Cyclodextrin-tamoxifen citrate inclusion compound drug loading system and application thereof

Abstract

The invention belongs to the technical field of antitumor drugs, and relates to a cyclodextrin-tamoxifen citrate inclusion compound drug loading system and application thereof. The invention aims to solve the problems of low solubility and poor stability of tamoxifen citrate and poor material adaptability in the existing cyclodextrin inclusion technology. The cyclodextrin-tamoxifen citrate inclusion compound drug loading system disclosed by the invention is prepared from tamoxifen citrate, cyclodextrin, a buffer solution, propylene glycol alginate and leucine. The compound can be prepared into preparations such as tablets and granules and is used for preparing anti-tumor drugs. Through cooperation of the adaptive inclusion material and the auxiliary materials and combination of a temperature control process, the drug inclusion rate and stability are remarkably improved, and the process is simple and controllable, is suitable for industrialization and has clinical application value.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of antitumor drugs, and particularly relates to a cyclodextrin-tamoxifen citrate inclusion compound drug delivery system and application thereof. BACKGROUND

[0002] The information disclosed in this Background section is for the purpose of increasing the understanding of the background of the application without admitting that such information forms prior art.

[0003] Tamoxifen citrate is a first-line endocrine therapy drug for breast cancer that is widely used in clinical practice, and is particularly suitable for early and advanced breast cancer patients with positive estrogen receptors. Its core mechanism of action is to compete with estrogen for binding to estrogen receptors in tumor cells, thereby inhibiting estrogen-mediated tumor cell proliferation. It has irreplaceable clinical value in reducing the recurrence rate of breast cancer and prolonging the survival of patients.

[0004] However, tamoxifen citrate itself has obvious defects in physicochemical properties and pharmacokinetic characteristics, which seriously limit the development of its preparations and the exertion of its clinical efficacy, mainly in the following aspects: (1) Low solubility and dissolution rate: Tamoxifen citrate belongs to BCS II class drugs, which is slightly soluble in water, and has a slow and incomplete dissolution rate in the gastrointestinal tract, resulting in poor absorption of the drug after oral administration, low bioavailability, and large inter-individual absorption differences, which affect the stability of the therapeutic effect.

[0005] (2) Poor chemical stability: Tamoxifen citrate contains unstable groups such as double bonds and amino groups in its molecular structure, which are easily oxidized and degraded under light, high temperature, and high humidity, generating inactive or potentially toxic metabolites, which not only reduce the drug efficacy but also increase the risk of adverse reactions, and impose strict requirements on the storage and transportation conditions of the preparation.

[0006] To solve the above problems, the prior art has tried various drug delivery system improvement schemes, and the Chinese patent with publication number CN103494787 A discloses a citrate tamoxifen drop pill, the inclusion material is a-cyclodextrin, the weight ratio of citrate tamoxifen to the inclusion material is 1:2, the slow-release drop pill includes citrate tamoxifen inclusion compound, a mixture of poloxamer, polyethylene glycol 8000 and stearic acid, a combination of sodium sulfite and sodium phosphate, and the condensate is dimethyl silicone oil. However, the inner diameter of the cavity of a-cyclodextrin is only 0.45-0.53 nm, while the molecular dynamics diameter of citrate tamoxifen is about 0.8-1.0 nm, the cavity adaptability of the two is very poor, efficient and stable inclusion cannot be achieved, and the drug leakage rate is high and the long-term stability is insufficient, which still cannot meet the dual requirements of high bioavailability and high stability of the preparation in the clinic.

[0007] Therefore, it is urgent to develop a new drug delivery system with simple preparation process, high inclusion rate and the ability to significantly improve drug stability to meet the high efficiency and safety requirements of citrate tamoxifen preparations in the clinic. SUMMARY

[0008] To overcome the defects of the prior art, the present application provides a cyclodextrin-citrate tamoxifen inclusion compound drug delivery system through systematic innovation of inclusion materials, functional excipients and preparation processes, and the specific technical solutions are as follows: (I) Formula of the cyclodextrin-citrate tamoxifen inclusion compound drug delivery system The drug delivery system is composed of the following components by weight: The main drug is citrate tamoxifen 5-10 parts by weight; the inclusion material is cyclodextrin 35-80 parts by weight (preferably hydroxypropyl-β-cyclodextrin); the pH stabilizer is a buffer solution 40-100 parts by weight (preferably a citrate buffer solution, adjusted to pH 4.0-5.5); the functional excipient is propylene glycol alginate 0.5-2 parts by weight and leucine 1-3 parts by weight.

[0009] The selection of the inclusion material hydroxypropyl-β-cyclodextrin depends on the "cavity size and drug molecule adaptability" and "water solubility", the selected hydroxypropyl-β-cyclodextrin in the present application has improved cavity space adaptability after hydroxypropyl modification, can form a "moderate tightness" inclusion structure with citrate tamoxifen molecules, and the hydroxypropyl modification significantly improves the water solubility, can form a stable saturated solution, provides sufficient cyclodextrin monomers for efficient inclusion, and solves the core problems of "poor adaptability of inclusion materials and insufficient water solubility" in the prior art.

[0010] Functional adjuvants: the synergistic application of the two adjuvants in the citric acid tamoxifen inclusion system has not been reported in the prior art, and through a large number of screenings (including polyethylene glycol 4000, valine, mannitol and more than 20 kinds of adjuvants), it is found that when PGA and leucine are combined in a weight ratio of 0.5-2:1-3, the synergistic system formed by the two can improve the encapsulation rate and reduce the leakage rate, which is much better than single adjuvant or other adjuvant combinations.

[0011] (II) Preparation method of cyclodextrin-citric acid tamoxifen inclusion complex drug delivery system The preparation method and component design of the present application are highly matched, and by precisely controlling the key parameters such as temperature and pH, the encapsulation efficiency and stability are ensured, and the specific steps are as follows: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60±5℃ (preheating can increase the solubility of cyclodextrin by 30%-40%, quickly form a clear saturated solution, and avoid the influence of unsolved cyclodextrin on the uniformity of inclusion), and stir and dissolve in a 30-40℃ constant temperature water bath; (2) Adjusting the pH and stability of the system: add a buffer solution to the cyclodextrin solution to adjust the pH to 4.0-5.5 (precise pH control ensures drug molecule stability and provides the best environment for the inclusion reaction); (3) Drug inclusion reaction: add citric acid tamoxifen to the above solution and maintain 35-45℃ water bath stirring for 2-4 hours (this temperature range can balance the "inclusion reaction rate" and "drug stability": too low temperature will result in incomplete inclusion reaction, and too high temperature will increase the rate of drug oxidation degradation); (4) Add functional adjuvants: first add propylene glycol alginate, heat to 45-50℃ and stir until dissolved (high temperature ensures that PGA is completely dissolved, avoiding the influence of undissolved particles on the uniformity of the inclusion complex); then cool to 30-35℃ and add leucine and stir (low temperature can prevent leucine from denaturing at high temperature, ensuring its hydrogen bonding ability); (5) Inclusion solidification and purification: transfer the mixed solution to a brown light-proof container, place it in a 2-8℃ refrigerator for 12-24 hours (low temperature promotes the crystallization of the inclusion complex, improving the inclusion integrity); collect the filter cake by microfiltration, and wash it with 5-10℃ ice purified water for 2-3 times to remove the free drugs and adjuvants that are not included; (6) Drying and molding: dry in a 45-55℃ vacuum drying oven until the weight is constant, crush and sieve to obtain the product.

[0012] (III) Formulations and applications based on the drug delivery system The inclusion complex drug delivery system of the present application has excellent formability, and can be prepared into various clinical commonly used preparations such as tablets, granules, capsules and oral liquids, thereby solving the problems of slow dissolution and poor stability of traditional tamoxifen citrate preparations. Meanwhile, the drug delivery system can be used for preparing anti-tumor drugs, and is particularly suitable for the treatment of early and late breast cancer positive for estrogen receptor.

[0013] The creativity of the present application lies in the systematic innovation of "inclusion material-adjuvant synergy-technological parameter", rather than simple component replacement or parameter superposition. Firstly, the present application breaks through the limitation of alpha-cyclodextrin in the prior art, and selects hydroxypropyl-beta-cyclodextrin as the inclusion material. Based on the scientific analysis of "cavity size-drug molecule adaptability" and "water solubility-inclusion efficiency correlation", the core problem of mismatch between the inclusion material and the drug molecule is solved, which is the creative improvement of the application of cyclodextrin inclusion technology in tamoxifen citrate.

[0014] Compared with the prior art, the technical effect of the present application is that: (1) The inclusion rate is significantly improved: the encapsulation rate of examples 1-3 of the present application is 94.4%-96.3%, which is much higher than that of comparative examples 1-6, proving that the components and process of the present application can achieve efficient inclusion. (2) The stability is greatly improved: the leakage rate of examples 1-3 is only 2.1%-3.0% after 6 months of accelerated test (40℃±2℃, RH75%±5%), while the leakage rate of comparative example 5 is 28.1%; the leakage rate of examples 1-3 is only 2.2%-2.8% after 12 months of long-term test, while the leakage rate of comparative example 5 is 19.2%, proving that the present application can effectively inhibit drug leakage and degradation, and meet the clinical storage requirements.

[0015] (3) High clinical application value: based on the fact that the drug delivery system can be prepared into tablets, granules and oral liquids, more stable and efficient treatment options are provided for breast cancer patients. BRIEF DESCRIPTION OF DRAWINGS

[0016] Figure 1 : The encapsulation rate of the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system.

[0017] Figure 2 : The leakage rate of the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system in accelerated test.

[0018] Figure 3 : The leakage rate of the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system in long-term test. DETAILED DESCRIPTION

[0019] In order to make the purpose, technical scheme of the present application more clear, the following embodiments are used to further explain the present application, but the protection scope of the present application is not limited to these embodiments, and the embodiments are only used to explain the present application. Those skilled in the art should understand that any change or equivalent replacement without departing from the concept of the present application is included in the protection scope of the present application.

[0020] Example 1: Cyclodextrin-tamoxifen citrate inclusion complex drug delivery system Formula: Tamoxifen citrate 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, propylene glycol alginate 1g, leucine 2g.

[0021] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60°C, place in a 35°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjusting the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=5.0; (3) Main drug inclusion reaction: add tamoxifen citrate to the above solution, maintain a 40°C water bath, stir for 3 hours; (4) Add functional excipients: add propylene glycol alginate, heat to 48°C, stir until dissolved, cool to 32°C, add leucine, stir; (5) Inclusion complex solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5°C refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven to constant weight, crush, sieve, and obtain.

[0022] Example 2: Cyclodextrin-tamoxifen citrate inclusion complex drug delivery system Formula: Tamoxifen citrate 5g, hydroxypropyl-β-cyclodextrin 35g, buffer solution 40g, propylene glycol alginate 0.5g, leucine 1g.

[0023] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 55°C, place in a 30°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjusting the pH and stability of the system: add phosphate buffer solution to the cyclodextrin solution to adjust pH=4.0; (3) Main drug inclusion reaction: add tamoxifen citrate to the above solution, maintain a 35°C water bath, stir for 2 hours; (4) Add functional excipients: add propylene glycol alginate, heat to 45°C, stir until dissolved, cool to 30°C, add leucine, stir; (5) Inclusion complex solidification and purification: transfer the above mixture to a brown light-proof container, place in a 2°C refrigerator for 12 hours, microfiltration, collect the filter cake; wash the filter cake with 5°C ice-purified water for 2-3 times; (6) Drying and molding: dry in a 45°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0024] Example 3 Cyclodextrin-tamoxifen citrate inclusion complex drug delivery system Formulation: Tamoxifen citrate 10g, hydroxypropyl-β-cyclodextrin 80g, buffer solution 100g, propylene glycol alginate 2g, leucine 3g.

[0025] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 65°C, place in a 40°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add lactate buffer solution to the cyclodextrin solution to adjust pH=5.5; (3) Drug inclusion reaction: add tamoxifen citrate to the above solution, maintain 45°C water bath, stir for 4 hours; (4) Add functional excipients: add propylene glycol alginate, heat to 50°C, stir until dissolved, cool to 35°C, add leucine, stir; (5) Inclusion complex solidification and purification: transfer the above mixture to a brown light-proof container, place in an 8°C refrigerator for 24 hours, microfiltration, collect the filter cake; wash the filter cake with 10°C ice-purified water for 2-3 times; (6) Drying and molding: dry in a 55°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0026] Example 4 Cyclodextrin-tamoxifen citrate inclusion complex drug delivery system Formulation: Tamoxifen citrate 7g, α-cyclodextrin 50g, buffer solution 60g, propylene glycol alginate 1.5g, leucine 2g.

[0027] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60°C, place in a 35°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=4.5; (3) Main drug inclusion reaction: add the citrate tamoxifen into the above solution, maintain 40°C water bath, stir for 3 hours; (4) Add functional excipients: add propylene glycol alginate, warm up to 45°C, stir until dissolved, cool down to 35°C, add leucine, stir; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5°C refrigerator for 18 hours, microfiltration, collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0028] Example 5 Cyclodextrin-citrate tamoxifen inclusion compound drug delivery system Formulation: Citrate tamoxifen 8g, β-cyclodextrin 65g, buffer solution 80g, propylene glycol alginate 1g, leucine 2g.

[0029] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60°C, place in a 35°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=5.0; (3) Main drug inclusion reaction: add the citrate tamoxifen into the above solution, maintain 45°C water bath, stir for 3 hours; (4) Add functional excipients: add propylene glycol alginate, warm up to 50°C, stir until dissolved, cool down to 35°C, add leucine, stir; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5°C refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0030] Example 6 Citrate tamoxifen tablets Formulation (per 1000 tablets): Example 1 inclusion compound (containing citrate tamoxifen 10g), lactose (filler) 30g, microcrystalline cellulose (filler / disintegrating agent) 15g, hydroxypropyl methyl cellulose (adhesive) 3g (prepared into a 5% aqueous solution with purified water), cross-linked polyvinylpyrrolidone (disintegrating agent) 4g, magnesium stearate (lubricant) 1.25g.

[0031] Preparation method: Pretreatment: Example 1 inclusion complex, lactose, microcrystalline cellulose, crosslinked polyvinylpyrrolidone were passed through 80 mesh sieve, ready for use; Granulation: the above mixed powder was placed in a wet granulator, 5% HPMC aqueous solution was slowly added, stirred into soft material, and 18 mesh sieve was used to prepare wet granules; Drying: the wet granules were placed in a 45-50°C air drying oven and dried to a moisture content of 2%-3%, then taken out and cooled; Granulation: the dried granules were granulated with a 16 mesh sieve, magnesium stearate was added, and mixed evenly (total mixing time 5 minutes), and then tableted.

[0032] Example 7 Citrate tamoxifen granules Formula (per 100 bags): Example 2 inclusion complex (containing 1 g of citrate tamoxifen), sucrose (filler / taste corrector) 60 g, dextrin (filler / binder) 23 g, aspartame (taste corrector) 1.5 g, povidone (binder) 0.375 g (prepared into a 10% solution w / v with 70% ethanol), lemon flavor (taste corrector) 0.2 ml (added after dilution with ethanol).

[0033] Preparation method: Screening powder: inclusion complex, sucrose, dextrin, aspartame were passed through 80 mesh sieve and mixed evenly; Granulation: 10% PVP ethanol solution was added to the mixed powder while stirring to form soft material, and 16 mesh sieve was used to prepare wet granules; Drying: the wet granules were placed in a 45°C air drying oven and dried to a moisture content of ≤2%, then cooled; Granulation: the dried granules were granulated with a 14 mesh sieve, and diluted lemon flavor was sprayed in and mixed for 30 minutes in a closed container; Packaging: the granules were packaged into aluminum-plastic composite bags using a granule packaging machine.

[0034] Example 8 Citrate tamoxifen oral solution Formula (per 1000 bottles): Example 3 inclusion complex (containing 1 g of citrate tamoxifen), purified water (solvent) 950 ml, hydroxyethyl benzoate (preservative) 0.5 g, EDTA-2Na (stabilizer) 0.2 g, stevioside (taste corrector) 1 g, lemon flavor (taste corrector) 1 ml, 0.1 mol / L hydrochloric acid / sodium hydroxide (pH adjuster) as needed (adjust pH to 4.5-5.0).

[0035] Preparation method: Dissolution adjuvant: take 500 ml purified water, heated to 60℃, add hydroxyphenyl ethyl ester, EDTA-2Na, steviol glycoside, stirring until completely dissolved, cool to room temperature; Add the main drug: the inclusion complex of example 3 is added to the above solution, stirring until completely dissolved; Flavor and pH adjustment: add lemon flavor, adjust pH to 4.5-5.0 with 0.1 mol / L hydrochloric acid or sodium hydroxide; constant volume and filtration: add purified water to a total volume of 1000 ml, stir evenly, filter with 0.22 μm microporous filter membrane to clear; fill and sterilize.

[0036] Comparative example 1 cyclodextrin-tamoxifen citrate inclusion complex drug delivery system (no addition of propylene glycol alginate) Formula: Tamoxifen citrate 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, leucine 2g.

[0037] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add preheated to 60℃ purified water, placed in a 35℃ constant temperature water bath, stirring to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=5.0; (3) Main drug inclusion reaction: add tamoxifen citrate to the above solution, maintain 40℃ water bath, stir for 3 hours; (4) Add functional adjuvant: cool to 32℃, add leucine, stir; (5) Inclusion complex solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5℃ refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8℃ ice purified water 2-3 times; (6) Drying and molding: dry in a 50℃ vacuum drying oven to constant weight, crush, sieve, get it.

[0038] Comparative example 2 cyclodextrin-tamoxifen citrate inclusion complex drug delivery system (no addition of leucine) Formula: Tamoxifen citrate 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, propylene glycol alginate 1g.

[0039] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add preheated to 60℃ purified water, placed in a 35℃ constant temperature water bath, stirring to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=5.0; (3) Main drug inclusion reaction: add the citrate tamoxifen into the above solution, maintain 40°C water bath, stir for 3 hours; (4) Add functional excipients: add propylene glycol alginate, warm to 48°C, stir until dissolved; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5°C refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0040] Comparative Example 3 Cyclodextrin-citrate tamoxifen inclusion compound drug delivery system (replace propylene glycol alginate with polyethylene glycol 4000) Formulation: Citrate tamoxifen 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, polyethylene glycol 4000 1g, leucine 2g.

[0041] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60°C, place in a 35°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjust the pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH=5.0; (3) Main drug inclusion reaction: add the citrate tamoxifen into the above solution, maintain 40°C water bath, stir for 3 hours; (4) Add functional excipients: add polyethylene glycol 4000, warm to 48°C, stir until dissolved, cool to 32°C, add leucine, stir; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5°C refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0042] Comparative Example 4 Cyclodextrin-citrate tamoxifen inclusion compound drug delivery system (replace leucine with valine) Formulation: Citrate tamoxifen 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, propylene glycol alginate 1g, valine 2g.

[0043] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60°C, place in a 35°C constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjusting pH and stability: add citrate buffer solution to the cyclodextrin solution to adjust pH = 5.0; (3) Main drug inclusion reaction: add citrate tamoxifen to the above solution, maintain 40℃ water bath, stir for 3 hours; (4) Add functional excipients: add propylene glycol alginate, heat to 48℃, stir until dissolved, cool to 32℃, add valine, stir; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5℃ refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8℃ ice purified water for 2-3 times; (6) Drying and molding: dry in a 50℃ vacuum drying oven until constant weight, crush, sieve, and obtain.

[0044] Comparative Example 5 Cyclodextrin-citrate tamoxifen inclusion compound drug delivery system (no propylene glycol alginate and leucine) Formulation: Citrate tamoxifen 8g, hydroxypropyl-β-cyclodextrin 50g.

[0045] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60℃, place in a 35℃ constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjusting pH and stability: add citrate buffer solution to the cyclodextrin solution to adjust pH = 5.0; (3) Main drug inclusion reaction: add citrate tamoxifen to the above solution, maintain 40℃ water bath, stir for 3 hours; (4) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place in a 5℃ refrigerator for 20 hours, microfiltration, collect the filter cake; wash the filter cake with 8℃ ice purified water for 2-3 times; (5) Drying and molding: dry in a 50℃ vacuum drying oven until constant weight, crush, sieve, and obtain.

[0046] Comparative Example 6 Cyclodextrin-citrate tamoxifen inclusion compound drug delivery system (temperature of 4 steps) Formulation: Citrate tamoxifen 8g, hydroxypropyl-β-cyclodextrin 50g, buffer solution 60g, propylene glycol alginate 1g, leucine 2g.

[0047] Preparation method: (1) Preparation of cyclodextrin stock solution: take cyclodextrin, add purified water preheated to 60℃, place in a 35℃ constant temperature water bath, stir to dissolve, form a clear cyclodextrin saturated solution; (2) Adjusting pH and stability of the system: add citrate buffer solution to the cyclodextrin solution to adjust pH to 5.0; (3) Main drug inclusion reaction: add citrate tamoxifen to the above solution, maintain 40°C water bath, and stir for 3 hours; (4) Add functional excipients: maintain 40°C, add propylene glycol alginate and leucine, and stir; (5) Inclusion compound solidification and purification: transfer the above mixture to a brown light-proof container, place it in a 5°C refrigerator for 20 hours, microfiltration, and collect the filter cake; wash the filter cake with 8°C ice purified water for 2-3 times; (6) Drying and molding: dry in a 50°C vacuum drying oven until constant weight, crush, sieve, and obtain.

[0048] Encapsulation rate determination The encapsulation rate (EE) reflects the inclusion ability of cyclodextrin to citrate tamoxifen, and the calculation formula is: EE (%) = (actual content of citrate tamoxifen in inclusion compound / drug amount of citrate tamoxifen) x 100%.

[0049] Table 1. Encapsulation rate of cyclodextrin-citrate tamoxifen inclusion compound drug delivery system Table 1 shows that the use of hydroxypropyl-β-cyclodextrin in the present application, combined with the addition of propylene glycol alginate and leucine, and the addition of excipients under specific temperature conditions, can significantly improve the encapsulation rate, and exhibit better drug inclusion effect. However, the absence of any key functional excipients, the replacement of other excipients, or the change of excipient addition temperature will all lead to a decrease in encapsulation rate, reducing the inclusion ability of cyclodextrin to citrate tamoxifen.

[0050] Leakage rate determination The leakage rate (LR) reflects the release stability of the inclusion compound during storage, and the calculation formula is: LR (%) = (initial drug content - drug content after storage) / initial drug content x 100%. Through accelerated test (simulating extreme storage conditions) and long-term test (simulating actual storage conditions), the leakage rate at different time points is investigated to evaluate the stability. Accelerated test: 40°C ± 2°C, relative humidity (RH) 75% ± 5%, sampling time points: 1, 2, 3, 6 months. Long-term test: 25°C ± 2°C, RH 60% ± 5%, sampling time points: 3, 6, 9, 12 months.

[0051] Table 2. Leakage rate of accelerated test Table 2 shows that the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system of the present application exhibits excellent storage stability, low drug leakage and a slow change in leakage rate over time, and can effectively inhibit the release of drugs under extreme conditions. In contrast, the comparative examples, which lack key functional excipients (propylene glycol alginate or leucine), replace other excipients, or change the addition temperature of the excipients, have higher drug leakage rates under extreme storage conditions, and the leakage intensifies over time. The drug delivery system that completely lacks the two key excipients has the worst stability and the most prominent drug leakage problem.

[0052] Table 3 Long-term test leakage rate Table 3 shows that under simulated actual storage conditions, the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system of the present application has good long-term storage stability, and the drug leakage rate remains low after long-term storage, effectively ensuring the stability of the drug content during the actual storage period. The drug leakage rates of Comparative Examples 1-6 are higher than that of the present application during long-term storage, and the leakage is more pronounced as the storage time increases, making it difficult to meet the stability requirements during actual storage.

Claims

1. A cyclodextrin-tamoxifen citrate inclusion complex drug delivery system, characterized in that, The cyclodextrin-tamoxifen citrate inclusion complex drug delivery system comprises: 5-10 parts by weight of tamoxifen citrate, 35-80 parts by weight of cyclodextrin, 40-100 parts by weight of buffer solution, 0.5-2 parts by weight of propylene glycol alginate, and 1-3 parts by weight of leucine.

2. The cyclodextrin-tamoxifen citrate inclusion complex drug delivery system according to claim 1, characterized in that, The cyclodextrin is selected from at least one of α-cyclodextrin, β-cyclodextrin, and hydroxypropyl-β-cyclodextrin.

3. The cyclodextrin-tamoxifen citrate inclusion complex drug delivery system according to claim 1, characterized in that, The cyclodextrin is hydroxypropyl-β-cyclodextrin.

4. The cyclodextrin-tamoxifen citrate inclusion complex drug delivery system according to claim 1, characterized in that, The buffer solution is selected from at least one of citrate buffer solution, phosphate buffer solution, and lactate buffer solution.

5. The cyclodextrin-tamoxifen citrate inclusion complex drug delivery system according to claim 1, characterized in that, The buffer solution is a citrate buffer solution.

6. A method for preparing the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system according to claim 1, characterized in that, The preparation method includes the following steps: (1) Preparation of cyclodextrin stock solution: Take cyclodextrin, add purified water, place in a constant temperature water bath at 30-40℃, stir to dissolve, and form a clear saturated cyclodextrin solution; (2) Adjusting the pH and stability of the system: Add buffer solution to the cyclodextrin solution to adjust the pH; (3) Inclusion reaction of the main drug: Add tamoxifen citrate to the above solution, maintain a water bath at 35-45℃, and stir for 2-4 hours; (4) Add functional excipients: Add propylene glycol alginate, heat to 45-50℃, stir until dissolved, cool to 30-35℃, add leucine, and stir; (5) Solidification and purification of inclusion complex: Transfer the above mixture to a brown light-proof container, place it in a refrigerator at 2-8℃ and let it stand for 12-24 hours, microfilter and collect the filter cake; wash the filter cake 2-3 times with ice-cold purified water at 5-10℃. (6) Drying and shaping: Dry in a vacuum drying oven at 45-55℃ until constant weight, crush and sieve to obtain the product.

7. The preparation method according to claim 6, characterized in that, The buffer solution is adjusted to pH 4.0-5.

5.

8. The preparation method according to claim 6, characterized in that, In the step of preparing the cyclodextrin stock solution, the purified water is preheated to 60±5℃.

9. A formulation comprising the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system of claim 1, characterized in that, The preparations are tablets, granules, capsules, or oral liquids.

10. The use of the cyclodextrin-tamoxifen citrate inclusion complex drug delivery system of claim 1 in the preparation of antitumor drugs.

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