Glucose-responsive insulin delivery system using hyoxia-sensitive nanocomposites

A technology of sensitivity and insulin, applied in the direction of enzyme, drug combination, capsule delivery, etc., can solve the problem of glucose control accompanied by pain

Active Publication Date: 2018-01-02
NORTH CAROLINA STATE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this self-administration may be accompanied by pain and limited glucose control

Method used

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  • Glucose-responsive insulin delivery system using hyoxia-sensitive nanocomposites
  • Glucose-responsive insulin delivery system using hyoxia-sensitive nanocomposites
  • Glucose-responsive insulin delivery system using hyoxia-sensitive nanocomposites

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Embodiment 1

[0223] Representative synthesis of hypoxia-sensitive hyaluronic acid

[0224] Hypoxia-sensitive hyaluronic acid (HS-HA) was synthesized by chemically conjugating HA to 6-(2-nitroimidazole)hexylamine via amide formation. All chemicals were purchased from Sigma-Aldrich (St. Louis, MO, USA) and were used as received unless otherwise stated. Sodium hyaluronate (molecular weight 300 kilodaltons (kDa)) was purchased from Freda Biochem Co., Ltd. (Shandong China).

[0225] First, 6-(2-nitroimidazolium)hexylamine was synthesized for reaction with carboxylic acid of HA. Briefly, nitroimidazole (NI, 0.15 g, 1.3 mmol) was dissolved in DMF, to which was added K 2 CO 3 (0.28 g, 2.0 mmol). Then, 6-(tert-butoxycarbonylamino)hexyl bromide (ie, 6-(BOC-amino)hexyl bromide, 0.39 g, 1.4 mmol) was added dropwise to the solution and stirred at 80°0 for 4 hours. Solid impurities were removed from the reaction mixture by filtration and washed with methanol. The residual solvent was then evaporate...

Embodiment 2

[0229] Synthesis and Characterization of Glucose Responsive Vesicles (GRV)

[0230] GRVs were prepared by self-assembly in aqueous solution. Briefly, 20 mg of amphiphilic HS-HA was dissolved in water / methanol (2 / 1, v / v), followed by the addition of 10 mg of human insulin and 1.0 mg of GOx. Human recombinant insulin (zinc (Zn) salt, 27.5 international units per milligram (IU / mg)) was purchased from Life Technology (Carlsbad, California, United States of America). Place the emulsion at 4°. Stir for 2 hours. Methanol was then removed by dialysis against deionized water for 1 day. The pH of the resulting GRV solution was adjusted to 5.3 (the isoelectric point (pI) of insulin) to remove unloaded insulin by centrifugation at 8,000 rpm for 10 minutes and passed through a centrifugal filter (100,000 Da molecular weight cutoff, Millipore, Billerica, Massachusetts, United States of America) was further filtered at pH 7.4. The final GRV solution was stored at 4°C for subsequent stud...

Embodiment 3

[0234] In vitro glucose-responsive insulin release from GRV

[0235] To assess the glucose responsiveness of GRV, GRV was incubated with 100 μM NADPH and 5 μg / mL cytochrome c reductase in 600 μL PBS buffer (NaCl, 137 mM; KCl, 2.7 mM; NaCl, 2.7 mM; 2 HPO 4 , 10mM; KH 2 PO 4 , 2mM; pH 7.4). Different amounts of glucose were added to provide solutions with a final glucose concentration of 0 mg / dL, 100 mg / dL or 400 mg / dL. The 400 mg / dL glucose concentration solution represents a typical hyperglycemic glucose level, the 100 mg / dL glucose concentration solution represents a normoglycemic glucose level, and the 0 mg / dL glucose concentration solution is used as a control. The mixture was incubated at 37°7 in a vessel with an oxygen concentration of 21% by adjusting with a mass flow meter. At predetermined times, the pH of each mixture was recorded using a pH meter (AB15, Thermo Fisher Scientific Inc., Waltham, Massachusetts, United States of America), and then adjusted to the pI ...

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Abstract

A closed-loop insulin delivery system is described. More particularly, the presently disclosed insulin delivery system can comprise glucose-responsive vesicles that release insulin in response to hypoxia triggered by enzymatic reduction of glucose. In addition or as an alternative to insulin, the delivery system can release other diabetes treatment agents, such as non-insulin-based diabetes treatment agents. The vesicles can be prepared from a hypoxia sensitive polymer, such as a hypoxia-sensitive hyaluronic acid (HS-HA). The HS-HA can comprise hydrophobic groups that can be reduced in hypoxicenvironments to form hydrophilic groups. The vesicles can be loaded into microneedles and microneedle array patches for use in the treatment of diabetes or to otherwise regulate blood glucose levelsin subjects in need of such treatment.

Description

[0001] related application [0002] This application claims priority and benefit to US Provisional Patent Application No. 62 / 150,622, filed April 21, 2015, the disclosure of which is incorporated herein by reference in its entirety. technical field [0003] The subject matter of the present disclosure relates to systems and compositions, such as vesicles, nanoparticles, microneedles and microneedle arrays, for the glucose sensitive delivery of diabetes therapeutics such as insulin and / or its biologically active derivatives. The disclosed subject matter further relates to methods of making the compositions and methods of delivering diabetes therapeutics to a subject in need thereof. [0004] abbreviation [0005] ℃ = degrees Celsius [0006] % = percentage [0007] μL = microliter [0008] μm = micrometer or micron [0009] μs = microsecond [0010] a.u. = absorbance unit [0011] BOC = tert-butoxycarbonyl [0012] CD = circular dichroism [0013] DI = deionized [00...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K9/50A61K9/51A61K31/00A61K31/04A61K38/28A61K38/43A61K38/44
CPCA61K38/28A61K45/00A61K9/0021A61K47/42A61K47/24A61P3/10A61M37/0015A61K9/5161A61M2037/0046A61K9/0024A61K9/1075A61K9/7023A61K38/44A61K9/5192C12Y101/03004A61K2300/00A61M2037/0023A61M2207/00
Inventor 顾臻俞计成
Owner NORTH CAROLINA STATE UNIV
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