Pharmaceutical composition of paclitaxel conjugate and preparation method thereof

Abstract

The invention relates to the technical field of medicines, in particular to a pharmaceutical composition of a paclitaxel conjugate, which comprises paclitaxel, a paclitaxel analogue or a conjugate thereof, an organic solvent; a solubilizer; and, a pH regulator. The conjugate is ANG1005, the solubilizer comprises mPEG-DSPE, in the mPEG-DSPE, the molecular weight of PEG is 500-10000, the molecular weight of PEG is 500-10000, and in the mPEG-DSPE, the molecular weight of PEG is 500-1000. The weight ratio of the mPEG-DSPE to the ANG1005 is (3 to 15): 1. According to the preparation method, the active substance solution and the solubilizer solution are prepared respectively, and then the two solutions are mixed together, so that the prepared solution is good in physical stability. When the ANG1005 freeze-drying agent prepared by the invention is redissolved, only normal saline is needed as a redissolving agent, the clarification of the redissolving solution can be realized within 5 minutes, and the clinical use is more convenient; the osmotic pressure of the freeze-drying agent after redissolution is lower than that of an ANG1005 freeze-drying agent in the prior art; meanwhile, in the in-vivo metabolism process of the freeze-drying agent (redissolving solution), ANG1005 is higher in chemical stability and not prone to hydrolysis, paclitaxel released in blood is less, and side effects on the human body are smaller.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, specifically to a pharmaceutical composition of a paclitaxel conjugate and its preparation method. Background Technology

[0002] Paclitaxel is a highly effective, broad-spectrum natural anticancer drug that is widely used clinically for breast cancer, ovarian cancer, uterine cancer, and lung cancer. However, paclitaxel itself has poor solubility, and conventional paclitaxel injections can easily trigger allergic reactions in patients. Furthermore, paclitaxel as a chemotherapy drug can lead to drug resistance in tumors.

[0003] Brain metastases primarily originate from cancer cells in lung or breast cancer. Due to resistance to paclitaxel, it is unsuitable for treating secondary brain metastases, leading to the development of paclitaxel conjugates. Paclitaxel conjugates refer to paclitaxel molecules bound with biologically active amino acid fragments, such as aprotinin, biologically active aprotinin fragments, angiopeptide-1, angiopeptide-2, and their biologically active analogs, derivatives, or fragment amino acid sequences. Chinese patent application number 200480003544.8 discloses an angiopeptide that crosses the blood-brain barrier and is linked to paclitaxel. Chinese patent application number 200580049237.8 also discloses an amino acid sequence linked to paclitaxel and the manner in which the amino acid is linked to paclitaxel, i.e., three paclitaxel molecules are conjugated to a polypeptide via a linker. Chinese patent application number 201410334833.1 discloses the structure of a paclitaxel conjugate: two or three paclitaxel molecules are conjugated to a polypeptide structure via succinic acid to form a paclitaxel conjugate. Because it binds to a polypeptide, this paclitaxel conjugate can cross the blood-brain barrier for the treatment of tumors, particularly brain cancer. This paclitaxel conjugate can also be used for further treatment of cancer drug resistance.

[0004] ANG1005 is a paclitaxel conjugate, the specific structure of which is described in patent 200580049237.8. Due to the hydrophobicity of paclitaxel itself, ANG1005 has poor water solubility, making the development of injectable formulations difficult. To address this challenge, patent 20068003365.8 discloses a composition for treating cancer, which includes the use of polyethylene glycol 15-hydroxystearate in the composition (…). HS-15 (hereinafter referred to as solubilol) is used as a solubilizer. A lyophilized composition of ANG1005 is disclosed in Chinese Patent No. 200980117029.5. Solubilol is used as a solubilizer in this composition. The advantage of this formulation is that it eliminates the use of Cremophor, an excipient that easily causes allergic reactions. However, the ANG1005 nanomicelle formulation solution prepared using solubilol has poor physical stability; the particle size increases significantly within 24 hours, easily causing turbidity and complicating subsequent processes. Furthermore, in clinical use, lactated Ringer's solution containing 5% glucose is required as a resolvent for the lyophilized powder, with a resolution time of up to one hour, creating difficulties for clinical staff. Additionally, the osmotic pressure of the resolvented injection reaches 500 mOsmol / kg, exceeding the isotonic range of 280 mOsmol / kg-320 mOsmol / kg, easily leading to adverse reactions such as phlebitis. In addition, the ANG1005 nanomicelle formulation prepared using solubilol exhibits poor stability after entering the bloodstream, readily degrading into the active substance paclitaxel. Since the degraded paclitaxel lacks targeting peptides, it not only hinders the targeted delivery of paclitaxel to the brain but also, due to the high toxicity of paclitaxel, easily causes systemic side effects. Summary of the Invention

[0005] Therefore, there is an urgent need to screen for a novel excipient that can increase the solubility of ANG1005 while also improving the drug's in vivo and in vitro stability, increasing ease of use, reducing adverse reactions, and enhancing efficacy. To address these issues, this application provides a pharmaceutical composition of a paclitaxel conjugate and its preparation method, as detailed below.

[0006] A composition comprising: paclitaxel, a paclitaxel analogue or a paclitaxel conjugate; a solubilizer; and a pH adjuster.

[0007] Furthermore, the paclitaxel conjugate is ANG1005.

[0008] Furthermore, the solubilizer comprises mPEG-DSPE.

[0009] Furthermore, the pH adjuster is selected from one or more of lactic acid, phosphoric acid, acetic acid, citric acid, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

[0010] Furthermore, the composition also includes a lyophilization protectant selected from one or more of mannitol, glucose, galactose, lactose and sucrose.

[0011] Furthermore, in the mPEG-DSPE, the molecular weight of PEG is 500-10000;

[0012] Further preferably, in the mPEG-DSPE, the molecular weight of PEG is 1000-5000.

[0013] In one specific embodiment of this application, the weight ratio of mPEG-DSPE to ANG1005 is (3-15):1; preferably, the weight ratio of mPEG-DSPE to ANG1005 is (5-10):1.

[0014] This application also provides a method for preparing the composition, the steps of which include:

[0015] Paclitaxel, paclitaxel analogues, or paclitaxel conjugates are dissolved in an organic solvent to obtain an organic phase solution; an aqueous solution of the solubilizer is prepared.

[0016] The organic phase solution is mixed with the aqueous solution of the solubilizer, an optional lyophilization protectant is added and stirred until homogeneous, and the pH is adjusted by adding a pH adjuster to obtain a micelle solution; the micelle solution is then treated to obtain the composition.

[0017] Furthermore, the organic solvent is DMSO, and the weight of DMSO in the lyophilized powder is less than 0.2%.

[0018] Furthermore, when preparing the organic phase solution, paclitaxel, paclitaxel analogues, or paclitaxel conjugates are added to the acidified organic solvent.

[0019] Furthermore, to prepare an aqueous solution of the solubilizer, the solubilizer is added to the buffer, and then the pH is adjusted to 2.0-6.0 using a pH adjuster.

[0020] Furthermore, the buffer is citric acid and / or glycine.

[0021] Furthermore, the pH value of the micelle solution is 4.0-6.0.

[0022] The use of the composition provided in this application in the preparation of medicaments for treating breast cancer, ovarian cancer, uterine cancer and lung cancer.

[0023] A composition prepared by the method provided in this application is used in the preparation of medicaments for treating breast cancer, ovarian cancer, uterine cancer, and lung cancer.

[0024] Beneficial effects:

[0025] Unlike Solutol HS15, a solubilizer used in existing ANG1005 formulations, this application uses mPEG-DSPE as a solubilizer, which enhances the stability of micelle solutions containing ANG1005, maintaining clarity for better and longer periods, up to 72 hours or longer, meeting both production and clinical dosing requirements. In terms of preparation, this application employs a method of separately preparing the active substance solution and the solubilizer solution, and then mixing the two solutions together, resulting in a solution with good physical stability. Furthermore, the ANG1005 lyophilized preparation prepared in this application only requires physiological saline as a resolvent during reconstitution, achieving clarification of the reconstituted solution within 5 minutes, making clinical use more convenient. The osmotic pressure of the lyophilized preparation prepared in this application after reconstitution is lower than that of existing ANG1005 lyophilized formulations. In addition, during in vivo metabolism, the ANG1005 in the lyophilized preparation (reconstituted solution) prepared in this application exhibits stronger chemical stability, is less prone to hydrolysis, releases less paclitaxel in the blood, and has fewer side effects on the human body. Attached Figure Description

[0026] The accompanying drawings are provided to better understand this application and do not constitute an undue limitation thereof. Wherein:

[0027] Figure 1 The properties of the micelle solutions of each embodiment and comparative example in Experimental Example 1 of this application are shown, wherein, from left to right, they are the micelle solutions prepared by Example 1, Comparative Example 1, Comparative Example 2, Comparative Example 3, Comparative Example 4, Comparative Example 5, Comparative Example 6 and Comparative Example 7.

[0028] Figure 2 This shows a transmission electron microscope (TEM) image of the ANG1005 micelle nanoparticles prepared in Example 1 of this application.

[0029] Figure 3 The image shows a transmission electron microscope (TEM) image of ANG1005 micelle nanoparticles prepared by Chinese patent CN102026667B. Detailed Implementation

[0030] The following description provides exemplary embodiments of this application, including various details to aid understanding, and should be considered merely exemplary. Therefore, those skilled in the art will recognize that various changes and modifications can be made to the embodiments described herein without departing from the scope and spirit of this application. Similarly, for clarity and brevity, descriptions of well-known functions and structures are omitted in the following description.

[0031] In this application, "mPEG-DSPE" refers to distearate phosphatidylethanolamine-methoxy polyethylene glycol, a surface modifier commonly used in biomedical research and drug delivery systems. This compound combines methoxy polyethylene glycol (mPEG) and phospholipids (DSPE), where the molecular weight of mPEG is 500-10000. mPEG-DSPE is commonly used in the preparation of liposomes. Liposomes are nanoparticles composed of a phospholipid bilayer, used to deliver drugs or biomolecules. Specifically, mPEG2000-DSPE exhibits certain solubility and wetting properties, forming micelle structures in both water and organic solvents. It also possesses certain biocompatibility and biodegradability.

[0032] In this application, "mPEG500-DSPE" refers to methoxylated polyethylene glycol (mPEG) with a molecular weight of 500. Similarly, "mPEG2000-DSPE" refers to methoxylated polyethylene glycol (mPEG) with a molecular weight of 2000. The molecular weight of mPEG-DSPE mentioned in this application refers to the weight-average molecular weight. mPEG2000-DSPE possesses certain solubility and wetting properties, can form micelle structures in water and organic solvents, and also exhibits certain biocompatibility and biodegradability.

[0033] In this application, "solvent" refers to any solvent capable of dissolving a particular compound (e.g., a hydrophobic compound, such as a compound or combination containing paclitaxel or a paclitaxel analogue). This application describes exemplary solubilizers suitable for hydrophobic compounds.

[0034] In this application, "conjugate" is a carrier attached to a drug, and the conjugate can be chemical, such as via a linker, or genetic, such as via a protein fusion using recombinant gene technology.

[0035] In this application, "lyophilized powder" refers to a sterile powder composition prepared by freezing a pharmaceutical agent into a solid state under sterile conditions and then sublimating and drying the water under vacuum.

[0036] In this application, "purified water" refers to water with a resistivity greater than 0.1 × 10⁶ Ω*cm at a temperature greater than 25°C.

[0037] In this application, unless otherwise specified, "buffer" is a solution of citric acid and / or glycine.

[0038] In this application, the relevant structure and properties of “ANG1005” are described in Chinese Patent CN107921143A, and the preparation methods of ANG1005 are all referenced from Chinese Patent CN101160403B.

[0039] In this application, "substantially pure" or "isolated" means a compound (e.g., a polypeptide or conjugate) that is separate from other chemical components. Typically, a compound is substantially pure when it contains at least 30% by weight of no other components. In some embodiments, the formulation contains at least 50%, 60%, 75%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% by weight of no other components. Purified polypeptides can be obtained, for example, by expression of a recombinant polynucleotide encoding such a polypeptide or by chemical synthesis of the polypeptide. Purity can be determined by any suitable method, such as column chromatography, polyacrylamide gel electrophoresis, or by HPLC analysis.

[0040] In this application, a pharmaceutical composition that is "substantially free" of a certain substance means that the amount of the substance in the composition is less than 5%, 4%, 3%, 2%, 1%, 0.5%, 0.3%, 0.2%, 0.1%, 0.05%, or 0.01% of the dry weight of the composition.

[0041] In this application, "pharmaceutical" means any compound, such as an antibody, or a therapeutic agent, marker, tracer, or imaging compound.

[0042] In this application, "therapeutic agent" refers to a biologically active pharmaceutical agent. In some cases, the therapeutic agent is used to treat symptoms of disease, physical or mental condition, trauma or infection, and includes anticancer agents, antibiotics, anti-angiogenic agents, and molecules active at the central nervous system level.

[0043] In this application, "cancer" refers to the proliferation of any cell characterized by a loss of normal control, resulting in uncontrolled growth, lack of differentiation, or the ability to invade and metastasize tissues. Cancer can occur in any tissue or organ. Cancer is intended to include, but is not limited to, breast cancer, ovarian cancer, uterine cancer, lung cancer, brain cancer, liver cancer, kidney cancer, or spleen cancer. Other cancers are described herein.

[0044] In this application, "give" refers to the mode of delivery, including but not limited to oral, intra-arterial, intranasal, intraperitoneal, intravenous, intramuscular, subcutaneous, transdermal, or oral administration. The daily dose may be divided into one, two, or more doses in a suitable manner, thereby being administered once, twice, or more times over a period of time.

[0045] In this application, "reconstituted solution" refers to a solution obtained by placing lyophilized powder back into a solvent (such as physiological saline).

[0046] In this application, when the term "range" or "composition of substance" is mentioned in relation to a specific characteristic (e.g., temperature, concentration, time, etc.), the invention relates to and is expressly incorporated herein by reference to the combination of each and every specific member and its sub-ranges or subgroups. Thus, for example, a length of 9 to 18 amino acids should be understood to specifically include each and every single length, such as lengths of 18, 17, 15, 10, 9, and any number of lengths in between. Therefore, unless specifically indicated, each range mentioned herein should be understood to include the end value. For example, an expression of a length of 5 to 19 amino acids should be understood to include 5 and 19. Similarly, this also applies to other parameters, such as length, concentration, etc.

[0047] In this application, paclitaxel analogues include taxoid, (2α,5α,7β,9α,10β,13α)-5,10,13,20-tetraacetoxytaxo-11-en-2,7,9-triol, (2α,5α,9α,10β)-2,9,10-triacetoxy-5-((β-D-glucopyranosyl)oxy)-3,11-cyclotaxo-11-en-13-one, 1β-hydroxybaccatin I, 1,7-dihydroxytaxine (pine resin, taxinine), 1-acetyl-5,7,10-deacetyl-baccatin I, 1-dehydroxybaccatin VI, 1-hydroxy-2-deacetoxy-5-decinnamon Acyl-Taxotere J, 1-Hydroxy-7,9-Dideacetylbacardine I, 1-Hydroxybacardine I, 10-Acetyl-4-Deacetyltaxotere, 10-Deacetoxypaclitaxel, 10-Deacetylbacardine III disolvate, 10-Deacetyl-10-(3-aminobenzoyl)paclitaxel, 10-Deacetyl-10-(7-(diethylamino)coumarin-3-carbonyl)paclitaxel, 10-Deacetyl-9-dihydrotaxol (taxol), 10-Deacetylbacardine III, 10-Deacetylpaclitaxel, 10-Deacetyltaxine, 10-Deoxy-10- C-morpholine ethyl taxane (docetaxel), 10-O-acetyl-2-O-(cyclohexylcarbonyl)-2-debenzoyltaxyl texoterol, 10-O-sec-aminoethyl taxane, 11-demethyllolimanolide, 13-deoxy-13-acetoxy-7,9-diacetyl-1,2-dideoxytaxine (taxine), 13-deoxybacardine III, 14-hydroxy-10-deacetyl-2-O-debenzoylbacardine III, 14-hydroxy-10-deacetylbacardine III, 14β-benzoyloxy-13-deacetylbacardine IV, 14β-benzoyloxy-2-deacetylbacardine VI, 14β-benzoyloxybacardine IV, 1 9-Hydroxybacardine III, 2',2”-Methylene taxane, 2',2”-Methylene paclitaxel, 2'-(valine-leucyl-lysyl-p-aminoase-oxycarbonyl)paclitaxel, 2'-acetyltaxine, 2'-O-acetyl-7-O-(N-(4'-fluorescein carbonyl)alanyl)taxine, 2,10,13-triacetoxy-taxane-4(20),11-diene-5,7,9-triol, 2,20-O-diacetylditerpene taxane (taxumairol)N, 2-(4-azidobenzoyl)taxine, 2-deacetoxytaxine J, 2-debenzoyl-2-m-methoxybenzoyl-7-triethylsilyl-13-oxo-14-hydroxybacardine III 1,14-carbonate, 2-O-(cyclohexylcarbonyl)-2-debenzoylbacardine III, 13-O-(N-(cyclohexylcarbonyl)-3-cyclohexylisoserine ester), 2α,7β,9α,10β,13α-pentaacetoxytaxane-4(20), 11-dien-5-ol, 2α,5α,7β,9α,13α-pentahydroxy-10β-acetoxytaxane-4(20), 11-diene, 2α,7β,9α,10β,13-pentaacetoxy-11β-hydroxy-5α-(3'-N,N-dimethylamino-3'-phenyl)-propionyloxytaxane-4(20), 12-diene, 2α,7β-diacetoxy-5α,10β,13β- Trihydroxy-2(3-20)rosin (abeo)-taxo-4(20),11-dien-9-one, 2α,9α-dihydroxy-10β,13α-diacetoxy-5α-(3'-methylamino-3'phenyl)-propionyloxytaxo-4(20),11-diene, 2α-hydroxy-7β,9α,10β,13α-tetraacetoxy-5α-(2'-hydroxy-3'-N,N-dimethylamino-3'-phenyl)-propionyloxytaxo-4(20),11-diene, 3'-(4-azidobenzoylamino)taxoyl, 3'-N-(4-benzoyldihydrocinnamoyl)-3'-N-debenzoylpaclitaxel, 3'-N-m-aminobenzoylamino- 3'-Debenzoylaminopaclitaxel, 3'-p-hydroxypaclitaxel, 3,11-cyclotaxane NN-2,4-deacetyltaxane, 5,13-diacetoxy-taxane-4(20),11-diene-9,10-diol, 5-O-benzoyltaxane K, 5-O-phenylpropionyloxytaxane A, 5α,13α-diacetoxy-10β-cinnamoyloxy-4(20),11-taxadien-9α-ol, 6,3'-p-dihydroxypaclitaxel, 6α-hydroxy-7-deoxy-10-deacetylbacardine-III, 6-fluoro-10-acetyltaxene, 6-hydroxytaxane, 7,13-diacetoxy-5-cinnamoyloxy-2(3-20)-pine Taxyl-4(20),11-diene-2,10-diol, 7,9-bisdeacetylated bacardine VI, 7-(5'-biotinylamidopropanoyl)paclitaxel, 7-acetylpaclitaxel, 7-deoxy-10-deacetylated bacardine-III, 7-deoxy-9-dihydropaclitaxel, 7-epitaxyl, 7-methylthiomethylpaclitaxel, 7-O-(4-benzoyldihydrocinnamoyl)paclitaxel, 7-O-(N-(4'-fluorescein carbonyl)alanyl)paclitaxel, 7-xyloside-10-deacetylated paclitaxel, 8,9-mono-epoxybrassyl (8,9-single-epoxy brevifolin), 9-dihydrobacardine III, 9-dihydrotamethasone, 9α-hydroxy-2α,10β,13α-triacetoxy-5α-(3'-N-dimethylamino-3'phenyl)-propionyloxytaxane-4(20),11-diene, bacardine III, bacardine III13-O-(N-benzoyl-3-cyclohexylisoserine ester), BAY59, benzoyltamethasone, BMS181339, BMS18566 0. BMS188797, brevifoliol, cephalomannine, dantaxusin A, dantaxusin B, dantaxusin C, dantaxusin D, dibromo-10-deacetylcephalomannine, taxane, glutarylpaclitaxel, 6-aminohexanol glucoside, isolarimide, lauroyl, MST 997, N-(paclitaxel-2'-O-(2-amino)phenylpropionate)-O-(β-glucuronyl)carbamate, N-(paclitaxel-2'-O-3,3-dimethylbutyrate)-O-(β-glucuronyl)carbamate, N-desbenzoyl-N-(3-(dimethylamino)benzoyl)paclitaxel, nonataxel, octreotide-conjugated paclitaxel, paclitaxel, paclitaxel-transferrin, PNU 166945, polyethylene glycol-conjugated paclitaxel-2'-glycine ester, polyglutamic acid-paclitaxel, paclitaxel precursor, RPR 109881A, SBT-101187, SBT-1102, SBT-1213, SBT-1214, SBT-1250, SBT-12843, tasumatrol E (taxanes), taxane-4(20), 11(12)-diene-5-yl acetate, taxane-4(20),11(12)-Dien-5-ol, Taxane, Taxcultine D, Taxezopidine M, Taxezopidine N, Taxine, Taxine A, Taxine M, Taxine NN-1, Taxine NN-7, Taxol C-7-xylose, Taxol-sialyl conjugate, Diterpenoid Taxane A, Diterpenoid Taxane B, Diterpenoid Taxane G, Diterpenoid Taxane H, Diterpenoid Taxane I, Diterpenoid Taxane K, Diterpenoid Taxane M, Diterpenoid Taxane N, Diterpenoid Taxane O, Diterpenoid Taxane U, Diterpenoid Taxane V, Diterpenoid Taxane W, Diterpenoid Taxane-X, Diterpenoid Taxane-Y, Diterpenoid Taxane-Z, Taxusin, Taxuspinanane A) Taxuspinanane B, Taxuspine C, Taxuspine D, Taxuspine F, Taxuyunnanine C, Taxuyunnanine S, Taxuyunnanine T, Taxuyunnanine U, Taxuyunnanine V, tRA-96023.

[0048] In this application, other paclitaxel analogues include 1-deoxypaclitaxel, 10-deacetoxy-7-deoxypaclitaxel, 10-O-deacetylpaclitaxel 10-succinyl monoester, 10-succinylpaclitaxel, 12b-acetoxy-2a,3,4,4a,5,6,9,10,11,12,12a,12b-dodecylhydro-4,11-dihydroxy-12-(2,5-dimethoxybenzyloxy)-4a,8,13,13-tetramethyl-5-oxo-7,11-bridged methylene(methano)-1H-cyclodecano(3,4)benzo(1,2-b)oxet-9-yl 3-(tert-butoxycarbonyl)amino-2-hydroxy-5-methyl-4-hexenoester, 130-nm albumin-bound paclitaxel, and 2'-paclitaxel methyl 2-pyranoselusuccinate. Ester, 3'-(4-azidophenyl)-3'-dephenylpaclitaxel, 4-fluoropaclitaxel, 6,6,8-trimethyl-4,4a,5,6,7,7a,8,9-octahydrocyclopentano(4,5)cycloheptano(1,2-c)-furan-4,8-diol 4-(N-acetyl-3-phenylisoserine ester), 6,6,8-trimethyl-4,4a,5,6,7,7a,8,9- Octahydrocyclopentano(4,5)cycloheptano(1,2-c)-furan-4,8-diol 4-(N-tert-butoxycarbonyl-3-phenylisoserine ester), 7-(3-methyl-3-nitrosobutyryl))paclitaxel, 7-deoxypaclitaxel, 7-succinotaxel, albumin-bound paclitaxel, AZ10992, isopataxel, MAC321, NKl 05, polyglutamic acid paclitaxel (paclitaxelpoliglumex), paclitaxel-EC-1 conjugate and TXD 258.

[0049] In this application, "micelle solution" refers to a thermodynamically stable colloidal aggregate formed by the self-assembly of molecules in an aqueous solution when a surfactant reaches a certain concentration.

[0050] In this application, when visually inspecting the clarification of the micelle solution, it can be found that the solution has the properties of being clear, opalescent, and milky white. "Opacity" refers to the scattering of light caused by particles in the solution being smaller than the wavelength of visible light, and the particle size of the sample is slightly larger, usually about 100-1000 nm. "Milky white" refers to the solution being white to off-white and opaque, and the particle size of the sample is relatively large, usually greater than 1000 nm. "Clear" refers to the solution being colorless and transparent, and the particle size of the sample is relatively small, usually less than 100 nm.

[0051] Unless otherwise stated, all mPEG-DSPE used in this application was purchased from Jiangsu Southeast Nanomaterials Co., Ltd.

[0052] In this application, "AUClast" refers to the area under the drug-time curve from the start of dosing to the last point.

[0053] In this application, "AUCinf" represents the area under the drug-time curve from the time of administration to the theoretical extrapolated infinity.

[0054] In this application, "Cmax" refers to the highest plasma drug concentration that can be achieved after administration.

[0055] In this application, "T1 / 2" refers to the half-life of a drug in the blood or body.

[0056] This application provides a composition comprising ANG1005, mPEG-DSPE, and a pH adjuster.

[0057] This application provides a composition comprising ANG1005, a lyophilization protectant, a pH adjuster, and mPEG-DSPE.

[0058] This application provides a composition comprising ANG1005, a lyophilization protectant, a pH adjuster, a buffer, and mPEG-DSPE.

[0059] This application provides a composition comprising ANG1005, a lyophilization protectant, a pH adjuster, a buffer, an osmotic pressure regulator, and mPEG-DSPE.

[0060] This application provides a composition comprising ANG1005, a lyophilization protectant, a pH adjuster, a buffer, an osmotic pressure regulator, and mPEG-DSPE.

[0061] This application provides a composition comprising ANG1005, glycine, citric acid, and mPEG2000-DSPE.

[0062] In this application, the lyophilization protectant used in the composition and preparation method thereof is a commonly used lyophilization protectant in the art, such as one or more of mannitol, glucose, galactose, lactose and sucrose.

[0063] In this application, the pH adjuster used in the composition and preparation method provided herein is a pH adjuster commonly used in the art, such as one or more of lactic acid, phosphoric acid, acetic acid, citric acid, sodium carbonate, sodium bicarbonate and sodium hydroxide.

[0064] In one specific embodiment of this application, the weight ratio of mPEG-DSPE to ANG1005 in the composition is (3-15):1, for example, it can be 3:1, 3.5:1, 4:1, 4.5:1, 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, 10:1, 10.5:1, 11:1, 11.5:1, 12:1, 12.5:1, 13:1, 13.5:1, 14:1, 14.5:1, or 15:1.

[0065] Preferably, the weight ratio of mPEG-DSPE to ANG1005 is (5-10):1, for example, it can be 5:1, 5.5:1, 6:1, 6.5:1, 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, or 10:1.

[0066] The composition of this application can be prepared by the following preparation method, wherein the content of DMSO in the composition is less than 0.2% by weight.

[0067] This application provides a method for preparing a composition, the steps of which include:

[0068] Weigh out DMSO and add it to citric acid solution to obtain a mixed solution;

[0069] Add ANG1005 to the mixed solution and stir to dissolve, to obtain a DMSO solution of ANG1005;

[0070] Weigh out purified water and add solid glycine or citric acid to obtain an acidified solution;

[0071] Add a solubilizer to the acidified solution and adjust the pH to obtain a solubilized solution;

[0072] After preheating the solubilizing solution, add DMSO solution of ANG1005 and adjust the pH to obtain a micelle solution.

[0073] This application provides a method for preparing a composition, the steps of which include:

[0074] Weigh out DMSO and add it to citric acid solution to obtain acidified DMSO solution;

[0075] Add ANG1005 to the acidified DMSO solution, stir to dissolve, and obtain a DMSO solution of ANG1005.

[0076] Weigh out purified water and add solid glycine or citric acid to obtain an acidified solution;

[0077] Add a solubilizer to the acidified solution and adjust the pH to obtain a solubilized solution;

[0078] After preheating the solubilizing solution, add DMSO solution of ANG1005, stir evenly, add lyophilization protectant, adjust pH, and obtain micelle solution.

[0079] The micelle solution is filtered, filled, and freeze-dried in a freeze dryer to obtain a freeze-dried powder, which is the composition of the above application, wherein the weight of DMSO in the freeze-dried powder is less than 0.2%.

[0080] In one specific embodiment of this application, the solubilizer is selected from water-soluble organic solvents (e.g., polyethylene glycol 300, polyethylene glycol 400, ethanol, propylene glycol, glycerol, N-methyl-2-pyrrolidone, dimethylacetamide, and dimethyl sulfoxide), nonionic surfactants (e.g., polyoxyethylene castor oil EL (Cremophor EL), polyoxyethylene castor oil RH40 (Cremophor RH 40), polyoxyethylene castor oil RH60 (Cremophor RH 60), D-α-tocopherol polyethylene glycol 1000 succinate, polysorbate 20, polysorbate 80, Solutol HS15 (polyethylene glycol 15-hydroxystearate), sorbitan monooleate, poloxamer 407, oleic acid polyethylene glycol glycerol ester (Labrafil M-1944CS), linoleic acid polyethylene glycol glycerol ester (Labrafil M-1944CS). M-2125CS), PEG-6 caprylic / capric glyceride (Labrasol), PEG-6 caprylic / capric glyceride (Softigen) 767), and mono- and di-fatty acid esters of polyethylene glycol (PEG) 300, 400 or 1750, water-soluble lipids (e.g., medium-chain triglycerides of castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oil, hydrogenated soybean oil, and coconut oil and palm kernel oil), organic liquid / semi-solids (beeswax, d-α-tocopherol, oleic acid, medium-chain mono- and di-glycerides), cyclodextrins (e.g., α-cyclodextrin, β-cyclodextrin, hydroxypropyl-β-cyclodextrin, and sulfobutyl ether-β-cyclodextrin), and phospholipids (e.g., hydrogenated soybean phosphatidylcholine, distearyl phosphatidylglycerol, l-α-dimyristoyl phosphatidylcholine, l-α-dimyristoyl phosphatidylglycerol).

[0081] In one specific embodiment of this application, the solubilizer is mPEG-DSPE, wherein the molecular weight of mPEG-DSPE is 500-10000, for example, the molecular weight can be 500, 1000, 1500, 2000, 2500, 3000, 3500, 4000, 4500, 5000, 5500, 6000, 6500, 7000, 7500, 8000, 8500, 9000, 9500, or 10000.

[0082] In one specific embodiment of this application, the pH adjuster added during the preparation of the composition is a commonly used pH adjuster in the art, selected from one or more of lactic acid, phosphoric acid, acetic acid, citric acid, sodium carbonate, sodium bicarbonate and sodium hydroxide.

[0083] In one specific embodiment of this application, the freeze-drying protectant added during the preparation of the composition is selected from one or more of mannitol, glucose, galactose, lactose and sucrose.

[0084] In one specific embodiment of this application, during the preparation of the composition, the pH of the solubilizing solution needs to be maintained between 2.0 and 6.0, for example, pH=2.0, pH=3.0, pH=4.0, pH=5.0, or pH=6.0.

[0085] In one specific embodiment of this application, during the preparation of the composition, the pH of the micelle solution is maintained at 4.0-6.0, for example, pH=4.0, pH=5.0, or pH=6.0.

[0086] In one specific embodiment of this application, an osmotic pressure regulator is added during the preparation of the composition to adjust the osmotic pressure.

[0087] In this application, the added osmotic pressure regulator is a commonly used regulator in the art, such as one or more of sodium chloride, potassium chloride, glucose and glycerol.

[0088] Example

[0089] English Abbreviation Reference Table

[0090] English abbreviations Chinese translation DMSO Dimethyl sulfoxide mPEG-DSPE Distearate phosphatidylethanolamine-methoxy polyethylene glycol mPEG-PLGA Polyethylene glycol monomethyl ether-polylactic acid block copolymer mPEG-PLA Polyethylene glycol monomethyl ether-polylactic acid glycol acetic acid copolymer RH Indoor humidity Z-Ave Average particle size

[0091] Example 1

[0092] To prepare the DMSO acidified solution of ANG1005, weigh 137.5 mg of DMSO, add 2.86 mg of 1 mol / L citric acid solution, mix well, and then add a total of 15 mg of ANG1005 to the mixed solution and stir to dissolve.

[0093] To prepare the solubilizing solution, weigh 2.5 g of purified water, add 28.125 mg of solid glycine, and stir until completely dissolved to obtain a glycine solution. Add 125 mg of solubilizer mPEG2000-DSPE to the glycine solution, stir until completely dissolved, and adjust the pH to 4.5 with 1 mol / L sodium carbonate aqueous solution.

[0094] The solubilizing solution was preheated at 40°C, and acidified DMSO solution of ANG1005 was slowly added dropwise. The mixture was stirred until homogeneous to obtain a micelle solution.

[0095] Comparative Example 1

[0096] The difference between this comparative example and Example 1 is that the solubilizer added is Solutol HS-15.

[0097] Comparative Example 2

[0098] The difference between this comparative example and Example 1 is that the added solubilizer is polyoxyethylene (40) hydrogenated castor oil.

[0099] Comparative Example 3

[0100] The difference between this comparative example and Example 1 is that the solubilizer added is Tween 80.

[0101] Comparative Example 4

[0102] The difference between this comparative example and Example 1 is that the solubilizer added is polyoxyethylene (35) castor oil.

[0103] Comparative Example 5

[0104] The difference between this comparative example and Example 1 is that the solubilizer added is poloxamer 188.

[0105] Comparative Example 6

[0106] The difference between this comparative example and Example 1 is that the solubilizer added is mPEG. 2000 -PLA.

[0107] Comparative Example 7

[0108] The difference between this comparative example and Example 1 is that the solubilizer added is mPEG. 2000 -PLGA.

[0109] Table 1. Components of each embodiment and comparative example

[0110]

[0111] Experimental Example 1

[0112] The micelle solutions prepared in Example 1 and Comparative Examples 1-7 were placed at room temperature, and the clarity of the solutions was visually inspected and recorded in Table 2.

[0113] Table 2 Clarity of micelle solutions in each example and comparative example

[0114]

[0115] From Table 2 and reference Figure 1It can be seen that the micelle solution prepared using mPEG2000-DSPE in Example 1 remained clear, while the micelle solutions obtained in Comparative Examples 1, 2, 4, and 5 showed an opalescent appearance, and the solutions obtained in Comparative Examples 3, 6, and 7 produced a milky white appearance. Therefore, for ANG1005, mPEG2000-DSPE is the optimal solubilizer.

[0116] Example 2

[0117] To prepare the DMSO acidified solution of ANG1005, weigh 7.0 g of DMSO, add 146 mg of 1 mol / L citric acid solution, mix well, and then add a total of 770 mg of ANG1005 to the mixed solution and stir to dissolve.

[0118] To prepare the solubilizing solution, weigh 108g of purified water, add 257mg of solid citric acid, and stir until completely dissolved to obtain a citric acid solution. Add 3850mg of solubilizer mPEG500-DSPE to the citric acid solution, stir until completely dissolved, and adjust the pH to 4.0 with 1mol / L sodium carbonate aqueous solution.

[0119] Preheat the solubilizing solution to 40°C, stir the solubilizing solution containing mPEG500-DSPE rapidly, slowly add acidified DMSO solution of ANG1005 dropwise, stir until homogeneous to obtain a micelle solution, add 10g of lactose after the micelle solution has clarified, stir until homogeneous at room temperature, adjust the pH to 5.0 with 1mol / L sodium carbonate aqueous solution, and filter through a 0.2μm microporous membrane.

[0120] Example 3

[0121] The difference between this embodiment and Embodiment 2 is that the molecular weight of the added mPEG-DSPE is 1000.

[0122] Example 4

[0123] The difference between this embodiment and Embodiment 2 is that the molecular weight of the added mPEG-DSPE is 2000.

[0124] Example 5

[0125] The difference between this embodiment and Embodiment 2 is that the molecular weight of the added mPEG-DSPE is 5000.

[0126] Example 6

[0127] The difference between this embodiment and Embodiment 2 is that the molecular weight of the added mPEG-DSPE is 10000.

[0128] Table 3 Components of each embodiment

[0129]

[0130] Experiment Example 2

[0131] The micelle solutions prepared in Examples 2-6 were placed at room temperature, and the clarity of the solution was visually inspected. When any condition affecting the clarity, such as opalescence or milky whiteness, could be observed in the solution, the duration of maintaining clarity was recorded in Table 4 below.

[0132] Table 4 Clarification time of micelle solutions in each example

[0133]

[0134] As shown in Table 4, mPEG is used. 2000 Micellar solutions prepared with DSPE exhibited the longest clarification time of 72 hours at room temperature, demonstrating the highest physical stability. (Using mPEG...) 1000 -DSPE and mPEG 5000 The micelle solution prepared by DSPE can be maintained for 60 hours, exhibiting high physical stability.

[0135] Example 7

[0136] To prepare the DMSO acidified solution of ANG1005, weigh 7.0 g of DMSO, add 146 mg of 1 mol / L citric acid solution, mix well, and then add a total of 770 mg of ANG1005 to the mixed solution and stir to dissolve.

[0137] To prepare the solubilizing solution, weigh 108g of purified water, add 257mg of solid citric acid, and stir until completely dissolved to obtain a citric acid solution. Add 2310mg of solubilizer mPEG2000-DSPE to the citric acid solution, stir until completely dissolved, and adjust the pH to 4.0 with 1mol / L sodium carbonate aqueous solution.

[0138] Preheat the solubilizing solution to 40°C, stir the solubilizing solution containing mPEG2000-DSPE rapidly, slowly add acidified DMSO solution of ANG1005 dropwise, stir until homogeneous to obtain a micelle solution, add 10g of lactose after the micelle solution has clarified, stir until homogeneous at room temperature, adjust the pH to 3.0 with 1mol / L sodium carbonate aqueous solution, and filter through a 0.2μm microporous membrane.

[0139] Example 8

[0140] The difference between this embodiment and Embodiment 7 is that the added mPEG 2000 -DSPE dosage is 3850mg.

[0141] Example 9

[0142] The difference between this embodiment and Embodiment 7 is that the added mPEG 2000 -DSPE dosage is 6545mg.

[0143] Example 10

[0144] The difference between this embodiment and Embodiment 7 is that the added mPEG 2000 -DSPE dosage is 7700mg.

[0145] Example 11

[0146] The difference between this embodiment and Embodiment 7 is that the added mPEG 2000 -DSPE dosage is 11550mg.

[0147] Table 5 Components of each embodiment

[0148]

[0149]

[0150] Experimental Example 3

[0151] The micelle solutions prepared in Examples 7-11 were placed at room temperature, and the clarity of the solution was visually inspected. When any condition affecting the clarity, such as opalescence or milky whiteness, could be observed in the solution, the duration of maintaining clarity was recorded in Table 6. At the same time, the viscosity of the solution was measured using a rotational viscometer. The rotational viscometer used in this experiment was an NDS-5S, rotor No. 1, 30 rpm.

[0152] Table 6 Clarification time and flowability of micelle solutions in each example.

[0153]

[0154] As can be seen from Table 6, mPEG was used in Examples 8-11. 2000 When the mass ratio of DSPE to ANG1005 is 5:1 to 10:1, the prepared micelle solution has good physical stability at room temperature, low viscosity, remains clear after 72 hours, and has good fluidity. In Example 12, although the clarification time is also long, the micelle viscosity is high at 46 mPa·s, resulting in poor fluidity, which is not conducive to subsequent sample freeze-drying.

[0155] Example 12

[0156] To prepare the DMSO acidified solution of ANG1005, weigh 7.04 g of DMSO, add 146.43 mg of 1 mol / L citric acid solution, mix well, and then add a total of 768 mg of ANG1005 to the mixed solution and stir to dissolve.

[0157] To prepare the solubilizing solution, weigh 103.2 g of purified water, add 192 mg of solid citric acid, and stir until completely dissolved to obtain a citric acid solution. Then, add 3840 mg of the solubilizer mPEG to the citric acid solution. 2000 -DSPE, stir until completely dissolved, and adjust the pH to 4.5 with a 1 mol / L sodium carbonate aqueous solution.

[0158] Preheat the solubilizing solution to 40°C and stir rapidly with the solution containing mPEG. 2000 The DSPE solubilizing solution was slowly added dropwise to an acidified DMSO solution of ANG1005, and stirred until homogeneous to obtain a micelle solution. After the micelle solution became clear, 12.8 g of mannitol was added, and the mixture was stirred until homogeneous at room temperature. The pH value was adjusted to 5.5 with a 1 mol / L sodium carbonate aqueous solution, and then filtered through a 0.2 μm microporous membrane to obtain the filtered micelle solution.

[0159] Repeat the above steps to prepare the solution and fill it into 10ml vials, 4ml per vial. Place the vials in a freeze dryer to freeze dry and obtain freeze-dried powder.

[0160] Comparative Example 8

[0161] The lyophilized micelle solution containing Solutol and its lyophilized powder are prepared according to the preparation process of the exemplary ANG1005 composition and pharmaceutical product manufacturing process flow chart in Chinese Patent CN102026667B.

[0162] Measure 1 ml of DMSO solution, acidify it with hydrochloric acid to pH 3.5 at room temperature, and mix thoroughly. Heat to 42°C, add 120 mg of ANG1005 and 4000 mg of Solutol HS15 while stirring, and continue mixing until dissolved to obtain a mixed solution of ANG1005 and Solutol HS15.

[0163] Weigh 13.48g of purified water, and add 300mg of glycine, 580mg of sodium chloride, and 520mg of mannitol in sequence under constant temperature water bath stirring at 42℃, and stir until completely dissolved to obtain a buffer solution.

[0164] Weigh 2.976 g of buffer solution and slowly add it to the mixed solution of ANG1005 and Solutol, stirring to dissolve.

[0165] The mixture was then cooled to 25±2℃ within 20 minutes, filtered through a 0.2μm microporous membrane, and freeze-dried to obtain freeze-dried powder. The freeze-drying parameters were those specified in Table 7 of Chinese Patent CN102026667B.

[0166] Experiment Example 4

[0167] Electron microscopy was performed on the micelle solutions in Example 12 and Comparative Example 8. The concentration in Example 12 was 0.6 mg / ml mPEG2000-DSPE, and the concentration in Comparative Example 8 was 6 mg / ml Solutol. The morphologies of the nanoparticles in the micelle solutions of Example 12 and Comparative Example 8 were as follows: Figure 2 , Figure 3 As shown. From Figure 2 and Figure 3 It can be seen that the nanomicelles prepared in Example 12 and Comparative Example 8 are uniform particles with a size of about 10 nm. The particle density of Comparative Example 8 is higher than that of Example 12.

[0168] Experimental Example 5

[0169]

[0170] The pharmacokinetic studies of the lyophilized powders in Example 12 and Comparative Example 8 were conducted using the above-mentioned equipment and the LC / MS / MS method. After reconstitution, each sample was intravenously injected into three male rats at a dose of 15 mg / kg. Blood samples were collected intravenously at 0.5, 1, 2, 4, 6, 8, 12, and 24 hours to detect the concentrations of ANG1005 and its active degradation product paclitaxel in the blood. The main pharmacokinetic parameters are calculated and are shown in Tables 8 and 9 below.

[0171] Table 8. Pharmacokinetics of ANG1005 in rats after intravenous injection of the reconstituted solution.

[0172]

[0173] Table 9. Pharmacokinetics of paclitaxel after intravenous injection of the reconstituted solution in rats.

[0174]

[0175] As shown in the table above, the lyophilized reconstituted solution of Example 12, prepared with mPEG2000-DSPE as a solubilizer, showed comparable plasma exposure (AUClast and AUCinf), maximum plasma concentration (Cmax), and half-life (T1 / 2) of ANG1005 in the blood compared to the lyophilized reconstituted solution of Comparative Example 8, prepared with Solutol HS15 as a solubilizer. However, after the drug entered the bloodstream, the plasma exposure (AUClast and AUCinf) and maximum plasma concentration (Cmax) of paclitaxel, the active substance produced by degradation from the lyophilized reconstituted solution of Example 12 prepared with mPEG2000-DSPE as a solubilizer, were only about one-third of those of the lyophilized reconstituted solution of Comparative Example 8 prepared with Solutol HS15 as a solubilizer. The lower paclitaxel exposure means that the formulation of Example 12 prepared with mPEG2000-DSPE as a solubilizer has lower systemic toxicity.

[0176] Experimental Example 6

[0177] The lyophilized powders from Example 12 and Comparative Example 8 were reconstituted at room temperature. The time it took for the two lyophilized powders to reach clarity after reconstitution was observed and recorded in Table 10 below.

[0178] Table 10. Reconstitution and Clarification Time of Lyophilized Powder in Examples 12 and Comparative Example 8

[0179]

[0180] As can be seen from Table 10, the reconstitution time of the lyophilized powder in Example 12 is much shorter than that of the lyophilized powder in Comparative Example 8, and the lyophilized powder in Example 12 is more convenient for clinical use.

[0181] Experimental Example 7

[0182] The lyophilized powders in Example 12 and Comparative Example 8 were reconstituted at room temperature and allowed to clarify. The micelle solutions prepared in Example 12 and Comparative Example 8 and the clarified lyophilized powder reconstituted solutions in Example 12 and Comparative Example 8 were observed under the same conditions. The clarity of the solutions was visually inspected. When any condition affecting the clarity, such as opalescence or milky whiteness, could be observed in the solution, the duration of maintaining clarity was recorded in Table 11.

[0183] Table 11 Clarification time of reconstituted solution of micelle solution in Examples 12 and Comparative Example 8

[0184]

[0185] The results above show that in Example 12, mPEG with only 5 times the mass ratio of ANG1005 was used. 2000The micelle solution prepared by DSPE showed significantly better stability than the micelle solution prepared by Solutol HS15 using ANG1005 at a mass ratio greater than 20 times in Comparative Example 8. The better stability of the micelle solution provides sufficient time for subsequent production processes such as solution transfer, filtration and sterilization, and filling.

[0186] The physical stability of the lyophilized powder reconstituted solution prepared in Example 12 was also significantly better than that of the lyophilized powder reconstituted solution prepared in Comparative Example 8. The better stability of the reconstituted solution can provide sufficient time for clinical drug preparation and patient use.

[0187] Experimental Example 8

[0188] The lyophilized powders from Example 12 and Comparative Example 8 were reconstituted with physiological saline at room temperature, and then diluted 4 times with physiological saline to 1.5 mg / ml. The osmotic pressure of the reconstituted solution was measured using an osmometer, and the results are shown in Table 12 below.

[0189] Table 12 Osmotic Pressure of Lyophilized Powder Reconstituted and Diluted Solutions

[0190] name Example 12 Comparative Example 8 osmotic pressure 310mOsmol / kg 448mOsmol / kg

[0191] The results showed that the osmotic pressure of Example 12 was lower than that of Comparative Example 8, and the side effects after clinical administration were less.

[0192] Example 13

[0193] To prepare the DMSO acidified solution of ANG1005, weigh 7.04 g of DMSO, add 146.43 mg of 1 mol / L citric acid solution, mix well, and then add a total of 768 mg of ANG1005 to the mixed solution and stir to dissolve.

[0194] To prepare the solubilizing solution, weigh 103.2 g of purified water, add 192 mg of solid citric acid, and stir until completely dissolved to obtain a citric acid solution. Then, add 6400 mg of the solubilizer mPEG to the citric acid solution. 2000 -DSPE, stir until completely dissolved, and adjust the pH to 4.0 with a 1 mol / L sodium carbonate aqueous solution.

[0195] Preheat the solubilizing solution to 45°C and stir rapidly with the solution containing mPEG. 2000 The solubilizing solution of DSPE was slowly added dropwise to an acidified DMSO solution of ANG1005, and stirred until homogeneous to obtain a micelle solution. After the micelle solution became clear, 12.8 g of mannitol was added, and the mixture was stirred until homogeneous at room temperature. The pH value was adjusted to 5.0 with a 1 mol / L sodium carbonate aqueous solution, and then filtered through a 0.2 μm microporous membrane to obtain the filtered micelle solution.

[0196] Repeat the above steps to prepare the solution and fill it into 10ml vials, 4ml per vial. Place the vials in a freeze dryer to freeze dry and obtain freeze-dried powder.

[0197] Experimental Example 9

[0198] The lyophilized powder in Example 13 was reconstituted at room temperature and allowed to become clear. The micelle solution prepared in Example 13 and the lyophilized powder reconstituted solution after clarification in Example 13 were observed under the same conditions. The clarity of the solution was visually inspected. When any condition affecting the clarity, such as opalescence or milky whiteness, could be observed in the solution, the duration of maintaining clarity was recorded in Table 13.

[0199] Table 13 Clarification Time of Micellar Solutions and Lyophilized Powder Reconstituted Solutions

[0200] name Solution clarification time Micellar solution (6 mg / ml) 72h Lyophilized powder reconstituted solution (reconstituted with physiological saline, 6 mg / ml) 72h

[0201] The results above show that in Example 13, only 10 times the mass ratio of ANG1005 was used in mPEG. 2000 The micelle solution prepared by DSPE showed significantly better stability than the micelle solution prepared by Solutol HS15 using ANG1005 at a mass ratio greater than 20 times in Comparative Example 8.

[0202] The physical stability of the lyophilized powder reconstituted solution prepared in Example 13 was also significantly better than that of the lyophilized powder reconstituted solution prepared in Comparative Example 8. The better stability of the reconstituted solution can provide sufficient time for clinical drug preparation and patient use.

[0203] Although the embodiments of this application have been described above, this application is not limited to the specific embodiments and application fields described above. The specific embodiments described above are merely illustrative and instructive, and not restrictive. Those skilled in the art can make many other forms based on the guidance of this specification and without departing from the scope of protection of the claims of this application, and these are all within the scope of protection of this application.

Claims

1. A composition comprising: Paclitaxel, paclitaxel analogues or paclitaxel conjugates; Solubilizer; as well as, pH adjuster.

2. The composition according to claim 1, wherein, The paclitaxel conjugate is ANG1005.

3. The composition according to claim 1, wherein, The solubilizer comprises mPEG-DSPE.

4. The composition according to claim 1, wherein, The pH adjuster is selected from one or more of lactic acid, phosphoric acid, acetic acid, citric acid, sodium carbonate, sodium bicarbonate, and sodium hydroxide.

5. The composition according to claim 1, wherein, The composition further includes a lyophilization protectant selected from one or more of mannitol, glucose, galactose, lactose, and sucrose.

6. The composition according to claim 3, wherein, In the mPEG-DSPE, the molecular weight of PEG is 500-10000; preferably, the molecular weight of PEG in the mPEG-DSPE is 1000-5000.

7. The composition according to claim 3, wherein, The weight ratio of mPEG-DSPE to ANG1005 is (3-15):1; preferably, the weight ratio of mPEG-DSPE to ANG1005 is (5-10):

1.

8. A method for preparing the composition according to any one of claims 1-7, comprising the steps of: Paclitaxel, paclitaxel analogues, or paclitaxel conjugates are dissolved in an organic solvent to obtain an organic phase solution; Prepare an aqueous solution of the solubilizer; The organic phase solution is mixed with the aqueous solution of the solubilizer, and a lyophilization protectant is optionally added and stirred until homogeneous. The pH is adjusted by adding a pH adjuster to obtain a micelle solution. The micelle solution is treated to obtain the lyophilized powder of the composition according to any one of claims 1-7, preferably, the organic solvent is DMSO, and the weight of DMSO in the lyophilized powder is less than 0.2%.

9. The method according to claim 8, wherein, When preparing the organic phase solution, paclitaxel, paclitaxel analogues, or paclitaxel conjugates are added to the acidified organic solvent.

10. The method according to claim 8, wherein, The aqueous solution of the solubilizer is prepared by adding the solubilizer to the buffer and then adjusting the pH to 2.0-6.0 with a pH adjuster. Preferably, the buffer is a solution of citric acid and / or glycine.

11. The method according to claim 8, wherein, The pH value of the micelle solution is 4.0-6.

0.

12. Use of the composition according to any one of claims 1-8 in the preparation of medicaments for treating breast cancer, ovarian cancer, uterine cancer and lung cancer.

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