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Tacrolimus sustained-release thermosensitive gel and preparation method thereof

A tacrolimus and temperature-sensitive gel technology, which is applied in the field of tacrolimus sustained-release temperature-sensitive gel and its preparation, can solve the problems of easy depolymerization, fast drug release rate, poor stability of temperature-sensitive gel, etc., and achieve excellent curative effect and curative effect Significant, convenient dosing effect

Active Publication Date: 2019-02-01
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Although adding poloxamer 188 can increase the phase transition temperature of poloxamer 407, or adding a thickener can improve the mechanical strength of the gel; but the in vivo stability of poloxamer 407 thermosensitive gel is poor and easy to depolymerize, resulting in Drug release rate in vivo is too fast (McKenzie M, Betts D, Suh A, Bui K, Kim LD, Cho H. Hydrogel-based drug delivery systems for poorly water-soluble drugs. Molecules. 2015, 20(11):20397-408)
So far there is no research report on Soluplus as a thermosensitive gel

Method used

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  • Tacrolimus sustained-release thermosensitive gel and preparation method thereof
  • Tacrolimus sustained-release thermosensitive gel and preparation method thereof
  • Tacrolimus sustained-release thermosensitive gel and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0043] Example 1 Preparation of Tacrolimus-Soluplus and Tacrolimus-Poloxamer 407 Thermosensitive Gels

[0044] Isotonic phosphate buffer solution is prepared as follows: Weigh 8g of NaCl, KH 2 PO 4 0.2g, Na 2 HPO 4 12H 2 Add O2.9g and KCl 0.2g into the container, then add 1000mL of degassed water for injection to dissolve, and adjust the pH to 7.4 with NaOH.

[0045] Add Soluplus to isotonic phosphate buffer solution, swell at 4°C to obtain a uniform dispersion system, and then pass through 0.45 μm and 0.22 μm microporous membranes to sterilize the obtained dispersion system at 0-30°C to obtain a temperature-sensitive gel matrix system; dissolving tacrolimus in ethanol to prepare a tacrolimus solution; then adding the tacrolimus solution to the Soluplus or Poloxamer 407 thermosensitive gel matrix system under stirring at room temperature to obtain tacrolimus Division-Soluplus thermosensitive gel (stored at 0-30°C for later use, in a uniformly dispersed dispersion system)...

Embodiment 2

[0051] Example 2 Determination of In Vitro Release of Tacrolimus-Soluplus and Tacrolimus-Poloxamer 407 Thermosensitive Gel

[0052] Take the temperature-sensitive gel preparation prepared in Example 1, and adopt the filmless release rate measurement method. Accurately weigh 0.2 mL of tacrolimus thermosensitive gel respectively, place them in test tubes, and let them stand at 37°C for 5 minutes until they are completely gelled; add 4 mL of pH 7.4 PBS solution (containing 0.5% Tween80, w / v) at the same temperature , shake in a water bath at constant temperature (37°C, 100rpm), sample 1mL at different time points, and add 1mL of fresh medium at the same temperature. The sample was centrifuged at 10,000 rpm for 5 min, and the supernatant was taken, and the concentration of tacrolimus was determined by HPLC. Comparison of Tacrolimus-Soluplus and Tacrolimus-Poloxamer 407 Thermosensitive Gel in Vitro Release figure 1 .

[0053] Conclusion: When 20% poloxamer 407 was used as the th...

Embodiment 3

[0054] Example 3 Comparison of In Vivo Formability, Retention and Release of Tacrolimus-Soluplus and Tacrolimus-Poloxamer 407 Thermosensitive Gels

[0055] In Example 1, respectively, tacrolimus-Soluplus (10%, 20%) or tacrolimus-F127 (20%) thermosensitive gel was injected into 0.2 mL of mice (ICR, male, body weight 30 ± 5g, subcutaneous in the back of Zhejiang Academy of Medical Sciences), 3 mice in each group, the mice were sacrificed regularly, the subcutaneous section was cut open and the gelation of the preparation in vivo was observed, and the drug content in the residual gel was determined by HPLC. Comparison of in vivo formability of tacrolimus-Soluplus and tacrolimus-poloxamer 407 thermosensitive gel figure 2 .

[0056] Conclusion: 6 hours after subcutaneous injection of 20% poloxamer 407 drug-loaded gel, there is only a very small amount of gel residue in the injection site, and the residual drug concentration measured by HPLC method is only 23.4±0.9% of the injecte...

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Abstract

The invention provides tacrolimus sustained-release temperature-sensitive gel and a preparation method of the tacrolimus sustained-release temperature-sensitive gel. The tacrolimus sustained-release temperature-sensitive gel is prepared from the following materials in percentage by weight: 0.05%-20% of tacrolimus, 0.5%-27% of an organic solvent, and the balance of a temperature-sensitive gel substrate based on Soluplus. The phase-transition temperature of the tacrolimus sustained-release temperature-sensitive gel system is more close to the body temperature compared with the gelatinization temperature of poloxamer 407 temperature-sensitive gel, therefore, the administration is convenient, moreover, the strength of the gel formed in the body is greater than the strength of the poloxamer 407 temperature-sensitive gel, after subcutaneous injection, the drug sustained release of the tacrolimus sustained-release temperature-sensitive gel can be maintained for at least seven days, while the sustained release of the poloxamer 407 temperature-sensitive gel only lasts for one day. The tacrolimus sustained-release temperature-sensitive gel is used for local injection drug delivery or ocular drug delivery, can treat rheumatoid arthritis, organ grafting or autoimmunity eye diseases and the like, and the curative effects are significant and superior to those of the tacrolimus poloxamer 407 temperature-sensitive gel.

Description

(1) Technical field [0001] The invention relates to a novel tacrolimus sustained-release temperature-sensitive gel and a preparation method thereof. (2) Background technology [0002] Tacrolimus (Tacrolimus, also known as FK506), is a powerful new immunosuppressant, which mainly inhibits the function of T lymphocytes by inhibiting the release of interleukin-2 (IL-2). (CsA) is 100 times stronger. Clinically, it is mainly used for liver, kidney, heart, lung, intestine, bone marrow and other organ tissue transplantation; and autoimmune diseases such as atopic dermatitis (AD), systemic lupus erythematosus (SLE), autoimmune eye disease, etc. Currently commercially available dosage forms mainly include capsules, injections, ointments, sustained-release capsules and sustained-release tablets, etc. The formulation studies reported in the literature include microspheres (Kojima R, Yoshida T, Tasaki H, Umejima H, Maeda M, Higashi Y, Watanabe S, Oku N. Release mechanisms of tacrolimu...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K9/06A61K31/436A61K47/10A61P19/02A61P29/00A61P37/06A61P27/02A61P37/02
CPCA61K9/0019A61K9/0048A61K9/06A61K31/436A61K47/22
Inventor 熊素彬吴慧敏尹小东
Owner ZHEJIANG UNIV OF TECH
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