CN117598986A - Cabazitaxel self-assembled lipid nano injection composition and preparation method thereof - Google Patents
Cabazitaxel self-assembled lipid nano injection composition and preparation method thereof Download PDFInfo
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- CN117598986A CN117598986A CN202311370326.9A CN202311370326A CN117598986A CN 117598986 A CN117598986 A CN 117598986A CN 202311370326 A CN202311370326 A CN 202311370326A CN 117598986 A CN117598986 A CN 117598986A
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- Prior art keywords
- cabazitaxel
- composition
- injection
- phospholipid
- lipid
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- XOFYZVNMUHMLCC-ZPOLXVRWSA-N prednisone Chemical compound O=C1C=C[C@]2(C)[C@H]3C(=O)C[C@](C)([C@@](CC4)(O)C(=O)CO)[C@@H]4[C@@H]3CCC2=C1 XOFYZVNMUHMLCC-ZPOLXVRWSA-N 0.000 description 1
- 229940095453 prednisone 10 mg Drugs 0.000 description 1
- 230000003449 preventive effect Effects 0.000 description 1
- 238000011324 primary prophylaxis Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 206010037844 rash Diseases 0.000 description 1
- 208000037922 refractory disease Diseases 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 238000002390 rotary evaporation Methods 0.000 description 1
- 238000011076 safety test Methods 0.000 description 1
- 238000001338 self-assembly Methods 0.000 description 1
- 208000013220 shortness of breath Diseases 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 229940083466 soybean lecithin Drugs 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 150000003431 steroids Chemical class 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
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- 238000001132 ultrasonic dispersion Methods 0.000 description 1
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K9/10—Dispersions; Emulsions
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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Abstract
The invention discloses a cabazitaxel self-assembled lipid nano injection composition and a preparation method thereof, wherein the composition is mainly prepared by combining cabazitaxel with phospholipid, cholesterol, ethanol and water, the phospholipid consists of negatively charged phospholipid and uncharged neutral phospholipid, the composition can be self-assembled to form lipid nano suspension, and the particle size of lipid nano particles is in the range of 300nm-450 nm. The composition of the invention has the advantages of simple preparation process and low cost, and the lipid nanometer composition is easy and convenient to prepare before use.
Description
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to a cabazitaxel self-assembled lipid nano injection composition and a preparation method thereof.
Background
Tumors are serious refractory diseases threatening human life health, and the treatment of tumors has been closely focused worldwide. At present, tumors gradually replace cardiovascular and cerebrovascular diseases and become global head killers. According to the 2022 chinese latest cancer report issued by the national cancer center: the onset of the 2016 malignant tumor is about 406.4 thousands, the male is higher than the female (207.03/10 vs168.14/10 tens of thousands), and the total death rate is: 241.4 ten thousand.
Cabazitaxel (Cabazitaxel) is an antitumor drug and has the action mechanism similar to that of docetaxelSimilarly, a microtubule inhibitor. Cabazitaxel binds to tubulin and promotes its assembly into microtubules, while inhibiting its breakdown, which results in microtubule stabilization, thereby inhibiting mitosis and interphase cell function. Is mainly suitable for treating patients with refractory hormone metastatic prostate cancer who use the treatment scheme containing docetaxel in combination with prednisone clinically. The original research company is Sainophenanthrene company and has the trade name JECTANA. JEOTANA injection is 60mg/1.5mL of a sterile, pyrogen-free, clear yellow to brown yellow viscous solution, contained in single dose vials containing 60mg of cabazitaxel and 1.56g of Tween-80 (i.e., polysorbate 80) per vial (citric acid monohydrate is also added for adjusting the pH of the polysorbate between 3.3 and 3.8), corresponding to 40mg of cabazitaxel (anhydrous) and 1.04g of Tween-80 per mL. The JEVTANA dilution is a clear, colorless, sterile, pyrogen-free solution containing 13% (w/w) ethanol for injection, about 5.7mL. JEVTANA requires two dilutions prior to intravenous infusion: the preparation was diluted with JEVTANA diluent, then with 0.9% sodium chloride solution or 5% dextrose solution, and then administered intravenously. The dosing regimen and dosage were: during the treatment period, JECTANA was infused intravenously with JECTANA 20mg/m once every three weeks 2 Prednisone 10mg is administered orally at the same time, once daily. At the discretion of the physician, some patients may use 25mg/m 2 Is a dose of (a). JEVTANA has serious adverse reactions such as hematological toxicity and anaphylactic reaction, and black frame warnings have been proposed in the specification.
There are reports of the death caused by neutropenia, and in order to monitor the occurrence of neutropenia, frequent blood counts should be performed in all patients receiving JEVTANA treatment. JECTANA is forbidden for neutrophil count less than or equal to 1,500/mm 3 Is a patient of (a). G-CSF prophylaxis in patients with high risk clinical features was suggested, at all receiving 25mg/m 2 Primary prophylaxis was considered in patients at doses using G-CSF.
Severe hypersensitivity reactions may occur, which may include systemic rash/erythema, hypotension and bronchospasm. If a severe response occurs, please immediately terminate JEVTANA and immediately proceed with the appropriate treatment.
JEVTANA should be disabled if there is a severe history of hypersensitivity to cabazitaxel or to drugs formulated with polysorbate 80. Also mentioned within the preventive regimen of the instructions for use of the drug is the intravenous administration of the following drug at least 30 minutes prior to each JEVTANA administration:
1) Antihistamines (dexchlorpheniramine 5mg or diphenhydramine 25mg or equivalent antihistamines);
2) Corticosteroids (dexamethasone 8mg or equivalent steroid);
3) An H2 antagonist (ranitidine 50mg or equivalent H2 antagonist).
From the above, it can be seen that the hematological toxicity and allergic reaction of cabazitaxel injection are very serious. Neutropenia is common to the class of cytotoxic drugs such as taxanes, e.g., docetaxel, cabazitaxel, and hypersensitivity is caused by the use of large amounts of the surfactant tween-80 (i.e., polysorbate 80) as a solubilizing agent in the formulation. A large number of studies have shown that after intravenous administration of injection solutions containing Tween-80, some patients develop severe allergic reactions, such as drug rash, shortness of breath, bronchospasm, hypotension, hemolysis, fluid retention, and thus clinical application is greatly affected. Therefore, in addition to myelosuppression (neutropenia, leukopenia, anemia) caused by the taxane drugs themselves, the main side effects of the currently clinically used cabazitaxel injection also include anaphylactic reaction caused by tween-80.
In view of the fact that the cabazitaxel injection on the market at present contains the solubilizing agent tween-80, and the tween-80 is considered to be related to serious anaphylactic reaction, new cabazitaxel preparations without tween-80 are developed in various countries so as to avoid obvious toxic and side effects caused by the tween-80 and improve the compliance of medication.
In order to overcome the above-mentioned defects, chinese patent CN201010268940.0 discloses a drug delivery system of a poorly soluble drug, which uses phospholipid and oil for injection as main carrier materials, dissolves the poorly soluble drug in a solvent or oil for injection or their mixture, then adds phospholipid and other components in the prescription, and stirs the mixture to obtain a liquid composition. The system can be used for delivering taxane medicines such as docetaxel, cabazitaxel and the like. The composition can be diluted by glucose for injection before use, and is self-emulsified to form emulsion injection, and the emulsion injection formed by the composition is stable in physical property, good in dispersibility and easy to clinically use. The taxane liquid composition disclosed in chinese patent CN201010268940.0 has been found to contain a large amount of injectable oil (e.g. soybean oil) although tween-80 is avoided, but natural oil contains substances such as oleic acid which are easily oxidized and rancid, which adversely affect the chemical stability of taxane, and tween-80 is formed by esterification of oleic acid, polyethylene glycol and sorbitan (also known as polyoxyethylene sorbitan monooleate of tween-80), and oleic acid itself has a certain allergy. Taxane compounds such as docetaxel have poor biostability in emulsions, are easily replaced by and combined with albumin in plasma, and do not cause adverse effects on blood systems such as granulocytopenia to a lesser extent than conventional docetaxel injections.
CN201610128739.X discloses a cabazitaxel phospholipid composition, a preparation method and application thereof. The cabazitaxel phospholipid composition comprises cabazitaxel lipid complex, phospholipid and cholesterol, solves the problems of unstable medicine, complicated preparation steps before clinical use, poor in-vivo and in-vitro stability of the existing lipid preparation and the like, improves the in-vivo circulation time of the medicine, has a certain targeting function, ensures that the medicine is enriched at a tumor part, reduces toxic and side effects, and greatly improves the bioavailability. The preparation process of the cabazitaxel phospholipid composition comprises the steps of dissolving cabazitaxel and negatively charged phospholipid in an organic reagent, removing the organic solvent by adopting a rotary evaporation or spray drying method to obtain a cabazitaxel lipid compound, adding water to hydrate to form a suspension, and homogenizing or extruding under high pressure to form cabazitaxel lipid. These are conventional methods for preparing lipids, and although cabazitaxel phospholipid complexes can be obtained, the preparation method is complicated and requires expensive equipment such as a homogenizer. Accordingly, there is a need to provide a novel cabazitaxel pharmaceutical composition which ensures good dispersibility of cabazitaxel without using tween-80, improves pharmacokinetic properties while avoiding allergic reactions caused by tween-80, and reduces severe neutrophil cytotoxicity. In addition, the preparation method has the characteristics of simplicity and low cost compared with the conventional preparation method of the lipid.
The inventor discovers that the purposes of avoiding Tween 80, improving the pharmacokinetic characteristics and relieving the reduction of neutrophil can be achieved by simply adding a certain proportion of lipid into the cabazitaxel pharmaceutical composition, and the lipid nanosuspension can be formed by self-assembly due to temporary reformulation, so that complex preparation equipment and process are not needed, and the preparation method has the advantages of simplicity and low cost.
Disclosure of Invention
The invention aims to provide a cabazitaxel self-assembled lipid nano injection composition and a preparation method thereof. The injection composition can self-assemble to form lipid nanometer suspension without complex preparation equipment and process, and has the advantages of simple preparation and low cost.
To achieve the object of the present invention, the following embodiments are provided:
in one embodiment, the self-assembled lipid nano injection composition of the cabazitaxel mainly comprises cabazitaxel, phospholipid and cholesterol which are dissolved in ethanol and water, wherein the phospholipid consists of negatively charged phospholipid and uncharged neutral phospholipid, the composition can be self-assembled into lipid nano suspension after being diluted by 5% glucose injection before injection, and the average particle size of the lipid nano particles is in the range of 300nm-450 nm.
Preferably, the injection composition of the invention comprises the following components of (5-10): (45-50): 24:5.
preferably, the injection composition of the invention comprises the following components in parts by weight: 983:200.
in some embodiments, the negatively charged phospholipid is selected from one or more of 1, 2-dimyristoyl-sn-glycero-3-phosphate (DMPA), 1, 2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA), 1, 2-distearoyl-sn-glycero-3-phosphate (DSPA), dilauroyl phosphatidic acid (DLPA), phosphatidylserine (DPPS), phosphatidylinositol (PI), dilauroyl phosphatidylglycerol (DLPG), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG), and dimyristoyl phosphatidylglycerol (DMPG) and salts thereof, preferably from one or more of DMPA, DSPA, DPPS, DPPG and DMPG and salts thereof, preferably sodium and potassium salts thereof.
In some embodiments, the neutral, uncharged phospholipid is selected from egg yolk lecithin, soybean lecithin, hydrogenated soybean lecithin (HSPC), distearoyl phosphatidylcholine (DSPC), 1, 2-dioleoyl phosphatidylcholine (DOPC), dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC), dilauryl phosphatidylcholine (DLPC), distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphatidylethanolamine (DMPE), or one or more of their salts or polyethylene glycol modifications, preferably DSPC and DSPE-PEG2000.
In some preferred embodiments, the injectable composition of the invention, the uncharged neutral phospholipids consist of DSPC and DSPE-PEG2000, wherein the mass ratio of DSPC to DSPE-PEG2000 is 5:3.
in some preferred embodiments, the injection composition of the present invention, the pharmaceutical excipients further comprise citric acid, wherein the mass ratio of citric acid to cabazitaxel is 1: (5-10).
In some preferred embodiments, the injectable composition of the present invention is heated to 50 ℃ in a water bath prior to injection (i.e., at the time of use) and then rapidly injected into a 5% glucose injection at room temperature to prepare Cheng Kaba tacrolimus lipid nanosuspension, which is administered intravenously at a concentration of about 0.1mg/mL.
In another embodiment, the invention also provides a preparation method of the cabazitaxel self-assembled lipid nano injection composition, which comprises the steps of mixing the cabazitaxel with phospholipid, cholesterol, ethanol and water in a prescription amount, stirring and dissolving at the water bath temperature of 50 ℃, filtering and sterilizing by a 0.2 mu m filter, and rolling a cover after filling.
The self-assembled lipid nano injection composition refers to the injection composition provided by the invention, after being injected into a 5% glucose injection, the self-assembled lipid nano suspension can be directly self-assembled and then injected intravenously without implementing the conventional preparation process of lipid, such as complex processes of injection method, film dispersion method, ultrasonic dispersion method, high-pressure emulsion method and the like.
The invention relates to application of a cabazitaxel self-assembled lipid nano injection composition in preparing a medicament for treating prostatic cancer.
Compared with the currently marketed cabazitaxel injection JEVTANA, the cabazitaxel self-assembled lipid nano injection composition has good stability, does not need special diluent and does not need two-step preparation, and only needs to be heated to 50 ℃ in a water bath when in use, and is rapidly injected into 5% glucose injection at room temperature after being sucked out by a needle tube, and the self-assembled cabazitaxel injection is prepared into a liquid medicine with the concentration of Cheng Kaba tam of about 0.1mg/mL for intravenous injection.
The cabazitaxel self-assembled lipid nano injection composition prepared by the invention can be used for treating prostate cancer. The in vivo pharmacokinetic test results of animals show that compared with the currently marketed cabazitaxel injection JECTANA, the bioavailability is improved and the in vivo half-life is prolonged. The administration dosage can be reduced under the condition of not reducing the anti-tumor curative effect, thereby greatly reducing the serious toxic and side effect of the reduction of the neutrophil.
The composition for self-assembled lipid nano injection of cabazitaxel has good stability, can be self-assembled into lipid nano suspension in 5% glucose injection, and has the average particle size range of lipid nanoparticles of 300-450 nm and good uniformity.
Drawings
FIG. 1 is a plot of neutrophil density versus time for animal safety test results;
fig. 2 is a plot of tumor volume size versus time for animal pharmacodynamic experimental results.
Detailed Description
The following examples are presented to aid one skilled in the art in better understanding the present invention and should in no way be construed as limiting the scope of the invention.
Examples 1 to 4
The components and amounts of the compositions of examples 1-4 are shown in Table 1.
TABLE 1 Components and amounts of the compositions of examples 1-4
The preparation method comprises the following steps:
(1) Sequentially weighing the components with the prescription amounts in the table 1, mixing, stirring and dissolving at the water bath temperature of 50 ℃ to prepare a mixture solution;
(2) The solution was sterilized by filtration through 0.2 μm and filled into penicillin bottles (injection devices), 6g of the mixture solution was filled per bottle, and the cap was rolled.
Investigation of physicochemical Properties:
the appearance of the compositions prepared in examples 1-4 was examined:
the compositions of examples 1-4 were all homogeneous transparent pale yellow solutions in appearance with no apparent difference in appearance for each formulation of the different formulations.
The preparation method before use comprises the following steps:
the compositions prepared in examples 1-4 were prepared before use, the compositions prepared in examples 1-4 were heated to 50 ℃ in a water bath, and rapidly injected into a 5% glucose injection at room temperature after aspiration with a needle tube, and mixed well up and down with shaking for 20 times to obtain a cabazitaxel lipid nanosuspension (cabazitaxel about 0.1 mg/mL), wherein the 5% glucose injection was used in an amount to dilute the cabazitaxel at a concentration of about 0.1mg/mL, respectively. The particle diameters (emulsion droplet diameters) of lipid nanoparticles in the suspensions formed were measured at 0h, 4h, 6h, and 8h, respectively, and the precipitation of cabazitaxel crystals was observed. As a result, it was found that the compositions of examples 1 to 4 all formed slightly opalescent suspensions after dilution, and after standing at room temperature for 8 hours, the respective suspensions were not precipitated and the cabazitaxel crystallized out except that the crystalline form was eluted at 8 hours in example 4. The results of the emulsion droplet size and the drug precipitation of the lipid are shown in Table 2.
TABLE 2 average particle size (nm) of lipid suspensions formulated with the compositions of examples 1-4
The results in Table 2 show that the compositions of examples 1-4, after being diluted to prepare suspensions, have a certain change in particle size with time, but the compositions of examples 1-3 have no precipitation, cabazitaxel crystallization and the like, and the particle sizes of the lipid nanoparticles are within the acceptable range of the injection.
Examples 5 to 8
The components and amounts of the compositions of examples 5-8 are shown in Table 3.
TABLE 3 Components and amounts of the compositions of examples 5-8
The preparation method comprises the following steps:
(1) Sequentially weighing the components with the prescription amounts in table 3, mixing, stirring and dissolving at the water bath temperature of 50 ℃ to prepare a mixture solution;
(2) The solution was sterilized by filtration through 0.2 μm and filled into penicillin bottles (injection devices), 6g of the mixture solution was filled per bottle, and the cap was rolled.
Investigation of physicochemical Properties:
the appearance of the compositions prepared in examples 5-8 was examined:
the compositions of examples 5-8 were all homogeneous transparent pale yellow solutions in appearance with no apparent difference in appearance for each formulation of the different formulations.
The preparation method before use comprises the following steps:
the compositions prepared in examples 5-8 were prepared before use, the compositions prepared in examples 5-8 were heated to 50℃in a water bath, and rapidly injected into a 5% glucose injection at room temperature after aspiration with a needle tube, and mixed up and down with shaking for 20 times to obtain a cabazitaxel lipid nanosuspension (cabazitaxel about 0.1 mg/mL), wherein the 5% glucose injection was used in an amount to dilute the cabazitaxel at a concentration of about 0.1mg/mL, respectively. The particle diameters (emulsion droplet diameters) of lipid nanoparticles in the suspensions formed were measured at 0h, 4h, 6h, and 8h, respectively, and the precipitation of cabazitaxel crystals was observed. As a result, it was found that the compositions in examples 5 to 8 all formed slightly opalescent suspensions after dilution, and after standing at room temperature for 8 hours, the respective suspensions were not precipitated and the cabazitaxel crystallized out except that the crystalline form was eluted at 8 hours in example 8. The emulsion droplet size and the drug precipitation of the lipid are shown in Table 4.
TABLE 4 average particle size (nm) of lipid nanoparticles in suspension formulated with the compositions of examples 5-8
The results in Table 4 show that the compositions of examples 5-8, after being diluted into suspension, have a certain change in particle size with time, but neither of examples 5-8 shows precipitation, cabazitaxel crystallization, etc., and the lipid nanoparticle particle size is within the acceptable range for injection, but the particle size of example 8 increases significantly with increasing cabazitaxel ratio.
Examples 9 to 12
The components and amounts of the compositions of examples 9-12 are shown in Table 5.
TABLE 5 Components and amounts of the compositions of examples 9-12
The preparation method comprises the following steps:
(1) Sequentially weighing the components with the prescription amounts in table 5, mixing, stirring and dissolving at the water bath temperature of 50 ℃ to prepare a mixture solution;
(2) The solution was sterilized by filtration through 0.2 μm and filled into penicillin bottles (injection devices), 6g of the mixture solution was filled per bottle, and the cap was rolled.
Investigation of physicochemical Properties:
the appearance of the compositions prepared in examples 9-12 was examined:
the compositions of examples 9-12 were all homogeneous transparent pale yellow solutions in appearance with no apparent difference in appearance for each formulation of the different formulations.
The preparation method before use comprises the following steps:
the compositions prepared in examples 9-12 were prepared before use, the compositions prepared in examples 9-12 were heated to 50℃in a water bath, and rapidly injected into a 5% glucose injection at room temperature after aspiration with a needle tube, and mixed up and down with shaking for 20 times to obtain a cabazitaxel lipid nanosuspension (cabazitaxel about 0.1 mg/mL), wherein the 5% glucose injection was used in an amount to dilute the cabazitaxel at a concentration of about 0.1mg/mL, respectively. The particle diameters (emulsion droplet diameters) of lipid nanoparticles in the suspensions formed were measured at 0h, 4h, 6h, and 8h, respectively, and the precipitation of cabazitaxel crystals was observed. As a result, it was found that the compositions in examples 5 to 8 all formed slightly opalescent suspensions after dilution, and after standing at room temperature for 8 hours, the respective suspensions were not precipitated and the cabazitaxel crystallized out except that the crystal form was eluted at 8 hours in example 12. The emulsion droplet size and the drug precipitation of the lipid are shown in Table 6.
TABLE 6 average particle size (nm) of lipid nanoparticles in suspension prepared from the compositions of examples 9-12
The results in Table 6 show that the compositions of examples 9-12, after being diluted into suspensions, had a certain change in particle size over time, but that neither of examples 9-11 had precipitation, cabazitaxel crystallization, etc., and that the lipid nanoparticle particle sizes were within the acceptable range for injection.
Examples 13 to 16
The components and amounts of the compositions of examples 13-16 are shown in Table 7.
TABLE 7 Components and amounts of the compositions of examples 13-16
The preparation method comprises the following steps:
(1) Sequentially weighing the components with the prescription amounts in the table 7, mixing, stirring and dissolving at the water bath temperature of 50 ℃ to prepare a mixture solution;
(2) The solution was sterilized by filtration through 0.2 μm and filled into penicillin bottles (injection devices), 6g of the mixture solution was filled per bottle, and the cap was rolled.
Investigation of physicochemical Properties:
the appearance of the compositions prepared in examples 13-16 was examined:
the compositions of examples 13-16 were all homogeneous transparent pale yellow solutions in appearance with no apparent difference in appearance for each formulation of the different formulations.
The preparation method before use comprises the following steps:
the compositions prepared in examples 13-16 were prepared before use, the compositions prepared in examples 13-16 were heated to 50℃in a water bath, and rapidly injected into a 5% glucose injection at room temperature after aspiration with a needle tube, and mixed up and down with shaking for 20 times to obtain a cabazitaxel lipid nanosuspension (cabazitaxel about 0.1 mg/mL), wherein the 5% glucose injection was used in an amount to dilute the cabazitaxel at a concentration of about 0.1mg/mL, respectively. The particle diameters (emulsion droplet diameters) of lipid nanoparticles in the suspensions formed were measured at 0h, 4h, 6h, and 8h, respectively, and the precipitation of cabazitaxel crystals was observed. As a result, it was observed that the compositions of examples 13 to 16 all formed slightly opalescent suspensions after dilution, and that neither of the suspensions had precipitated nor crystallized cabazitaxel after standing at room temperature for 8 hours. The emulsion droplet size and the drug precipitation of the lipid are shown in Table 8.
TABLE 8 average particle size (nm) of lipid nanoparticles in suspension prepared from the compositions of examples 13-16
| Examples numbering | Average particle size of 0h | Average particle size for 4 hours | Average particle size for 6 hours | Average particle size for 8 hours |
| Example 13 | 284.3 | 286.3 | 290.2 | 287.1 |
| Example 14 | 300.2 | 298.7 | 289.2 | 301.2 |
| Example 15 | 320.0 | 331.5 | 327.5 | 319.4 |
| Example 16 | 351.9 | 362.3 | 358.4 | 376.3 |
The results in Table 8 show that the compositions of examples 13-16, after being diluted into suspensions, had a certain change in particle size over time, but that neither of examples 13-16 had precipitation, cabazitaxel crystallization, etc., and that the lipid nanoparticle particle sizes were within the acceptable range for injection.
Examples 17 to 20
The components and amounts of the compositions of examples 17-20 are shown in Table 9.
TABLE 9 Components and amounts of the compositions of examples 17-20
The preparation method comprises the following steps:
(1) Sequentially weighing the components with the prescription amounts in the table 9, mixing, stirring and dissolving at the water bath temperature of 50 ℃ to prepare a mixture solution;
(2) The solution was sterilized by filtration through 0.2 μm and filled into penicillin bottles (injection devices), 6g of the mixture solution was filled per bottle, and the cap was rolled.
Investigation of physicochemical Properties:
the appearance of the compositions prepared in examples 17-20 was examined:
the compositions of examples 17-20 were all homogeneous transparent pale yellow solutions in appearance with no apparent difference in appearance for each formulation of the different formulations.
The preparation method before use comprises the following steps:
the compositions prepared in examples 17-20 were prepared before use, the compositions prepared in examples 17-20 were heated to 50 ℃ in a water bath, and rapidly injected into a 5% glucose injection at room temperature after aspiration with a needle tube, and mixed up and down with shaking for 20 times to obtain a cabazitaxel lipid nanosuspension (cabazitaxel about 0.1 mg/mL), wherein the 5% glucose injection was used in an amount to dilute the cabazitaxel at a concentration of about 0.1mg/mL, respectively. The particle diameters (emulsion droplet diameters) of lipid nanoparticles in the suspensions formed were measured at 0h, 4h, 6h, and 8h, respectively, and the precipitation of cabazitaxel crystals was observed. As a result, it was observed that the compositions of examples 17 to 20 all formed slightly opalescent suspensions after dilution, and after standing at room temperature for 8 hours, no precipitate and cabazitaxel crystallization were observed in each of the other suspensions except for example 20. The emulsion droplet size and the drug precipitation of the lipid are shown in Table 10.
Table 10 average particle size (nm) of lipid nanoparticles in suspension prepared from the compositions of examples 17-20
The results in Table 10 show that the compositions of examples 17-20, after being diluted into suspensions, had a certain change in particle size over time, but that neither of examples 17-19 had precipitation, cabazitaxel crystallization, etc., and that the lipid nanoparticle particle size was within the acceptable range for injection.
EXAMPLE 21 animal pharmacokinetic, pharmacodynamic and safety Studies
Animal pharmacokinetic experiments
Adult male healthy Sprague-dawley rats were taken in 48, randomly grouped into 8 groups, and given intravenously for one hour. The control group was JEVTANA marketed, and the test group was injected with the compositions prepared in examples 2, 6, 10, 14, and 18, and prepared with 5% glucose injection. The dose and the blood sampling point are shown in Table 11, and the blood sample was measured for cabazitaxel concentration by LC/MS/MS. The results are shown in Table 11 and Table 12.
Table 11 animal pharmacokinetic experiment dosing and blood sampling points
TABLE 12 pharmacokinetic experiment results
From the pharmacokinetic experiments of Table 12, it can be seen that the AUClast of the lipid nanoparticle formulation is significantly higher than the marketed JECTANA group. The relative bioavailability, after conversion to the same dose, was 771% (example 2), 720% (example 6), 763% (example 10), 796% (example 14), 731% (example 18) of JEVTANA group, respectively.
Safety experiment:
adult male healthy sprague-dawley rats were taken 24, randomly grouped 6 per group, and given intravenously for one hour. The negative control group was normal saline, the positive control group was JEVTANA marketed, the test group was the composition prepared in example 2 and example 14, and a lipid nanosuspension was prepared by using 5% glucose injection, and the administration was by injection. Dosage of administration: JETTANA group was 2.5mg/kg, test group was 0.3mg/kg, and blood was collected on days 5, 10, 15, and 20 after administration, and the number of neutrophils was measured. The results are shown in FIG. 1.
Animal safety experimental data indicate that: the cabazitaxel self-assembled lipid nanoparticle composition of the invention is obviously superior to the currently marketed product JEVTANA in preventing neutropenia.
The cabazitaxel self-assembled lipid nanoparticle composition can greatly relieve the serious adverse reaction of neutropenia after the dosage is reduced. Next we examined the anti-tumor efficacy of the two formulations in animals.
Efficacy experiment:
adult male healthy BALB/c nude mice were taken 24, and the right forelimb axilla was inoculated subcutaneously (DU 145 cells 100. Mu.L, 10 total) 7 And is up to 100mm 3 Left and right size, 6 per group. The negative control group was physiological saline, the positive control group was JEVTANA marketed, the test group was the composition prepared in example 2 and example 14, and a lipid nanosuspension was prepared by using 5% glucose injection, and administered by injection. Dosage of administration: JEVTANA group was 2.5mg/kg, test group was 0.3mg/kg, and was administered by tail vein injection once every 15 days, twice in total. Tumor volumes were measured 5 days, 10 days, 15 days (second administration), 20 days, 25 days, and 30 days after the first administration, and tumor-inhibiting effects were observed. The results are shown in FIG. 2.
Animal pharmacodynamics experiment results show that the tumor inhibition rates are respectively as follows: JEVTANA group: 39.8%, example 2 group: 48.2%, example 14 group: 45.7%. But there were no statistical differences between the three groups.
Compared with the currently marketed cabazitaxel injection JECTANA, the cabazitaxel composition prepared by the invention has the advantages of improving the bioavailability, prolonging the half-life in vivo, and greatly reducing the serious toxic and side effects of neutrophil reduction by reducing the administration dosage under the condition of not reducing the anti-tumor curative effect.
Example 22 stability test
The stability of the compositions of the above examples was examined according to conventional stability test methods in the art, such as the accelerated test method, and the results showed that the entire solution composition was stable, the cabazitaxel was not degraded substantially, and the stability was good.
The above embodiments are representative only, and any simple variations and modifications within the spirit of the present invention also fall within the scope of the present invention.
Claims (10)
1. The self-assembled lipid nanometer injection composition of cabazitaxel is mainly formed by combining cabazitaxel with phospholipid, cholesterol, water and ethanol, wherein the phospholipid consists of negatively charged phospholipid and uncharged neutral phospholipid, the composition can be self-assembled to form lipid nanometer suspension, and the average particle size of lipid nanoparticles is in the range of 300nm-450 nm.
2. The composition of claim 1, wherein the weight ratio of cabazitaxel to negatively charged phospholipids, uncharged neutral phospholipids and cholesterol is (5-10): (45-50): 24:5.
3. the composition of claim 1, wherein the weight ratio of cabazitaxel to ethanol and water is (1-2): 983:200.
4. a composition according to any one of claims 1-3, wherein the negatively charged phospholipid is selected from one or more of 1, 2-dimyristoyl-sn-glycero-3-phosphate (DMPA), 1, 2-dipalmitoyl-sn-glycero-3-phosphate (DPPA), 1, 2-dioleoyl-sn-glycero-3-phosphate (DOPA), 1, 2-distearoyl-sn-glycero-3-phosphate (DSPA), dilauroyl phosphatidic acid (DLPA), phosphatidylserine (DPPS), phosphatidylinositol (PI), dilauroyl phosphatidylglycerol (DLPG), dipalmitoyl phosphatidylglycerol (DPPG), distearoyl phosphatidylglycerol (DSPG) and dimyristoyl phosphatidylglycerol (DMPG) and salts thereof, preferably from one or more of DMPA, DSPA, DPPS, DPPG and DMPG and salts thereof, preferably sodium and potassium salts thereof.
5. A composition according to any one of claims 1 to 3, wherein the uncharged neutral phospholipid is selected from egg yolk lecithin, soybean phospholipid, hydrogenated Soybean Phospholipid (HSPC), distearoyl phosphatidylcholine (DSPC), 1, 2-dioleoyl phosphatidylcholine (DOPC), dipalmitoyl phosphatidylcholine (DPPC), dimyristoyl phosphatidylcholine (DMPC), dilauryl phosphatidylcholine (DLPC), distearoyl phosphatidylethanolamine (DSPE), dipalmitoyl phosphatidylethanolamine (DPPE), dimyristoyl phosphatidylethanolamine (DMPE), or one or more of their salts or polyethylene glycol modifications, preferably DSPC and DSPE-PEG2000.
6. The composition of claim 5, wherein the uncharged neutral phospholipids are DSPC and DSPE-PEG2000 in a mass ratio of 5:3.
7. the composition of claim 1, wherein the auxiliary material further comprises citric acid, and the mass ratio of the citric acid to the cabazitaxel is 1: (5-10).
8. The composition of claim 1, wherein the nano-injection composition is heated to 50 ℃ in a water bath prior to injection and then injected into a 5% dextrose injection at room temperature to prepare Cheng Kaba tacrolimus lipid nano-suspension, wherein the concentration of cabazitaxel is about 0.1mg/mL for intravenous administration.
9. A method for preparing the cabazitaxel injection composition of claims 1-8, comprising the steps of sequentially weighing and mixing the components with the prescription amount, stirring and dissolving at the water bath temperature of 50 ℃, filtering and sterilizing by a 0.2 mu m filter, and rolling a cover after filling.
10. Use of the cabazitaxel injection composition of any one of claims 1 to 8 in the manufacture of a medicament for the treatment of prostate cancer.
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