CN1868455A - Intravenous nanometer suspension injection contg. oxaliplatin platinum phospholipid compound - Google Patents
Intravenous nanometer suspension injection contg. oxaliplatin platinum phospholipid compound Download PDFInfo
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- CN1868455A CN1868455A CNA2006100843578A CN200610084357A CN1868455A CN 1868455 A CN1868455 A CN 1868455A CN A2006100843578 A CNA2006100843578 A CN A2006100843578A CN 200610084357 A CN200610084357 A CN 200610084357A CN 1868455 A CN1868455 A CN 1868455A
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Abstract
A nano-class suspension injection of oxaliplatin-phoshpatide composition for intravenous injection is proportionally prepared from oxaliplatin, surfactant, pH regulator, isotonic agent, antioxidant, water for injection, and optional excipient (for the freeze-dried powder injection).
Description
Technical field:
The present invention relates to a kind of platinum complex series antineoplastic medicament preparation and preparation method thereof, exactly is the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable.
Background technology:
Oxaliplatin (oxaliplatin) be a kind of by Y.Kidani in 1978, the optical isomer of preparation from the mixture (dach-platinum) of diamino-cyclohexane derivant, i.e. (1R-is trans)-(1,2-ring: hexamethylene diamine-N, N ') [oxalic acid (2-)-O, O '] closes platinum.Be a kind of antineoplastic agent that suppresses cell, it is used as the polytype tumor treatment, and tumor particularly those colons, ovary, upper respiratory tract, and epidermoid tumor and germinal cell tumor.
Oxaliplatin (oxaliplatin)
Oxaliplatin is insoluble in aqueous carrier and the most organic solvent, and its clinical practice is greatly limited.
Oxaliplatin is insoluble in water, makes its clinical application volume bigger.At present, the oxaliplatin formulations of clinical practice has lyophilized preparation and two kinds of forms of injection.Lyophilized preparation has 50mg and two specifications of 100mg; Injection has 50mg:10ml and two specifications of 100mg:20ml.Oxaliplatin single therapy scheme clinically is: oxaliplatin 130mg/m
2, with 5% glucose solution 500ml dilution, vein input administration.By Chinese's average body surface area 1.7m
2Calculate, each about 220mg of dosage is equivalent to administration volume 44ml.
Oxaliplatin is insoluble to organic solvent and oils, hinders it by the parcel of known method in Emulsion, liposome etc.
The toxicity of oxaliplatin is bigger, mainly is systemic side effects such as peripheral neuralgia and lung toxicity.The untoward reaction of hematology aspect mainly is: anemia, leukopenia, granulocytopenia, thrombocytopenia, the untoward reaction of non-blood blood aspect mainly is: nausea,vomiting,diarrhea, peripheral neuritis etc.
For addressing the above problem, publication number is that the patent " Liposomal formulation that contains oxaliplatin " of the Japanese drug conveying company (Mebiopharm) of CN 1628638A provides a kind of by the oxaliplatin liposome preparation of hydrophilic polymer and aglucon derivatization, hydrophilic polymer is a Polyethylene Glycol, and aglucon is a transferrin.
Summary of the invention:
The oxaliplatin platinum phospholipid compound that the purpose of this invention is to provide a kind of non-liposome, adopt or do not adopt Freeze Drying Technique, it is formulated in the pharmaceutically acceptable aqueous diluent, make the nanometer suspension injection of the intravenously administrable of oxaliplatin platinum phospholipid compound, and its preparation method is provided.Use it for first-line treatment 6 months with transitivity colon, rectal cancer interior or invalid thereafter and recurrence.In addition, for advanced colorectal cancer conditions of patients recurrence or can not get for the effector, oxaliplatin and 5-fluorouracil/calcium folinate coupling will be effective especially medicine.It is identical to form used with the forming liposome substantially method of the used method of phosphatide complexes suspensoid, but the present invention is because adopt high medicine: the lipoid ratio, the mol ratio that is medicine and phospholipid (in phosphatidylcholine) is about 1: 1, formation be phosphatide complexes but not liposome basically.It renders a service the same medicine that is equal to or greater than free form substantially, and toxicity reduces greatly.
Phosphatide complexes had both improved the hydrophilic of medicine, had improved its lipotropy again.The improvement of water dissolution performance is relevant with the solubilization that the unformed feature of complex reaches phospholipid formation micelle in water; And fat-soluble improvement on the one hand is because its unformed state, then is that the polar end of complex Chinese medicine is with the phospholipid interaction and be subjected to certain sheltering on the other hand.
The medicine phosphatide complexes can form the micelle shape in water, similar liposome, but the two has basic difference.Liposome is that pharmaceutical pack is rolled in the vesicle of the sealing that is formed by phospholipid, and medicine is free in the interior solution of vesicle, or is dispersed between the multilayer film of phospholipid; Phosphatide complexes then be medicine by and the polar end of phospholipid between interact and form an integral body, this does not influence the both sexes effect of phospholipid and dispersive characteristic in water, when it carried drug molecule and disperses in water, intermolecular ordered arrangement formed the spheroid that is different from liposome.
The phosphatide complexes suspensoid has and the similar characteristics of liposome, as affinity and the intake of increase with cancerous cell, improves drug loading, reduces dosage, improves curative effect, reduction toxic and side effects etc.; Be carrier because of it uses the phospholipid of biocompatibility, in finished product, do not contain organic solvent, can avoid problems such as the toxicity brought with cosolvent solubilising insoluble drug and side effect; Can change interior distribution of body of medicine, obtain some preferable pharmacokinetic parameters.Have found that, nanometer suspension liquid dissolution is apparently higher than the micron suspension, blood drug level is higher, but because the medicine stripping is not instantaneous generation, so compare with solution, nanometer suspension liquid not only drug loading is big, and safety, low toxicity, and its storage storehouse formula at subcutaneous, intramuscular and Intradermal transmits and can produce slow release effect.
Oxaliplatin nano suspension provided by the invention, be intended to improve oxaliplatin drug loading, reduce toxicity, convenient clinical use, improve the patient compliance, reduce its zest to blood vessel, make it bring into play clinical efficacy better.Described oxaliplatin nano suspension is colloidal dispersion, can be liquid preparation, also can be the lyophilized preparation after the lyophilization, the injection for intravenous administration.
Oxaliplatin nanometer suspension injection of the present invention, be equally with the medicinal raw material oxaliplatin as the active drug composition, be grouped into (weight/volume percent, down with) by following one-tenth:
(a) oxaliplatin: 0.5%～5.0%;
(b) surfactant: 0.1%～20.0%;
(c) pH regulator agent: 0～1.0%, regulate pH value to 4.0～9.0;
(d) isotonic agent: 0～10.0%;
(e) antioxidant: 0～0.1%;
(f) surplus is a water for injection.
The lyophilizing suspensoid that is used to inject also contains 0.5%～10.0% excipient.
Preferred proportioning is:
(a) oxaliplatin: 0.5%～2.0%;
(b) surfactant: 0.5%～10.0%;
(c) pH regulator agent: 0～0.1%, regulate pH value to 4.0～7.0;
(d) isotonic agent: 0～5.0%;
(e) antioxidant: 0～0.05%;
(f) surplus is a water for injection.
The lyophilizing suspensoid that is used to inject also contains 1.0～5.0% excipient.
The feature of the preparation method of oxaliplatin nano suspension of the present invention is: by said proportional quantities, preparation oxaliplatin and surfactant and other additives blend earlier carried out homogenize, filtration, packing, sterilization again in the suspension of aqueous phase.Describedly all turn to ultrasound wave or homogenizer homogenize or its mixing; For making more homogeneous of particle size distribution, can select the aperture for use is the filtering with microporous membrane of 0.45 μ m or 0.22 μ m, and degerming can be adopted aseptic technique, membrane filtration technology or pass through the sterilization of autoclaving terminal point.Adopt the filtering with microporous membrane method, preferably selecting the aperture for use is the microporous filter membrane of 0.22 μ m.With the suspension packing behind the filtering with microporous membrane, packing volume 2～20ml, embedding is made the suspensoid of liquid, or is added the lyophilizing excipient, and packing volume 1～5ml makes the lyophilizing suspensoid through lyophilization.But the suspensoid injection for intravenous administration that obtains.
Oxaliplatin that the present invention is above-mentioned and surfactant and other additives blend have several different methods in the preparation of the suspension of aqueous phase.A kind of mode is: at first at a kind of solvent, for example in dimethyl sulfoxide or the methanol oxaliplatin is dissolved; For example soybean phospholipid or Ovum Gallus domesticus Flavus lecithin are dissolved in a kind of organic solvent with surfactant, as methanol, ethanol, isopropyl alcohol, chloroform, carbon tetrachloride and dichloromethane etc., and phospholipid solution mixed with drug solution, in this mixed solution, add water, for example distilled water or buffer such as oxalic acid or sodium oxalate solution, solvent evaporated under reduced pressure.Another kind of mode is: drug solution mixes with phospholipid solution, solvent evaporated under reduced pressure, and film former adds the water hydration in this film.Have a kind of mode to be again: the dry oxaliplatin platinum phospholipid thin film that obtains is resuspended in a kind of solvent, for example methanol, ethanol, isopropyl alcohol, chloroform, carbon tetrachloride and dichloromethane etc., and before this film hydration, reduction vaporization once more.Also have a kind of mode to be: after the medicine phospholipid membrane is carried out reduced vacuum drying or lyophilization processing, to add the water hydration again.
The surfactant that uses in the present composition is selected from soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydroxylated lecithin, hydrogenated phospholipid, synthetic phospholipid, cholesterol, C11～C22 alcohol, poloxamer, polyoxyethylene sorbitan monoleate, (deoxidation) sodium cholate, polyoxyethylene castor oil etc.Preferably soybean phospholipid or Ovum Gallus domesticus Flavus lecithin.The mol ratio of oxaliplatin and phospholipid (in phosphatidylcholine) is 1: 0.2～1: 5, preferably 1: 0.8～1: 1.5, and more preferably 1: 1.
It is 4.0～6.0 form that the present composition is mixed with pH, the salt that the pH regulator agent is selected from hydrochloric acid, phosphoric acid, citric acid or its alkali metal salt, oxalic acid or its alkali metal salt, sodium hydroxide (potassium), glacial acetic acid or its alkali metal salt, phosphate (as sodium dihydrogen phosphate and sodium hydrogen phosphate), glycine and pharmaceutically allows, preferably oxalic acid or Disodium oxalate..
By adding isotonic agent such as glycerol, sorbitol, xylitol, glucose, fructose or its mixture, the present composition and blood etc. are oozed.Preferred tension regulator is glycerol or glucose.
The antioxidant of the present composition is selected from derivant and deferoxamine mesylate or its mixture of vitamin E, cysteine hydrochloride, vitamin C, sulfites, ethylenediaminetetraacetic acid (EDTA), EDTA.
The excipient that uses during preparation lyophilizing suspensoid is selected from lactose, mannose, mannitol, sorbitol, dextran, glucose etc.
The solvent of the dissolving oxaliplatin that uses in the suspension preparation of above-mentioned oxaliplatin platinum phospholipid compound is selected from methanol or dimethyl sulfoxide.The solvent of dissolving phospholipid is selected from methanol, ethanol, isopropyl alcohol, chloroform, carbon tetrachloride and dichloromethane, and dichloromethane preferably is because it has hypotoxicity.
Advantage of the present invention is: suspensoid drug loading of the present invention is big, safety, low toxicity.The experiment proved that said preparation stability is high; Syringeability is good; There are not haemolysis and vein blood vessel zest; Preparation method is simple and easy to do, realizes commercialization easily.
The specific embodiment:
The specific embodiment of form is described in further detail foregoing of the present invention more by the following examples, but should not be interpreted as at this point that the scope of the above-mentioned theme of the present invention only limits to following example.Do not breaking away under the above-mentioned technological thought situation of the present invention, the corresponding replacement of making according to ordinary skill knowledge and customary means or the modification of change include within the scope of the invention.
Embodiment 1:
In round-bottomed flask, oxaliplatin 1.5g is dissolved in the 30ml dimethyl sulfoxide, soybean phospholipid 4.5g and vitamin E 30mg are dissolved in the 100ml chloroform, the mixed liquor that obtains produces thin film at 40 ℃ of decompression rotary evaporations on flask, the reduced vacuum drying is 1～2 day then.Take by weighing Disodium oxalate. 7.5mg, glycerol 3.0g, disodiumedetate 0.05g is dissolved in jointly in the 150ml distilled water and makes water.With dried membrane suspension at above-mentioned aqueous phase.Suspension transferred in the processor for ultrasonic wave handle, through the homogenizer homogenize, make suspension injection again to transparent.After the microporous filter membrane aseptic filtration through 0.22 μ m, packing volume 5ml, embedding.End-product contains the oxaliplatin of 10mg/ml.
Embodiment 2:
In round-bottomed flask, oxaliplatin 1.0g is added in the methanol of 1000ml, to groove type ultrasonic ripple processor, handles, add the dichloromethane solution (4.0g is in the 100ml dichloromethane) of Ovum Gallus domesticus Flavus lecithin to all dissolvings.Get oxalic acid 5.0mg, glucose 5.0g, disodiumedetate 0.03g, being dissolved in jointly must water in the 100ml distilled water.Water is added in the mixed liquor of said medicine and phospholipid, mix homogeneously in 40 ℃ of following decompression rotary evaporation solvents, is transferred to suspension in the processor for ultrasonic wave and to be handled to transparent, again through the homogenizer homogenize, makes suspension injection.After the microporous filter membrane aseptic filtration through 0.22 μ m, packing, packing volume 10ml.
Embodiment 3:
In round-bottomed flask, oxaliplatin 1.0g is added in the methanol of 1000ml, to groove type ultrasonic ripple processor, handle to all dissolvings, the chloroformic solution (4.g is in the 100ml chloroform) that adds Ovum Gallus domesticus Flavus lecithin, the mixed liquor that obtains produces thin film at 40 ℃ of decompression rotary evaporations on flask.Get oxalic acid 3.0mg, mannitol 1.0g, disodiumedetate 0.02g are dissolved in and get water in the 100ml distilled water.Membrane suspension at above-mentioned aqueous phase, is transferred to homogenizing in the high speed dispersing emulsification machine with suspension, be prepared into suspension, through the microporous filter membrane aseptic filtration of 0.22 μ m, packing, packing volume 3ml makes the lyophilizing suspensoid injectio through lyophilization.
Claims (10)
1, the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable is characterized in that: it by following composition by weight/percent by volume forms:
(a) oxaliplatin: 0.5%～5.0%;
(b) surfactant: 0.1%～20.0%;
(c) pH regulator agent: 0～1.0%, regulate pH value to 4.0～9.0;
(d) isotonic agent: 0～10.0%;
(e) antioxidant: 0～0.1%;
(f) surplus is a water for injection;
The lyophilizing suspensoid that is used to inject also contains 0.5%～10.0% excipient.
2, the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 is characterized in that: by following composition by weight/percent by volume forms:
(a) oxaliplatin: 0.5%～2.0%;
(b) surfactant: 0.5%～10.0%;
(c) pH regulator agent: 0～0.1%, regulate pH value to 4.0～7.0;
(d) isotonic agent: 0～5.0%;
(e) antioxidant: 0～0.05%;
(f) surplus is a water for injection;
The lyophilizing suspensoid that is used to inject also contains 1.0～5.0% excipient.
3, the nanometer suspension of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 and 2 is annotated preparation, and it is characterized in that: surfactant is selected from soybean phospholipid, Ovum Gallus domesticus Flavus lecithin, hydroxylated lecithin, hydrogenated phospholipid, synthetic phospholipid, cholesterol, C
11～C
22The mixture of one or more in alcohol, poloxamer, polyoxyethylene sorbitan monoleate, NaTDC, the polyoxyethylene castor oil.
4, the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 and 2 is characterized in that: the mol ratio of oxaliplatin and phospholipid is 1: 0.2～1: 5.
5, the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 and 2 is characterized in that: the pH regulator agent is selected from one or more the mixture in the salt that hydrochloric acid, phosphoric acid, citric acid or its alkali metal salt, oxalic acid or its alkali metal salt, sodium hydroxide, potassium hydroxide, glacial acetic acid or its alkali metal salt, phosphate, glycine pharmaceutically allow; Isotonic agent be selected from glycerol, sorbitol, xylitol, glucose, fructose and the salt that pharmaceutically allows in one or more mixture; Antioxidant is selected from one or more mixture of the derivant of vitamin E, ethylenediaminetetraacetic acid, ethylenediaminetetraacetic acid and deferoxamine mesylate, cysteine hydrochloride, vitamin C, sulphite apoplexy due to endogenous wind.
6, the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 and 2 is characterized in that: the excipient that preparation is used during lyophilized formulations is selected from one or more the mixture in lactose, mannose, mannitol, sorbitol, dextran, the glucose.
7, a kind of preparation method of the nanometer suspension injection as claim 1 or the described oxaliplatin platinum phospholipid compound intravenously administrable of claim 2, it is characterized in that: preparation method comprises the steps:
(a) oxaliplatin is dissolved in methanol or the dimethyl sulfoxide;
(b) one or more phospholipid being dissolved in one or more is selected from such as among methanol, ethanol, isopropyl alcohol, chloroform, carbon tetrachloride and the dichloromethane organic solvent;
(c) step (a) and solution (b) are mixed;
(d) water is added in the mixed solution of step (c);
(e) reduction vaporization is removed the solvent in the step (d), forms the suspension of oxaliplatin platinum phospholipid compound.
8, the preparation method of the nanometer suspension injection of oxaliplatin platinum phospholipid compound intravenously administrable according to claim 1 and 2, it is characterized in that: drug solution mixes with phospholipid solution, solvent evaporated under reduced pressure, film former, this film is in the aqueous phase hydration; The dry oxaliplatin platinum phospholipid thin film that obtains is resuspended in methanol, ethanol, isopropyl alcohol, chloroform, carbon tetrachloride and the dichloromethane solvent, and before this film hydration, once more reduction vaporization; Or after the medicine phospholipid membrane carried out reduced vacuum drying or lyophilization and handle, add the water hydration again.
9, according to the preparation method of the nanometer suspension injection of claim 7 or 8 described oxaliplatin platinum phospholipid compound intravenously administrables, it is characterized in that: described aqueous phase contains one or more the mixture in water for injection, buffer agent, isotonic agent, the antioxidant.
10, according to the preparation method of the nanometer suspension injection of claim 7 or 8 described oxaliplatin platinum phospholipid compound intravenously administrables, it is characterized in that: post-decompression solution need carry out suspension homogenize, filtration, packing, sterilization, describedly all turns to ultrasound wave or homogenizer homogenize or its mixing; It is the filtering with microporous membrane of 0.45 μ m or 0.22 μ m that the aperture is selected in filtration for use; Aseptic technique, membrane filtration technology or autoclaving are adopted in degerming, with the suspension packing behind the filtering with microporous membrane, and packing volume 2～20ml, the suspensoid of liquid is made in embedding, or adds the lyophilizing excipient, packing volume 1～5ml makes the lyophilizing suspensoid through lyophilization.
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| CN102525957A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation method of Oxaliplatin for injection |
| EP2481396A2 (en) * | 2009-09-21 | 2012-08-01 | JW Pharmaceutical Corporation | Oxaliplatin nanoparticles and method for preparing same |
| CN102697741A (en) * | 2012-06-29 | 2012-10-03 | 海南灵康制药有限公司 | Oxaliplatin vesicular phospholipid gel injection |
| CN102988293A (en) * | 2012-11-23 | 2013-03-27 | 杭州师范大学 | Oxaliplatin folic acid targeted lipidosome and application thereof |
| CN110917345A (en) * | 2019-09-26 | 2020-03-27 | 苏州百迈生物医药有限公司 | Chemotherapy immune combined medicine and preparation method thereof |
| CN112773728A (en) * | 2020-12-31 | 2021-05-11 | 江西科技师范大学 | Compound of nano-encapsulated resveratrol, preparation method and application thereof |
| WO2022107843A1 (en) * | 2020-11-19 | 2022-05-27 | 日本化薬株式会社 | Composition containing water-soluble drug capable of inducing vascular disorder, solution for use in preparation of administration solution containing water-soluble drug capable of inducing vascular disorder, kit, vascular disorder preventing agent, and solution containing nonionic surfactant |
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- 2006-05-20 CN CNA2006100843578A patent/CN1868455A/en active Pending
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| AU2010296180B2 (en) * | 2009-09-21 | 2016-05-05 | Bio-Synectics, Inc | Oxaliplatin nanoparticles and method for preparing same |
| EP2481396A2 (en) * | 2009-09-21 | 2012-08-01 | JW Pharmaceutical Corporation | Oxaliplatin nanoparticles and method for preparing same |
| CN102665689A (en) * | 2009-09-21 | 2012-09-12 | Jw制药公司 | Oxaliplatin nanoparticles and method for preparing same |
| JP2013505291A (en) * | 2009-09-21 | 2013-02-14 | ジェイダブリュー ファーマシューティカル コーポレイション | Oxaliplatin nanoparticles and method for producing the same |
| EP2481396A4 (en) * | 2009-09-21 | 2014-03-05 | Jw Pharmaceutical Corp | Oxaliplatin nanoparticles and method for preparing same |
| RU2563997C2 (en) * | 2009-09-21 | 2015-09-27 | Джей ДаблЮ ФАРМАСЬЮТИКАЛ КОРПОРЭЙШН | Oxaliplatin nanoparticles and method of obtaining thereof |
| CN102525957A (en) * | 2011-12-15 | 2012-07-04 | 苏州二叶制药有限公司 | Preparation method of Oxaliplatin for injection |
| CN102697741A (en) * | 2012-06-29 | 2012-10-03 | 海南灵康制药有限公司 | Oxaliplatin vesicular phospholipid gel injection |
| CN102988293A (en) * | 2012-11-23 | 2013-03-27 | 杭州师范大学 | Oxaliplatin folic acid targeted lipidosome and application thereof |
| CN102988293B (en) * | 2012-11-23 | 2014-11-05 | 杭州师范大学 | Oxaliplatin folic acid targeted lipidosome and application thereof |
| CN110917345A (en) * | 2019-09-26 | 2020-03-27 | 苏州百迈生物医药有限公司 | Chemotherapy immune combined medicine and preparation method thereof |
| WO2022107843A1 (en) * | 2020-11-19 | 2022-05-27 | 日本化薬株式会社 | Composition containing water-soluble drug capable of inducing vascular disorder, solution for use in preparation of administration solution containing water-soluble drug capable of inducing vascular disorder, kit, vascular disorder preventing agent, and solution containing nonionic surfactant |
| CN112773728A (en) * | 2020-12-31 | 2021-05-11 | 江西科技师范大学 | Compound of nano-encapsulated resveratrol, preparation method and application thereof |
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