Drug-loaded nanoparticle composition

Abstract

The present invention provides a drug-loaded nanoparticle composition suitable for drug delivery in vivo, wherein the drug-loaded nanoparticle composition is formed in the form of a non-covalent bond and comprises an active ingredient, cyclodextrin, and albumin. Drug-loaded nanoparticles or the composition thereof in the present invention are stable in a solution state, avoiding cumbersome operations of reconstitution and redissolution. Compared with a known freeze-dried powder of nanoparticles containing albumin, the nanoparticles in the present invention have a particle size of less than 150 nm, can remain stable for at least 7 days or more without change, and can be predicted to be stable for a long time.

Description

Nanoparticle drug delivery composition Technical Field

[0001] This invention relates to a protein nanoparticle system for in vivo delivery of docetaxel, cabazitaxel, and propofol. Specifically, this invention provides a nanoparticle drug delivery system composed of protein and cyclodextrin, which loads docetaxel, cabazitaxel, and propofol for in vivo delivery of the drugs. Background Technology

[0002] Intravenous administration allows for the rapid and direct delivery of drugs into the body. Injectable formulations often require various excipients to achieve a system that is easy to administer, convenient to use, does not precipitate, has few side effects, and exhibits good compatibility stability. Encapsulating pharmacologically active substances in nanoparticles can enhance stability, reduce side effects, prolong the half-life of pharmacologically active substances, and enable targeted release of these substances.

[0003] Taxanes, particularly the three currently marketed taxanes—paclitaxel, docetaxel, and cabazitaxel—are effective antitumor active ingredients.

[0004] Paclitaxel has very poor water solubility (less than 10 μg / mL). Therefore, commercially available liquid formulations contain polyoxyethylated castor oil (Cremophor) as a surfactant and high-concentration ethanol as a co-solvent for intravenous infusion in cancer patients. These liquid formulations have been associated with severe rashes, urticaria, flushing, dyspnea, tachycardia, and other hypersensitivity reactions. These reactions can be attributed at least in part to the high concentrations of ethanol and Cremophor used as solvents in the formulation.

[0005] Like paclitaxel, docetaxel and cabazitaxel are very poorly soluble in water. Currently available liquid formulations use Tween 80 and ethanol to dissolve docetaxel and cabazitaxel. Tween 80 also frequently causes hypersensitivity reactions such as water and sodium retention in patients.

[0006] One approach to addressing the poor water solubility of taxanes is to develop various formulations of taxanes, such as nanoparticles, oil-in-water emulsions, and liposomes. For example, Abraxane is a nanoparticle combination of paclitaxel and albumin. While the advent of albumin has brought great success to paclitaxel formulations, existing albumin formulations are all in lyophilized powder form, requiring a lengthy reconstitution process and a high level of operator skill. Injectable solutions, on the other hand, do not require reconstitution and are convenient and easy to use. Propofol, chemically known as 2,6-diisopropylphenol, is an organic compound with the chemical formula C6H2O. 12 H 18Propofol (O3) is a short-acting intravenous anesthetic used for the induction and maintenance of general anesthesia. It is often used concurrently with epidural or spinal anesthesia, and also frequently with analgesics, muscle relaxants, and inhaled anesthetics. Propofol is almost insoluble in water; commercially available formulations are solubilized using fat emulsion systems. However, the extensive use of fat emulsion excipients has led to adverse reactions such as allergic reactions and hyperlipidemia in clinical use. Therefore, the use of non-fat emulsion systems for propofol delivery is of significant clinical importance.

[0007] The albumin nano-injection solution of docetaxel, cabazitaxel and propofol provided by this invention does not require reconstruction and reconstitution, which perfectly meets the needs of clinical use. Summary of the Invention

[0008] On one hand, the present invention provides a composition containing active ingredient nanoparticles, wherein the active ingredient is encapsulated within human serum albumin; the weight ratio of active ingredient: cyclodextrin: human serum albumin is 1:16-160:0.5-50; and the average particle size of the nanoparticle composition is not greater than 150 nm.

[0009] On the other hand, some embodiments disclosed in this invention provide a composition of active ingredient nanoparticles containing the nanoparticles of this invention, wherein the particle size of the composition is not greater than 100 nm.

[0010] In some embodiments, the active ingredient nanoparticle composition is provided in liquid form. In some embodiments, the liquid composition is an injectable solution.

[0011] If required, the liquid form of this composition can be further processed into a lyophilized powder.

[0012] Some embodiments of the present invention provide a method for preparing a composition of active ingredient nanoparticles, comprising:

[0013] (1) Add cyclodextrin, active ingredient, and albumin to the solution and stir to form a solution;

[0014] (2) Filter and sterilize to obtain injection solution.

[0015] The active ingredient nanoparticle composition is provided in liquid form.

[0016] Some embodiments of the present invention provide a method for preparing a composition of active ingredient nanoparticles, comprising:

[0017] (1) Place the cyclodextrin and active ingredient into an aqueous solution and stir to form a solution;

[0018] (2) Add the solution obtained in (1) to the albumin solution and stir to form a solution; and

[0019] (3) Filter and sterilize to obtain injection solution.

[0020] The active ingredient nanoparticle composition is provided in liquid form.

[0021] Furthermore, the liquid can be further processed into freeze-dried powder as needed. Detailed Implementation

[0022] This invention provides a composition of drug-loaded nanoparticles containing albumin, cyclodextrin, and active ingredients, as well as a method for preparing and using the nanoparticle composition.

[0023] The nanoparticle drug delivery composition of this invention has one or more advantages:

[0024] (1) The nanoparticles of the present invention are stable in solution, avoiding the tedious operation of reconstruction and reconstitution.

[0025] (2) Compared with known lyophilized powder containing albumin nanoparticles, the nanoparticles in this invention have a particle size of less than 150 nm and can remain stable for at least 7 days without change, and it is foreseeable that they can remain stable for a long time.

[0026] Although the ranges of numbers and parameter approximations shown in this invention are broad, the values ​​described in the specific embodiments are recorded as accurately as possible. However, any value inherently contains a certain degree of error due to the standard deviation present in their respective measurements. Furthermore, all ranges disclosed herein should be understood to encompass any and all subranges contained therein. For example, the stated range "0.01 to 10" should be considered to include any and all subranges between the minimum value of 0.01 and the maximum value of 10 (inclusive); that is, all subranges starting with a minimum value of 1 or greater, such as 0.1 to 5, and subranges ending with a maximum value of 10 or less, such as 5.1 to 10.

[0027] It should also be noted that, as used herein, the singular form includes the plural form of the object it refers to, unless it is clearly and explicitly limited to a single object. The term "or" may be used interchangeably with the term "and / or" unless the context clearly indicates otherwise.

[0028] In rapidly growing tumor tissues, albumin is typically taken up by tumor cells as an amino acid and energy source. Tumor growth is inseparable from angiogenesis, and the gp60 protein, highly expressed on vascular endothelial cells, can bind to albumin and then transfer it to underlying tissues via transcytosis. Many studies have shown that SPARC protein is related to albumin uptake by tissue cells, and SPARC protein is highly expressed in many tumor tissues. Some research suggests that drug-albumin nanoparticles can also utilize the in vivo natural gp60-SPARC transmembrane transport pathway, allowing albumin-bound drugs to cross the tumor vascular endothelial cell barrier and be delivered to the tumor area via transcellular interactions. Reducing changes in the spatial structure of albumin after drug loading will facilitate the utilization of the in vivo natural gp60-SPARC transmembrane transport pathway by nanoparticles.

[0029] On one hand, the present invention provides a drug-loaded nanoparticle containing an active ingredient, comprising the active ingredient, cyclodextrin, and human serum albumin. In some embodiments, the cyclodextrin is sulfobutyl-β-cyclodextrin. The degree of substitution of sulfobutyl-β-cyclodextrin can be 1 to 11, with a degree of substitution of 6 to 7 being the most widely used.

[0030] In some implementations, the active ingredient is docetaxel.

[0031] In some implementations, the active ingredient is cabazitaxel.

[0032] In some implementations, the active ingredient is propofol.

[0033] In some embodiments, the average particle size of the drug-loaded nanoparticles or compositions thereof is selected from the range of 150 nm or less. Those skilled in the art will understand that any existing or suitable future method can be used to measure the particle size, including but not limited to sedimentation, sieving, microscopic observation, or laser particle size analyzer. It should also be understood that when there are multiple drug-loaded nanoparticles of this disclosure, not every therapeutic nanoparticle will have a uniform particle size, but as long as their average particle size meets the above-described limitations, they are also included within the scope of this disclosure.

[0034] In some specific embodiments, the particle size is determined using a Malvern laser particle size analyzer; the average particle size of the drug-loaded nanoparticles or their compositions is selected from any value not exceeding 150 nm.

[0035] In another specific embodiment, a nanoparticle composition comprising docetaxel, cyclodextrin and human serum albumin is provided, wherein the weight ratio of docetaxel, cyclodextrin and human serum albumin is 1:100:50, and the average particle size of the docetaxel nanoparticle composition is not greater than 100 nm at 1 mg / ml.

[0036] Example

[0037] The following examples are intended to better illustrate the drug-loaded nanoparticles and pharmaceutical compositions disclosed in this invention, and are not intended to limit any aspect of the invention.

[0038] Example 1

[0039] The prescribed amount of sulfobutyl cyclodextrin was dissolved in 5 ml of 5% albumin injection solution. Then, 5 mg of docetaxel was added to the above solution and stirred for 1 hour to form a solution. The solution could be successfully filtered through a 0.22-micron sterile filter membrane and no precipitation occurred after refrigeration for 7 days. The nanoparticle size in the solution was no greater than 150 nm.

[0040] Example 2

[0041] The prescribed amount of sulfobutylcyclodextrin was dissolved in 5 ml of 5% human serum albumin. Then, 15 mg of cabazitaxel was added to the above solution and stirred for 1 hour to form a solution, as detailed in Table 2. The solution could be successfully filtered through a 0.22-micron sterile filter membrane and no precipitation occurred after refrigeration for 7 days. The nanoparticle size in the solution was no greater than 150 nm.

[0042] Example 3 Propofol

[0043] The prescribed amounts of sulfobutylcyclodextrin, human serum albumin, propofol, and water were mixed and dissolved to form a solution, as detailed in Table 3. The solution passed smoothly through a 0.22-micron sterile filter membrane and showed no precipitation after refrigeration for 7 days. The nanoparticles in the solution had a particle size of no more than 150 nm.

[0044] Comparative Example 1

[0045] A composition of drug-loaded nanoparticles containing the active pharmaceutical ingredient was prepared by adding prescribed amounts of API, human serum albumin (HSA), and sulfobutyl cyclodextrin (SBECD). The results are shown in Table 4 below; a stable solution could not be formed. In the composition of this invention, API, human serum albumin (HSA), and SBECD are all indispensable.

Claims

1. A nanoparticle composition suitable for in vivo drug delivery, wherein the composition is formed in a non-covalent form of the nanoparticle composition, comprising an active ingredient, cyclodextrin, and albumin.

2. The nanoparticle composition according to claim 1, wherein the cyclodextrin is sulfobutylcyclodextrin, and the active ingredient is selected from docetaxel, cabazitaxel, and propofol.

3. The nanoparticle composition according to claim 1, wherein the mass ratio of the active ingredient, the cyclodextrin, and the albumin is 1:16-160:0.05-50.

4. The nanoparticle composition according to claim 1, wherein after loading the drug, the average particle size of the composition is not greater than 150 nm.

5. The nanoparticle composition according to claim 2, wherein the active ingredient is docetaxel or a pharmaceutically acceptable salt, isomer, or solvate thereof.

6. The nanoparticle composition according to claim 2, wherein the active ingredient is cabazitaxel or a pharmaceutically acceptable salt, isomer, or solvate thereof.

7. The nanoparticle composition according to claim 2, wherein the active ingredient is propofol or a pharmaceutically acceptable salt, isomer, or solvate thereof.

8. A method for preparing a drug-loaded nanoparticle composition, comprising: (1) Mix cyclodextrin, active ingredient and albumin to form a solution; (2) Filter and sterilize to obtain the nano-drug-loaded particle composition.

9. The method according to claim 8, wherein the cyclodextrin is sulfobutyl cyclodextrin, and the active ingredient is selected from docetaxel, cabazitaxel, and propofol.

10. The method according to claim 8, wherein the mass ratio of the active ingredient, the cyclodextrin, and the albumin is 1:16-160:0.05-50.

11. The method of claim 8, wherein after loading the drug, the average particle size of the composition is not greater than 150 nm.

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