Poloxamer hydrogel for hydrophobic drug release

Abstract

The application discloses a hydrophobic drug sustained-release hydrogel of polyethylene glycol-poloxamer, which realizes sustained release of a hydrophobic drug by using the hydrophobic groups of poloxamer to interact with the hydrophobic groups of the drug, and guarantees the stability of the drug sustained-release hydrogel in the body by using a crosslinking system formed by polyethylene glycol and a crosslinking agent.

Description

Technical Field

[0001] This invention belongs to the field of biomedical materials technology, and specifically relates to a method for preparing a hydrogel for sustained release of hydrophobic drugs. Technical Background

[0002] Sustained-release drug formulations can reduce the frequency of administration, improve efficacy, and enhance patient adherence. A significant portion of existing drugs are hydrophobic, exhibiting extremely low solubility in water and difficulty in absorption by the body. Compared to hydrophilic drugs, sustained release is even more challenging, limiting their application. Therefore, researching sustained-release systems for hydrophobic drugs to control the release rate, release time, and release site has significant medical value. Hydrogels are hydrophilic polymer networks that swell significantly in water but do not dissolve in it. Hydrophobic gels contain a certain amount of hydrophobic segments or groups within the gel structure. These groups can be groups within the hydrogel backbone or groups embedded in the second component of the hydrogel network. The hydrophobic groups in the hydrogel can bind to hydrophobic drugs, achieving the purpose of sustained release.

[0003] Poloxamer is a type of nonionic triblock copolymer composed of polyethylene oxide and polypropylene oxide (PEO-PPO-PEO), and it has become a research hotspot in drug sustained release in recent years. Some researchers have prepared insulin thermosensitive gels using poloxamer 407 (F127) as a carrier, which can slow down the release rate of insulin from the gel, but the maximum release time is only 8 hours, which is difficult to match long-term clinical needs (Pharm Dev Technol, 2010, 15(2):192-208.). Some researchers have prepared cationic microemulsion-in-situ gels based on poloxamer 407 and studied the sustained release effect of this drug release system using vitamin A palmitate as a model drug. The results showed that the time required for 90% in vitro drug release was 9 times that of Oculotect gel, highlighting its superior sustained release performance, but it was also completely released after 10 hours. Furthermore, poloxamer itself has poor stability in the body, is prone to migration from the target site, and has a short residence time in the body. Therefore, it is of clinical significance to develop a drug release system that can achieve longer-lasting drug release using poloxamer and maintain a stable drug release. Summary of the Invention

[0004] This invention provides a polyethylene glycol-poloxam hydrogel for sustained drug release, which utilizes the hydrophobic interaction between the hydrophobic groups of poloxamer and the drug to achieve sustained release of the hydrophobic drug, and utilizes the cross-linking system formed by polyethylene glycol and a cross-linking agent to ensure the stability of the sustained drug release hydrogel in vivo.

[0005] The specific technical solution of this invention is as follows:

[0006] A poloxamer hydrogel comprises a polyethylene glycol hydrogel and poloxamer, wherein the polyethylene glycol hydrogel is formed by crosslinking polyethylene glycol and / or star-shaped multi-arm polyethylene glycol with one or more of a polyamine compound and / or a polyhydrazide compound. The poloxamer is selected from one or more of poloxamer 124, poloxamer 188, poloxamer 237, poloxamer 338, and poloxamer 407. Poloxamer 407 is preferred.

[0007] The polyethylene glycol / or star-shaped multi-arm polyethylene glycol has a molecular weight of 2000-40000 Da. Preferably, it is 4000-40000 Da.

[0008] The gel contains 1-15% polyethylene glycol and 5-25% poloxamer by mass. More preferably, the concentration of polyethylene glycol is 5-10% and the concentration of poloxamer is 10-20%.

[0009] Preferably, the polyamino compound is polylysine and / or polyethyleneimine.

[0010] Preferably, the polyethylene glycol or star-shaped multi-arm polyethylene glycol has aldehyde end caps, and the aldehyde group is connected to the polyethylene glycol or star-shaped multi-arm polyethylene glycol by ester bond, amide bond, ether bond, urethane bond, imine bond or urea bond.

[0011] The aldehyde group is selected from one or more aromatic aldehyde groups and alkyl aldehyde groups. Benzaldehyde is preferred.

[0012] In a specific example of the present invention, the polyethylene glycol is a star-shaped multi-arm polyethylene glycol with benzaldehyde-terminated ends.

[0013] The degradation time of hydrogels can be adjusted by referring to the technical solutions disclosed in CN109939065A, CN109646723A, CN112225912A, and CN113461973A, by adjusting the ratio of polylysine to polyethyleneimine in the polyamino compound, the molar ratio of the amino group of the polyamino compound to the aldehyde group of the star-shaped multi-arm polyethylene glycol, and the linkage between the aldehyde group and the star-shaped multi-arm polyethylene glycol, so as to meet different clinical needs.

[0014] The hydrogel of this invention is prepared by the following method:

[0015] Polyethylene glycol or star-shaped multi-arm polyethylene glycol was added to pH 4-10 phosphate buffer and stirred to dissolve. Then, poloxamer was added in a 5°C water bath and stirred to dissolve, yielding solution A. Polyethyleneimine and polylysine were added to pH 4-10 phosphate buffer and stirred to dissolve. Then, poloxamer was added in a 5°C water bath and stirred to dissolve, yielding solution B. The two solutions were then mixed to obtain a poloxamer-polyethylene glycol hydrogel.

[0016] The drug can be dissolved in solution A and / or solution B, and equal volumes of solutions A and B are mixed to form a drug-loaded hydrogel. Another object of the present invention is to provide the application of the hydrogel in the preparation of a hydrophobic drug delivery system. Preferably, the hydrophobic drug is selected from ibuprofen, aspirin, insulin, azithromycin, puerarin, vitamin A, vitamin B2, vitamin B12, vitamin E, paclitaxel, enoxacin, meloxicam, or indomethacin.

[0017] Advantages of this invention:

[0018] This invention utilizes the hydrophobic interaction between the hydrophobic groups of poloxamer and the drug, while simultaneously employing a polyethylene glycol crosslinking network to encapsulate the poloxamer, extending the gel's degradation period and achieving sustained release of the hydrophobic drug. Furthermore, the crosslinking system formed by polyethylene glycol and the crosslinking agent ensures the stability of this sustained-release hydrogel in vivo. Detailed Implementation

[0019] The specific steps of the present invention are illustrated below through examples, but are not limited to these examples.

[0020] Unless otherwise stated, the terms used in this invention generally have the meanings commonly understood by those skilled in the art.

[0021] The present invention will now be described in further detail with reference to specific examples and data. It should be understood that these embodiments are merely illustrative of the invention and are not intended to limit the scope of the invention in any way.

[0022] In the following embodiments, various processes and methods not described in detail are conventional methods known in the art.

[0023] Example 1: Investigating the effect of poloxamer content on drug release

[0024] Comparison 1:

[0025] Dissolve 1.5 g of poloxamer 407 in 10 mL of deionized water to obtain a 15% poloxamer aqueous solution. Weigh 10 mg of indomethacin and dissolve it in 1 mL of ethanol. Add 9 mL of the 15% poloxamer aqueous solution prepared above and stir at 5 °C to obtain a 15% poloxamer hydrogel loaded with indomethacin.

[0026] Comparison 2:

[0027] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6) as solution A. A phosphate buffer (pH 8.9) solution containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared as solution B. 10mg of indomethacin was dissolved in 1mL of ethanol and added to 9mL of the prepared solution B. The two solutions A and B were mixed in equal volumes using a double syringe to form a polyethylene glycol hydrogel loaded with indomethacin.

[0028] Gel 1:

[0029] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6), and 3g of poloxamer 407 was added to prepare solution A. 20mL of phosphate buffer (pH 8.9) containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared, and 3g of poloxamer 407 was added to prepare solution B. 10mg of indomethacin was dissolved in 1mL of ethanol and added to 9mL of the prepared solution B. The two solutions A and B were mixed in equal volumes using a double syringe to form a polyethylene glycol-poloxam hydrogel loaded with indomethacin.

[0030] Gel 2:

[0031] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6), and 2g of poloxamer 407 was added to prepare solution A. 20mL of phosphate buffer (pH 8.9) containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared, and 2g of poloxamer 407 was added to prepare solution B. 10mg of indomethacin was dissolved in 1mL of ethanol and added to 9mL of the prepared solution B. The two solutions A and B were mixed in equal volumes using a double syringe to form a polyethylene glycol-poloxam hydrogel loaded with indomethacin.

[0032] Gel 3:

[0033] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6), and 4g of poloxamer 407 was added to prepare solution A. 20mL of phosphate buffer (pH 8.9) containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared, and 4g of poloxamer 407 was added to prepare solution B. 10mg of indomethacin was dissolved in 1mL of ethanol and added to 9mL of the prepared solution B. The two solutions A and B were mixed in equal volumes using a double syringe to form a polyethylene glycol-poloxam hydrogel loaded with indomethacin.

[0034] 0.5 g of drug-loaded hydrogels 1-3 and control samples were added to 10 mL of phosphate buffer solution with a pH of 7.4, and drug release experiments were conducted in a constant temperature water bath shaker at 37 °C. At specific time intervals, the solution was removed and replenished with 10 mL of solution. The removed solution was quantitatively measured using a UV spectrophotometer, and the cumulative drug release data were calculated, as shown in Table 1.

[0035] Table 1. Sustained-release data of indomethacin in hydrogels

[0036] Comparison 1 Poloxamer Gel 81.04％ 82.41％ - - - Comparison 2 polyethylene glycol hydrogel 63.82％ 81.85％ - - - Hydrogel 1 Poloxamer (15%) - Polyethylene Glycol Hydrogel 20.34％ 32.01％ 60.94％ 77.95％ 81.15％ Hydrogel 2 Poloxamer (10%) - Polyethylene Glycol Hydrogel 56.53％ 62.31％ 80.67％ - - Hydrogel 3 Poloxamer (20%) - Polyethylene Glycol Hydrogel 40.02％ 69.88％ 97.57％ - -

[0037] The results showed that, compared with the poloxamer hydrogel of control 1 and the polyethylene glycol hydrogel of control 2, the release of indomethacin in the polyethylene glycol-poloxamer hydrogel was significantly slowed down. When the concentration of poloxamer was 15%, the sustained release effect of indomethacin was the best, with a cumulative release ratio of 81.15% after 72 hours.

[0038] Example 2

[0039] Taking poloxamer (15%)-polyethylene glycol hydrogel as an example, the effect of poloxamer addition method on hydrogel properties was investigated. Gel 4:

[0040] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6), and then 6g of poloxamer 407 was added as solution A. Solution A was found to have excessive viscosity and poor flowability. The results indicate that dissolving all of poloxamer 407 in solution A is unsuitable for preparing polyethylene glycol-poloxam hydrogels.

[0041] Gel 5:

[0042] 3g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10kDa) was dissolved in 20mL of 0.02M phosphate buffer (pH 5.6) as solution A. 20mL of phosphate buffer (pH 8.9) containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared, and 6g of poloxamer 407 was added to prepare solution B. 10mg of indomethacin was dissolved in 1mL of ethanol and added to 9mL of the prepared solution B. Solutions A and B were mixed in equal volumes using a double syringe. The results showed that the formed gel had a loose and porous surface with adhesive liquid, indicating low cross-linking degree of polyethylene glycol and poor uniformity of poloxamer, making it unsuitable for preparing polyethylene glycol-poloxam hydrogels.

[0043] The above research results indicate that, to ensure the performance of the hydrogel, it is best to dissolve poloxamer in solutions A and B. Example 3: Polyethylene glycol-poloxamer hydrogel loaded with a hydrophilic drug.

[0044] Comparison 3:

[0045] Dissolve 1.5 g of poloxamer 407 in 10 mL of deionized water to obtain a 15% poloxamer aqueous solution. Weigh 50 mg of riboflavin and dissolve it in 5 mL of 0.1 M sodium hydroxide aqueous solution. Add 9 mL of the 15% poloxamer aqueous solution prepared above and stir at 5 °C to obtain a 15% poloxamer hydrogel loaded with riboflavin.

[0046] Comparison 4:

[0047] 3 g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10 kDa) was dissolved in 20 mL of 0.02 M phosphate buffer (pH 5.6) as solution A. A phosphate buffer (pH 8.9) solution containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8 kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared as solution B. 50 mg of riboflavin was dissolved in 5 mL of 0.1 M sodium hydroxide and added to 9 mL of the prepared solution B. Solutions A and B were mixed using a double syringe to form a riboflavin-loaded polyethylene glycol hydrogel.

[0048] Gel 6:

[0049] 3 g of 8-arm benzaldehyde-terminated polyethylene glycol (molecular weight 10 kDa) was dissolved in 20 mL of 0.02 M phosphate buffer (pH 5.6), and 3 g of poloxamer 407 was added to prepare solution A. 20 mL of phosphate buffer (pH 8.9) containing polylysine (molar ratio of aldehyde to amino group of polyethylene glycol 1:1.2) and polyethyleneimine (MW 1.8 kDa) (molar ratio of aldehyde to amino group of polyethyleneimine 1:1.5) was prepared, and 3 g of poloxamer 407 was added to prepare solution B. 50 mg of riboflavin was dissolved in 5 mL of 0.1 M sodium hydroxide and added to 9 mL of the prepared solution B. The two solutions A and B were mixed in equal volumes using a double syringe to form a riboflavin-loaded polyethylene glycol-poloxam hydrogel.

[0050] 0.5 g of drug-loaded control sample and hydrogel sample were added to 10 mL of phosphate buffer solution with a pH of 7.4, and drug release experiments were conducted in a constant temperature water bath shaker at 37 °C. At specific time intervals, the solution was removed and replenished with 10 mL of solution. The removed solution was quantitatively measured using a UV spectrophotometer, and the cumulative drug release data were calculated, as shown in Table 2.

[0051] Table 2. Sustained-release data of riboflavin in hydrogels

[0052] Comparison 3 Poloxamer Gel 44.52％ 44.85％ 80.29％ 80.52％ 80.90％ Compare with 4 polyethylene glycol hydrogel 74.02％ 91.81％ 99.28％ 99.30％ - Hydrogel 6 Poloxamer (15%) - Polyethylene Glycol Hydrogel 64.94％ 91.54％ 95.64％ 96.95％ 97.11％

[0053] The results showed that the riboflavin release effect of the polyethylene glycol-poloxam hydrogel was similar to that of control 3 (poloxam hydrogel) and control 4 (polyethylene glycol hydrogel). These results indicate that the polyethylene glycol-poloxam hydrogel described in this invention is not suitable for hydrophilic drugs.

Claims

1. A poloxamer hydrogel, characterized in that... The product comprises polyethylene glycol hydrogel and poloxamer. The polyethylene glycol hydrogel is formed by crosslinking polyethylene glycol and / or star-shaped multi-arm polyethylene glycol with one or more of polyamine compounds and / or polyhydrazide compounds. The mass percentage concentration of polyethylene glycol in the gel is 5-10%, and the mass percentage concentration of poloxamer is 10-20%. It is prepared using the following method: Solution A is prepared by dissolving polyethylene glycol and / or star-shaped multi-arm polyethylene glycol and poloxamer in a buffer solution. Solution B is prepared by dissolving a polyamino compound and / or a polyhydrazide compound and poloxamer in a buffer solution. A hydrophobic drug is dissolved in solution A and / or solution B. Equal volumes of solutions A and B are then mixed to form a hydrogel. The poloxamer is selected from poloxamer 407. The molecular weight of the polyethylene glycol and / or star-shaped multi-arm polyethylene glycol is 2000-40000 Da. The polyamino compound is polylysine and / or polyethyleneimine. The polyethylene glycol or star-shaped multi-arm polyethylene glycol has aldehyde-terminated ends, and the aldehyde group is connected to the polyethylene glycol or star-shaped multi-arm polyethylene glycol by an ester bond, amide bond, ether bond, urethane bond, imine bond, or urea bond. The hydrophobic drug is indomethacin.