Preparation methods and applications of lipid prodrugs and self-microemulsion formulations of taxane compounds

Abstract

This invention discloses the preparation method and application of lipid prodrugs and self-microemulsion formulations of taxane compounds, belonging to the field of pharmaceutical technology. This invention discloses two lipid prodrugs substituted with long-chain fatty acids at positions 1,3, bridged by disulfide bonds, as shown in the following formula. The aim is to improve the oral absorption efficiency of ralotathol and SB-T-1214, promote their specific release at the target site, and achieve synergistic effects and reduced toxicity. The self-microemulsion drug delivery system is suitable for lipid-soluble drugs and has advantages such as simple preparation process, high drug loading, and easy process scale-up. The prepared self-microemulsion formulation consists of ralotathol or SB-T-1214 lipid prodrugs and excipients. The excipients include an oil phase and an emulsifier. By mass percentage, the oil phase accounts for 40-75% of the self-microemulsion formulation, the emulsifier accounts for 25-60%, and the ralotathol or SB-T-1214 lipid prodrug accounts for 1-10% of the total mass of the excipients.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to the preparation of larotasoxetine or SB-T-1214 lipid prodrugs and self-microemulsion formulations and their application in the preparation of oral chemotherapy drugs. Background Technology

[0002] Chemotherapy remains the primary strategy for treating malignant tumors, mainly administered intravenously in clinical practice. However, the majority of chemotherapeutic drugs are highly cytotoxic, poorly soluble, and unstable. Their non-specific effects and the severe toxic side effects caused by increased solubilization significantly hinder their clinical application. Oral administration, as one of the most patient-compliant routes of administration, offers advantages such as convenience, safety, low treatment cost, and high compliance. However, oral delivery of chemotherapeutic drugs still faces challenges such as gastrointestinal toxicity and low oral bioavailability.

[0003] Among various chemotherapy drugs, taxanes are the most widely used, possessing strong antitumor activity. They are mainly used to treat ovarian cancer, breast cancer, lung cancer, and Kaposi's sarcoma. These drugs inhibit cancer cell proliferation by binding to β-tubulin subunits, inducing and promoting microtubule polymerization, stabilizing microtubule structure, preventing depolymerization, and thus inhibiting cancer cell proliferation. However, classic taxanes have poor solubility, numerous adverse reactions, and are prone to drug resistance. Intravenous injection can lead to severe hypersensitivity reactions, and oral administration has low bioavailability and side effects, severely limiting their clinical application. Lalotacept and SB-T-1214 are novel semi-synthetic taxanes and highly effective cytotoxic agents with broad-spectrum antitumor activity, showing significant efficacy against both multidrug-resistant and non-drug-resistant tumors. The three-membered ring at C-7 / C-8 of lalotasol can minimize the recognition of P-glycoprotein (P-gp), and the three-membered ring substituted at C-10 in the SB-T-1214 structure can also significantly reduce the affinity of the drug for P-gp, thereby reducing efflux and improving oral bioavailability. However, its poor solubility and poor membrane permeability still severely limit its application in oral administration.

[0004] Long-chain triglycerides are an important component of dietary lipids. After digestion and hydrolysis in the intestine, they are absorbed into the systemic circulation via lymphatic transport, avoiding the first-pass effect of the liver and improving oral bioavailability. The redox microenvironment of the tumor region has been widely used in the delivery of chemotherapy drugs, and disulfide bonds are classic reduction-sensitive bonds that can be broken under reducing conditions. Based on these principles, using the novel taxane anticancer drugs latasaxyl and SB-T-1214 as model drugs, two disulfide-bridged long-chain triglyceride oral prodrugs were designed and synthesized to mimic the digestive and absorption pathway of dietary lipids and improve the oral bioavailability of the drugs.

[0005] Self-microemulsifying drug delivery systems (SNEDDS) offer advantages such as simple preparation, high drug loading capacity, and easy process scaling, making them suitable for oral delivery of lipid prodrugs. The long-chain oil phase in this formulation can increase the drug loading capacity of lipophilic drugs, promote lymphatic transport, and thus enhance oral absorption. Summary of the Invention

[0006] Based on the digestive and absorption pathways of dietary lipids in vivo, this invention designs two taxane compounds with long-chain fatty acid substitutions at positions 1 and 3, forming triglyceride-like prodrugs: (a) lalotasone lipid prodrug and (b) SB-T-1214 lipid prodrug. The aim is to improve the oral absorption efficiency of lalotasone and SB-T-1214, which have extremely low water solubility. In addition, a reduction-sensitive linker is introduced to enable the prodrugs to specifically release the parent drug at the tumor target site, thereby enhancing efficacy and reducing toxicity.

[0007] Specifically, the first objective of this invention is to provide a lalotasol lipid prodrug of formula (I) or its geometric isomer, pharmaceutically acceptable salt, hydrate, or solvate; and an SB-T-1214 lipid prodrug of formula (II) or its geometric isomer, pharmaceutically acceptable salt, hydrate, or solvate.

[0008]

[0009] Wherein, R is a substituted or unsubstituted, branched or straight-chain, saturated or unsaturated aliphatic alkyl group containing more than 12 carbon atoms; the lalotasyl and SB-T-1214 may also be other taxane compounds.

[0010] A specific example is a lalotaxel-palmitate triglyceride prodrug or its geometric isomer, or a pharmaceutically acceptable salt, as shown in formula (III), denoted as LTX-SS-TG:

[0011]

[0012] A prodrug of SB-T-1214-palmitoyl triglyceride, as shown in formula (IV), or its geometric isomer, or a pharmaceutically acceptable salt thereof, is denoted as SBT-SS-TG:

[0013]

[0014] A second objective of this invention is to provide a method for preparing the prodrug. The specific preparation method is as follows:

[0015] (1) The fatty acid is dissolved in an organic solvent and esterified with 1,3-dihydroxyacetone under the catalysis of EDCI and DMAP to produce product 1, which is then reduced by sodium borohydride to obtain product 2.

[0016] (2) Dissolve 4,4'-dithiodibutyric acid in acetic anhydride and stir at room temperature to generate dithiodibutyric anhydride (product 3). React product 2 with product 2 under the catalysis of DMAP to obtain product 4.

[0017] (3) Product 4 was esterified with lalotasol or SB-T-1214 under the catalysis of DMAP and EDCI to obtain lalotasol or SB-T-1214 lipid prodrugs;

[0018] In step (1), the fatty acid is preferably palmitic acid (PA).

[0019] In the steps described, the organic solvent used is selected from dichloromethane, trichloromethane, tetrahydrofuran, and benzene.

[0020] The synthetic route for a lalotaxel-palmitate triglyceride prodrug is as follows:

[0021]

[0022] LTX stands for La Lotasai.

[0023] A third objective of this invention is to provide a simple and safe pharmaceutical composition containing larotasoxetine or SB-T-1214 lipid prodrug, said pharmaceutical composition being a self-microemulsion formulation of larotasoxetine or SB-T-1214 lipid prodrug, comprising larotasoxetine or SB-T-1214 lipid prodrug or its geometric isomer, pharmaceutically acceptable salts, hydrates, solvates, and excipients; said excipients include an oil phase, emulsifiers, short-chain alcohols or ether co-emulsifiers; by mass percentage, the oil phase accounts for 5-90% of the self-microemulsion formulation, the emulsifier accounts for 5-80% of the self-microemulsion formulation, and the short-chain alcohol or ether co-emulsifier accounts for 0-30% of the self-microemulsion formulation; larotasoxetine or SB-T-1214 lipid prodrug or its geometric isomer, pharmaceutically acceptable salts, hydrates, and solvates account for 1-20% of the total mass of the excipients.

[0024] Preferably, the pharmaceutical composition of the present invention comprises, by mass percentage, 40-75% of the oil phase from the microemulsion formulation, 25-60% of the emulsifier from the microemulsion formulation, 0-20% of the short-chain alcohol or ether co-emulsifier from the microemulsion formulation, and 1-10% of the total mass of the excipients for lalotasyl or SB-T-1214 lipid prodrug or its geometric isomers, pharmaceutically acceptable salts, hydrates, and solvates.

[0025] More preferably, the pharmaceutical composition of the present invention comprises, by mass percentage, 60-75% of the oil phase from the microemulsion formulation, 25-40% of the emulsifier from the microemulsion formulation, and 1-5% of the total mass of the excipients for lalotasyl or SB-T-1214 lipid prodrug or its geometric isomers, pharmaceutically acceptable salts, hydrates, and solvates.

[0026] Furthermore, the mass ratio of the mixed oil phase to the emulsifier is 1:1 to 5:1.

[0027] The oil phase is selected from long-chain triglycerides, mixed long-chain triglycerides, long-chain triglycerides, or combinations thereof, including: olive oil, almond oil, castor oil, corn oil, palm oil, peanut oil, rapeseed oil, sesame oil, soybean oil, sunflower seed oil, hydrogenated soybean oil, partially hydrogenated soybean oil, Maisine CC, Maisine 35-1, and Peceol, or one or more of these. Corn oil has been used as an oil phase in marketed oral lipid formulations. Maisine CC is a long-chain triglyceride and can be used as a lipid compatibilizer in self-emulsifying drug delivery systems. Appropriate addition of Maisine CC is beneficial for oil phase emulsification. The two have optimal compatibility at a 1:1 (m:m) ratio. Therefore, corn oil and Maisine CC are further preferred as a mixed oil phase at a 1:1 (m:m) ratio.

[0028] The emulsifier is a polyethylene glycol or polyol-type nonionic surfactant. Polyethylene glycol-type nonionic surfactants include, but are not limited to, castor oil polyoxyethylene ether (Cremophor EL), benzyl ethers, methyl ethers, polyethylene glycol-15-hydroxystearate, and polyoxyethylene-polyoxypropylene copolymer (Poloxamer). Polyol-type nonionic surfactants include, but are not limited to, fatty acid sorbitan (Span 20, Span 40, Span 60) and polyoxyethylene dehydrated sorbitan fatty acid esters (Tween 20, Tween 60, Tween 80). Cremophor EL has strong emulsifying ability and high safety under certain dosage conditions for oral administration; therefore, Cremophor EL is preferred as the emulsifier.

[0029] The short-chain alcohol or ether co-emulsifier is one of diethylene glycol monoethyl ether (Transcutol HP), propylene glycol monooctanoate, propylene glycol, glycerol, and ethanol; preferably Transcutol HP.

[0030] The self-microemulsion formulation of the lalostatin or SB-T-1214 lipid prodrug described in this invention is prepared by the following method:

[0031] Add the emulsifier to the oil phase and sonicate to mix it evenly to obtain a blank self-microemulsion formulation. Weigh out lalotasol or SB-T-1214 lipid prodrug and add it to the blank self-microemulsion formulation. Sonicate to completely dissolve the prodrug to obtain an oral prodrug self-microemulsion formulation.

[0032] When the oil phase is a mixture of corn oil and Maisine CC (1:1, m:m), the emulsifier is Cremophor EL, and the oil phase accounts for 40-75% of the microemulsion formulation, the emulsifier accounts for 25-60% of the microemulsion formulation, the co-emulsifier accounts for 0-20% of the microemulsion formulation, and the lipid prodrug of larotasoxetine or SB-T-1214 or its geometric isomers, pharmaceutically acceptable salts, hydrates, and solvates account for 1-10% of the total mass of the excipients, the resulting prodrug microemulsion formulation has the best particle size and particle size distribution, the best compatibility and stability, and can significantly improve the oral bioavailability of larotasoxetine and SB-T-1214.

[0033] This invention uses lalostatin and SB-T-1214 as model drugs to design and synthesize two disulfide-bridged palmitic acid-substituted triglyceride prodrugs. These prodrugs are then prepared into oral microemulsions using low-toxicity excipients. The preparation process is simple, highly reproducible, and easy to industrialize and store. A stable emulsion with a particle size less than 100 nm is obtained after dilution with deionized water by 10 times and simple stirring. The formulation exhibits strong self-microemulsification ability. This self-microemulsion prodrug formulation can further promote lymphatic transport of poorly soluble drugs, improving their oral bioavailability.

[0034] The application of the larotasone or SB-T-1214 lipid prodrug or its geometric isomer, pharmaceutically acceptable salt, hydrate, solvate, or the prodrug self-microemulsion formulation described herein in the preparation of oral drug delivery systems.

[0035] The use of the larotasone or SB-T-1214 lipid prodrug or its geometric isomer, pharmaceutically acceptable salt, hydrate, solvate or the self-microemulsion formulation of the prodrug described in this invention in the preparation of antitumor drugs.

[0036] The advantages of this invention are:

[0037] 1. Based on the oral absorption pathway of long-chain triglycerides, this invention designs larotaxyl and SB-T-1214 lipid prodrugs to promote drug lymphatic transport, reduce the first-pass effect, and thus improve their oral absorption efficiency.

[0038] 2. This invention introduces a reduction-sensitive disulfide bond structure, enabling the prodrug to specifically release the parent drug in the tumor microenvironment, thereby enhancing efficacy and reducing toxicity.

[0039] 3. The self-microemulsion formulation prepared by this invention has a simple preparation process, high reproducibility, is easy to industrialize, has stable properties, and can further promote the lymphatic transport of poorly soluble drugs and improve their oral bioavailability. Attached Figure Description

[0040] Figure 1This is a high-resolution mass spectrum of the lalotaxel-palmitate triglyceride prodrug (LTX-SS-TG) synthesized in Example 1 of this invention.

[0041] Figure 2 This is a high-resolution mass spectrum of the SB-T-1214-palmitic acid triglyceride prodrug (SBT-SS-TG) synthesized in Example 2 of this invention.

[0042] Figure 3 The lalotaxel-palmitate triglyceride prodrug (LTX-SS-TG) synthesized in Example 1 of this invention 1 H-NMR spectrum.

[0043] Figure 4 The SB-T-1214-palmitoyl triglyceride prodrug (SBT-SS-TG) synthesized in Example 2 of this invention 1 H-NMR spectrum.

[0044] Figure 5 The pseudo-ternary phase diagram for microemulsion formulation screening; A: the formulation proportion region that can emulsify rapidly; B: the formulation proportion region that can emulsify rapidly and exhibits a blue opalescence.

[0045] Figure 6 The images show the appearance, particle size distribution, and transmission electron microscopy (TEM) images of the corresponding emulsions for drug-loaded self-microemulsion formulations.

[0046] Figure 7 The diagram shows the gastric stability of the prodrug in artificial gastric fluid; A: Physical stability of the prodrug in artificial gastric fluid; B: Chemical stability of the prodrug in artificial gastric fluid; C: Release of lalotasol-related formulations in artificial gastric fluid; D: Release of SB-T-1214-related formulations in artificial gastric fluid.

[0047] Figure 8 The diagram shows the intestinal digestive stability of simulated digestive systems; A: Intestinal digestive stability of LTX-SS-TG; B: Intestinal digestive stability of SBT-SS-TG.

[0048] Figure 9 The following are the drug concentration-time curves for larostaphin-related oral formulations: A: Drug-time curve of free parent drug; B: Drug-time curve of overall parent drug after prodrug fragmentation treatment in the microemulsion group; C: Drug-time curve of free parent drug after lymphatic transport inhibition in the microemulsion group; D: Drug-time curve of free parent drug after lymphatic transport inhibition in the parent drug solution group.

[0049] Figure 10The following are the drug concentration-time curves for oral formulations related to SB-T-1214: A: Drug-time curve of free parent drug; B: Drug-time curve of overall parent drug after prodrug fragmentation treatment in the microemulsion group; C: Drug-time curve of free parent drug after lymphatic transport inhibition in the microemulsion group; D: Drug-time curve of free parent drug after lymphatic transport inhibition in the parent drug solution group.

[0050] Figure 11 Blood concentration-time curves of intravenously injected parent drug solution; A: Blood concentration-time curve of intravenously injected lalotasol parent drug solution; B: Blood concentration-time curve of intravenously injected SB-T-1214 parent drug solution.

[0051] Figure 12 Figure 1 shows the in vivo oral antitumor experiment. A, B: Tumor growth curves; C, D: Mouse body weight changes; E, F: Tumor bearing rate; G: Tumor images of each group. a: Blank control; b: Oral administration of larotasoxetine solution; c: Oral administration of SB-T-1214 solution; d: Oral administration of larotasoxetine parent drug via microemulsion; e: Oral administration of SB-T-1214 parent drug via microemulsion; f: Oral administration of larotasoxetine solution; g: Oral administration of SB-T-1214 solution; h: Oral administration of larotasoxetine prodrug via microemulsion; i: Oral administration of SB-T-1214 prodrug via microemulsion. Detailed Implementation

[0052] The present invention will be further illustrated by the following embodiments, but is not limited thereto.

[0053] Example 1

[0054] The preparation method of lalotasol palmitate triglyceride prodrug (LTX-SS-TG) includes the following steps:

[0055] The structure of the prodrug is as follows:

[0056]

[0057] (1) 5.13 g (20 mmol) palmitic acid, 3.83 g (20 mmol) EDCI·HCl and 1.22 g (10 mmol) DMAP were dissolved in 80 mL of dichloromethane and activated in an ice bath under nitrogen protection for 1 h. 0.90 g (10 mmol) 1,3-dihydroxyacetone was added to react with palmitic acid to form product 1, which was purified by column chromatography under the following conditions: hexane:ethyl acetate (30:1-15:1, v:v). 2.27 g (4 mmol) of product 1 was hydrogenated with 0.38 g (10 mmol) sodium borohydride to obtain product 2.

[0058] (2) 2.12 g (9 mmol) of 4,4'-dithiodibutyric acid was dissolved in 10 mL of acetic anhydride and reacted at room temperature for 2 h to produce product 3. Unreacted acetic anhydride was removed by rotary evaporation, and the product was redissolved in 50 mL of anhydrous dichloromethane. Product 2 dissolved in anhydrous dichloromethane and 0.54 g (4.5 mmol) of DMAP were added, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After the reaction was completed, the solvent was removed by rotary evaporation, and product 4 was obtained by column chromatography under the following separation conditions: hexane:ethyl acetate (15:1-8:1, v:v).

[0059] (3) Dissolve 0.67 g (1 mmol) of product 4, 0.38 g (2 mmol) of EDCI·HCl, and 0.12 g (1 mmol) of DMAP in 80 mL of anhydrous dichloromethane and activate in an ice bath for 1 h under nitrogen protection. Add 0.67 g (0.8 mmol) of lalotaxel dissolved in anhydrous dichloromethane and react at room temperature for 48 h under nitrogen protection. Remove solvent by rotary evaporation, and purify by column chromatography under the following conditions: hexane:ethyl acetate (8:1-2:1, v:v). The final product LTX-SS-TG was obtained by preparative liquid chromatography with a purity >99%.

[0060] 1 H NMR(400MHz,Chloroform-d)δ8.12(d,J=7.5Hz,1H),7.64(dt,J=34.8,7.4Hz,2H),7.44–7.32(m,2H),5.22(ddt,J=10.2,6.2 ,3.5Hz,1H),4.26(dd,J=12.0,4.1Hz,1H),4.20–4.09(m,2H),4.02(t,J=7.8Hz,1H),2.76–2.61(m,3H),2.49(td,J=7.2,2.6 Hz,1H),2.45–2.34(m,2H),2.33(d,J=18.9Hz,2H),2.28(d,J=7.4Hz,2H),2.12(d,J=8.4Hz,8H),1.98(d,J=6.9Hz,1H),1.82 (s,1H),1.58(dt,J=22.0,7.2Hz,3H),1.31(d,J=21.3Hz,10H),1.27(s,20H),1.19(s,2H),1.14(s,2H),0.92–0.83(m,3H).( Figure 3 )

[0061] ESI-HRMS:Calcd.For C 88 H 131 NO 21 S2[M+Na +1601.87 found 1624.8547.( Figure 1 )

[0062] The specific synthesis route is shown below:

[0063]

[0064]

[0065] Example 2

[0066] The preparation method of SB-T-1214-palmitate triglyceride prodrug (SBT-SS-TG) includes the following steps:

[0067] The structure of the prodrug is as follows:

[0068]

[0069] (1) 5.13 g (20 mmol) palmitic acid, 3.83 g (20 mmol) EDCI·HCl and 1.22 g (10 mmol) DMAP were dissolved in 80 mL of dichloromethane and activated in an ice bath under nitrogen protection for 1 h. 0.90 g (10 mmol) 1,3-dihydroxyacetone was added to react with palmitic acid to form product 1, which was purified by column chromatography under the following conditions: hexane:ethyl acetate (30:1-15:1, v:v). 2.27 g (4 mmol) of product 1 was hydrogenated with 0.38 g (10 mmol) sodium borohydride to obtain product 2.

[0070] (2) 2.12 g (9 mmol) of 4,4'-dithiodibutyric acid was dissolved in 10 mL of acetic anhydride and reacted at room temperature for 2 h to produce product 3. Unreacted acetic anhydride was removed by rotary evaporation, and the product was redissolved in 50 mL of anhydrous dichloromethane. Product 2 dissolved in anhydrous dichloromethane and 0.54 g (4.5 mmol) of DMAP were added, and the reaction was carried out at room temperature for 24 h under nitrogen protection. After the reaction was completed, the solvent was removed by rotary evaporation, and product 4 was obtained by column chromatography under the following separation conditions: hexane:ethyl acetate (15:1-8:1, v:v).

[0071] (3) Dissolve 0.67 g (1 mmol) of product 4, 0.38 g (2 mmol) of EDCI·HCl, and 0.12 g (1 mmol) of DMAP in 80 mL of anhydrous dichloromethane and activate in an ice bath for 1 h under nitrogen protection. Add 0.68 g (0.8 mmol) of SB-T-1214 dissolved in anhydrous dichloromethane and react at room temperature for 48 h under nitrogen protection. Remove solvent by rotary evaporation, and purify by column chromatography under the following conditions: hexane:ethyl acetate (8:1-2:1, v:v). The final product SBT-SS-TG was obtained by preparative liquid chromatography with a purity >99%.

[0072] 1 H NMR(400MHz,Chloroform-d)δ8.10(d,J=7.6Hz,1H),7.66(t,J=7.4Hz,1H),7.54(t,J=7.7Hz,1H),5.61(d,J=7.1Hz,1H),5.2 9–5.18(m,1H),4.86(d,J=4.0Hz,1H),4.37–4.22(m,2H),4.22–4.09(m,2H),2.81–2.69(m,2H),2.55(t,J=7.2Hz,1H),2.46– 2.35(m,2H),2.29(s,1H),2.07–1.93(m,2H),1.89(s,1H),1.72(d,J=11.7Hz,4H),1.58(d,J=14.0Hz,4H),1.36(s,4H),1.31 (d,J=6.9Hz,1H),1.29(s,4H),1.27(s,19H),1.13(d,J=16.4Hz,3H),1.00(ddd,J=17.9,8.0,4.2Hz,2H),0.92–0.84(m,3H).( Figure 4 )

[0073] ESI-HRMS:Calcd.For C 88 H 137 NO 22 S2[M+H + 1623.91 found 1624.9146.( Figure 2 )

[0074] The specific synthesis route is shown below:

[0075]

[0076] Example 3

[0077] Formulation screening of self-microemulsion formulations of larotasoxetine or SB-T-1214 lipid prodrugs

[0078] Oral absorption of larostasy or SB-T-1214 lipid prodrugs is highly dependent on lipid digestion. Self-microemulsifying drug delivery systems (SNEDDS) are ideal carriers for drugs with very low water solubility, high lipid solubility, and easy hydrolysis, offering advantages such as high drug loading capacity and ease of scaling up production.

[0079] 3.1 Selection of Emulsifier

[0080] The selection of emulsifiers is crucial for the formation of self-microemulsions. After comprehensively considering emulsifying performance and toxicity, egg yolk lecithin, Cremophor EL, and Tween 80 were selected as candidate emulsifiers. Screening was conducted based on the original laboratory self-microemulsion formulation (70% olive oil / 23% egg yolk lecithin / 7% Transcutol HP, m:m:m), and the results are shown in Table 1. Cremophor EL exhibited the strongest emulsifying ability, producing the smallest self-microemulsion particle size, and is already used in commercially available lipid formulations; mixed emulsifiers did not show ideal results. Therefore, Cremophor EL was selected as the emulsifier.

[0081] Table 1. Characterization of self-microemulsion formulations containing different types of emulsifiers.

[0082]

[0083]

[0084] 3.2 Selection of Oil Phase

[0085] It is known that most marketed lipid formulations use long-chain triglyceride structures such as corn oil and soybean oil as the oil phase, such as Roche's calcitriol soft capsules (launched in 1996), Norvartis' cyclosporine soft capsules (launched in 1995), and Sandimmune oral solution. To investigate the effect of oil phase composition on the emulsifying ability of self-microemulsion formulations, we propose introducing Maisine CC and long-chain oils as a mixed oil phase. Maisine CC is a long-chain mono- and triglyceride substituted with linoleic acid and oleic acid, which can be used as a lipid compatibilizer in self-emulsifying drug delivery systems. Appropriate addition is beneficial for oil phase emulsification; however, its monoglyceride components may be completely hydrolyzed and digested by lipases in the intestine, rapidly losing the solubilizing effect of the lipid excipient on the drug. Therefore, its usage should be minimized while still improving the self-emulsifying ability of the formulation.

[0086] The results of the compatibility study of the mixed oil phase are shown in Table 2. Under the condition of minimizing the amount of Maisine CC used, the corn oil:Maisine CC = 1:1 ratio showed the best compatibility and initial stability. The particle size of the single-oil-phase self-microemulsion formulation (70% corn oil / 23% Cremophor EL / 7% Transcutol HP, m:m:m) was 222.3±7.28 nm, and the PDI was 0.436±0.03; the particle size of the mixed-oil-phase self-microemulsion formulation (35% corn oil / 35% Maisine CC / 23% Cremophor EL / 7% Transcutol HP, m:m:m:m) was 59.8±0.27 nm, and the PDI was 0.381±0.03. The particle size of the emulsion decreased significantly after using the mixed oil phase, indicating that the introduction of the mixed oil phase can improve the self-emulsification ability of the formulation. Therefore, the oil phase of the microemulsion formulation was initially determined to be a mixed oil phase composed of corn oil and Maisine CC (m:m = 1:1).

[0087] Table 2. Investigation of the compatibility of mixed oil phases

[0088]

[0089] 3.3 Drawing of Pseudo-Ternary Phase Diagrams

[0090] A pseudo-ternary phase diagram was constructed using corn oil and Maisine CC as the mixed oil phase (1:1, m:m, 40-95%), Cremophor EL as the emulsifier (5-80%), and Transcutol HP as the co-emulsifier (0-20%) to conduct detailed screening of self-microemulsion formulations. Specific self-microemulsification regions were identified in the pseudo-ternary phase diagram by visual observation. The results are as follows: Figure 5 As shown. Figure 5 The formulation ratio shown in region A allows for rapid emulsification to form an emulsion. Figure 5 The formulation ratios shown in region B can rapidly emulsify to form an emulsion with a blue opalescent appearance. Among them, the three formulation ratios in Table 3 exhibit outstanding self-emulsification capabilities. Based on this, formulation A has the largest oil phase content, which is beneficial for oral lymphatic transport and pharmacokinetic effects; moreover, no co-emulsifiers are used, avoiding potential toxicity; and the particle size and PDI meet the requirements for oral administration. Therefore, formulation A was selected for all subsequent experimental studies.

[0091] Table 3. Proportion and characteristics of superior self-microemulsion formulations (n=3)

[0092]

[0093] 3.4 Self-microemulsion formulation excipient formulation

[0094]

[0095] Example 4

[0096] Preparation and characterization of self-microemulsion formulations of larotasoxetine or SB-T-1214 lipid prodrugs

[0097] 350 mg of corn oil, 350 mg of Maisine CC, and 300 mg of Cremophor EL were weighed and sonicated to obtain a uniformly mixed blank self-microemulsion formulation. 10 mg of the parent drug (larotasyl / SBT-1214) was accurately weighed and sonicated to dissolve in 1 g of the blank self-microemulsion formulation, yielding a 10 mg / g parent drug self-microemulsion formulation. 20 mg of the prodrug (LTX-SS-TG / SBT-SS-TG) was accurately weighed and sonicated to dissolve in 1 g of the blank lipid formulation, yielding a 20 mg / g prodrug self-microemulsion formulation.

[0098] Excess amounts of the parent drug and prodrug were weighed separately into 500 mg of a blank self-microemulsion formulation. The mixture was shaken at 25°C for 48 h to reach equilibrium. After centrifugation, 50 mg of the supernatant was accurately weighed, diluted with 1 mL of acetonitrile, and sonicated to form an emulsion. The contents of the parent drug and prodrug were immediately determined using high-performance liquid chromatography (HPLC), and the equilibrium solubility of the drug-loaded self-microemulsion formulation was then determined. The particle size, PDI, and morphology of the emulsion particles were measured and characterized using a Zetasizer particle size analyzer and transmission electron microscopy (TEM). The results are shown in Table 4. Figure 6 Both the parent drug and the prodrug self-microemulsion formulation can successfully self-emulsify to form emulsion particles with a particle size of less than 100 nm, regular morphology and uniform distribution, to meet the requirements of subsequent oral administration.

[0099] Table 4 Characterization of drug-loaded self-microemulsion formulations and their emulsions

[0100]

[0101] Example 5

[0102] Stability of larotasoxetine or SB-T-1214 lipid prodrug

[0103] 5.1 Gastric stability

[0104] The prodrug self-microemulsion formulation prepared in Example 4 was pre-dispersed and incubated at 37°C using simulated gastric fluid as the dispersion medium. Samples were taken at predetermined time points to examine the physical and chemical stability of the prodrug. The prodrug self-microemulsion formulation and the parent drug self-microemulsion formulation prepared in Example 4 were pre-dispersed, and a parent drug solution was prepared simultaneously. Simultaneously, simulated gastric fluid containing 30% ethanol at pH 1.2 was used as the release medium. The three formulations were encapsulated in dialysis bags and placed in the aforementioned medium. Samples were taken at predetermined time points to examine the release of different formulations in the stomach. The results are as follows: Figure 7As shown, the prodrug exhibits good physicochemical stability in artificial gastric fluid, and no formulation leakage occurred, indicating that the prodrug self-microemulsion formulation has high gastric safety and meets the requirements for oral administration.

[0105] 5.2 Intestinal stability

[0106] The prodrug self-microemulsion formulation and the parent drug self-microemulsion formulation prepared in Example 4 were pre-dispersed, and a parent drug solution was prepared simultaneously. Using simulated intestinal fluid (1.25 mM PC, 5 mM NaTDC) under fasting conditions as the dispersion medium, and with pancreatic lipase activity at 1000 IU / mL, in vitro simulated digestion was performed at 37°C. The results are as follows: Figure 8 As shown, most TG-structured prodrugs (LTX-SS-TG / SBT-SS-TG) were rapidly digested by pancreatic lipase within 15 minutes and completely degraded into other substances within 1 hour. Simultaneously, a large amount of MG-structured (monoglycerate-like) prodrugs were detected, consistent with the digestion trend of TG prodrugs, and remained stable for 2 hours. The rapid digestion of TG prodrugs and the stable presence of the digestion product MG lay the foundation for improving the oral absorption efficiency of prodrug formulations.

[0107] Example 6

[0108] Pharmacokinetics of larotasoxetine or SB-T-1214 lipid prodrug

[0109] Using SD rats as animal models, larotasoxetine solution (LTX Solution), SB-T-1214 solution (SBT Solution), larotasoxetine self-microemulsion (LTX SNEDDS), SB-T-1214 self-microemulsion (SBTSNEDDS), larotasoxetine prodrug self-microemulsion (LTX-SS-TG SNEDDS), and SB-T-1214 prodrug self-microemulsion (SBT-SS-TG SNEDDS) were administered by gavage at a dose of 15 mg / kg (prodrug relative to parent drug). Blood samples were collected from the orbital rim at regular intervals to determine the plasma concentration of the parent drug at different time points. Plasma concentration-time curves were plotted, and the corresponding pharmacokinetic parameters were calculated (Table 5). To calculate absolute bioavailability, larotasoxetine solution and SB-T-1214 solution were administered intravenously at a dose of 5 mg / kg, and the plasma content of the parent drug was measured. The pharmacokinetic-time curves of the free parent drug are shown below. Figure 9 China A and Figure 10 As shown in Figure A, the peak concentration C of the two prodrugs in the microemulsion group is... max The levels of the parent drug were greater than those in the oral microemulsion group and the parent drug solution group. The parent drug solution was administered intravenously. Figure 11The oral bioavailability of the prodrugs was calculated based on the data. The absolute oral bioavailability of LTX-SS-TG and SBT-SS-TG prodrugs from microemulsion reached 27% and 18.5%, respectively, which were significantly improved compared with the corresponding oral parent drug solutions (LTX Solution: 6.0%, SBT Solution: 5.4%), indicating that oral prodrugs of triglycerides can significantly improve the oral absorption of the parent drug.

[0110] Table 5. Main pharmacokinetic parameters of free parent drug after oral administration.

[0111]

[0112] Due to the unique absorption mechanism of triglyceride prodrugs, the original triglyceride prodrug cannot be detected in blood samples. Therefore, a fragmentation method is used to determine the total amount of parent drug, and the corresponding blood drug concentration-time curve is shown below. Figure 9 China B and Figure 10 As shown in Figure B, the pharmacokinetic parameters are shown in Table 6. The results indicate that the total amount of the fragmented parent drug is significantly greater than that of the free parent drug. The amounts of unreleased lalotazone and SB-T-1214 in the prodrug are 4.32 and 6.97 times the amounts of the free drug released into the bloodstream, respectively. This suggests that the active ingredient in the prodrug remains primarily in the prodrug form after oral absorption into the systemic circulation, reducing the concentration of the parent drug in plasma and improving the safety of drug administration.

[0113] Table 6. Main pharmacokinetic parameters of the total parent drug after fracture.

[0114]

[0115] To investigate and verify the oral absorption mechanism of the two prodrugs, colchicine, a lymphatic transport inhibitor, was injected intraperitoneally 1 hour before oral administration of the prodrug microemulsion and the parent drug solution to investigate the effect of lymphatic transport on the absorption of the parent drug and the prodrug. The results are as follows: Figure 9 C, D and Figure 10 As shown in C and D, after inhibiting lymphatic transport, the free blood concentration of the oral parent drug solution group was almost unaffected, indicating that the absorption of the parent drug in the solution does not depend on the lymphatic pathway; the free blood concentration of the prodrug group decreased significantly, indicating that the prodrug is mainly absorbed into the systemic circulation through lymphatic transport after oral administration, verifying the oral lymphatic transport absorption mechanism of the triglyceride-like prodrug structure.

[0116] Example 7

[0117] Pharmacodynamics of larotasyl or SB-T-1214 lipid prodrug

[0118] Using female Balb / C mice bearing 4T1 as a model, larotasoxetine solution (5 mg / kg) and SB-T-1214 solution (5 mg / kg) were administered via tail vein injection at 2-day intervals. Larotasoxetine solution (10 mg / kg), SB-T-1214 solution (10 mg / kg), larotasoxetine parent drug self-microemulsion (10 mg / kg), SB-T-1214 parent drug self-microemulsion (10 mg / kg), larotasoxetine prodrug self-microemulsion, and SB-T-1214 prodrug self-microemulsion (parent drug equivalent dose 10 mg / kg) were administered orally once daily at fixed times. A saline group served as a blank control. Results are as follows: Figure 12 As shown, the tumor volume in the lalotasone or SB-T-1214 lipid prodrug self-emulsification formulation group was the smallest, showing a significant difference from the control group, and there was no significant weight loss, demonstrating significant antitumor activity and high safety.

Claims

1. A self-microemulsifying formulation of a lipid prodrug of a taxane, characterized in that, The product is composed of lalotasol palmitate triglyceride prodrug or SB-T-1214 palmitate triglyceride prodrug or their pharmaceutically acceptable salts and excipients; wherein the excipients are an oil phase and an emulsifier; the oil phase is a mixture of corn oil and Maisine CC in a mass ratio of 1:1; the emulsifier is castor oil polyoxyethylene ether; by mass percentage, the oil phase accounts for 70% of the total mass of the excipients, and the emulsifier accounts for 30% of the total mass of the excipients; The structural formulas of the lalotasol-palmitoyl triglyceride prodrug or the SB-T-1214-palmitoyl triglyceride prodrug are as follows: 。 2. A method for preparing a self-microemulsion formulation of a taxane-based lipid prodrug as described in claim 1, characterized in that, Includes the following steps: Add the emulsifier to the oil phase and sonicate to mix it evenly to obtain a homogeneous blank self-microemulsion formulation. Take lalotaxel-palmitoyl triglyceride prodrug or SB-T-1214-palmitoyl triglyceride prodrug and add it to the blank self-microemulsion formulation. Sonicate to completely dissolve the prodrug in it to obtain a homogeneous self-microemulsion formulation.

3. The use of the self-microemulsion formulation of the lipid prodrug of the taxane compound as described in claim 1 in the preparation of antitumor drugs.

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