2003-12-31 | 成都思摩纳米技术有限公司 | Process for the manufacture of pacilitaxel nano granule |
| CN1883266A (en) * | 2006-07-05 | 2006-12-27 | 江苏省血吸虫病防治研究所 | A snail-killing medicine-nano suspension concentrate of niclosamide ethanolamine and method for preparing same |
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