Combination of coating and injectable hydrogel depot to improve the sustained delivery of insulin
Graphical abstract
Introduction
Diabetes mellitus is a common chronic metabolic disease caused by pancreatic β-cell dysfunction and insulin resistance. With the rapid aging of population, the incidence of diabetes and its complications increased year by year [1]. According to the data from International Diabetes Federation in 2015, about 415 million people around the world and 120 million people in China suffered from diabetes [2]. According to the pathogenesis, diabetes is mainly divided into typeⅠand typeⅡdiabetes (about 90%) [3]. Insulin is the first choice for clinical treatment of insulin-dependent diabetes mellitus (typeⅠ). Patients with typeⅠdiabetes need multiple insulin injections every day to reduce glucose concentrations [4,5]. Due to its large molecular weight, poor membrane permeability, instability in enzyme circumstance [[6], [7], [8]], subcutaneous (s.c.) injection is still the dominant route [9]. This gives the patient great pain and inconvenience [[10], [11], [12]].
Due to above problems of insulin, the development of insulin formulations to a large extent has been limited. Frequently s. c. injections can cause many discomforts, such as pain, nerve damage, local tissue necrosis and microbial contamination [[13], [14], [15]]. Because of these obstacles, diabetics are reluctant to receive frequently injections [16]. This situation has led to the development of long-acting insulin formulations that provide patients with long-term basal insulin release, thereby reducing the frequency of injections.
In order to decrease the frequency of injection, intermediate and long-acting insulin insulin analogs including Neutral Protamine Hagedorn (NPH) [17], Lente [18]and Ultrelente [19] as well as Glargine [20] and Determir [21] have been developed in the field regarding extended release insulin delivery. Although progress has been made with these products, it is still troublesome and painful for patients with diabetes to receive at least once daily injection to maintain basal insulin levels.
Hydrogel are three-dimensional, cross-linked networks of hydrophilic polymers that can swell in water and maintainthestructure. Thenetworksare formed by polymer chainscrosslinking with covalent bonds, hydrogen bonding, Van der Waals interactions [22]. Hydrogels has highly porous structure which can be modified by tuning the density of crosslinks and affinity. Their porosity also can load some of drugs into the hydrogel matrix and drug can release through the hydrogel network.
In all of hydrogels,thermo-sensitive hydrogel is a potential carrier for drug delivery [23]. It has a wide application in biomedical and pharmacy [24]. It can control drug release by changing the hydrogel structure from a solution state to a semi-solid state in response to temperature and drug stability can also be improved by wrapping drugs into the hydrogels.
Polaxamers are widely used or studied as a hydrogel matrix due to its low toxicity and safety characteristics. Poloxamersare non-toxic poly (ethylene oxide)/poly (propylene oxide)/poly (ethylene oxide) (PEO–PPO–PEO) triblock copolymers. The aqueous solution of poloxamers can produce a sol–gel transition with temperature increased. This reversible transition has made poloxamer applied in some pharmaceutical fields [[25], [26], [27]]. Because of its low toxicity, good biocompatibility and safety characteristics, poloxamers have been used as controlled release carriers for macromolecular drugs, such as interleukin-2 [28], urease [29], recombinant hirudin [25], insulin [30,31], rcombinant human growth hormone [32] and interleukin-1 receptor antagonist [33].
In this study, we developed in situ insulin loaded thermosensitivehydrogels to extend insulin hypoglycemic action time, hence improving therapeutic outcome with less side effects or toxicity. The in vitro characterization of their gelation temperature, rheological behaviors was examined. The in vivo hypoglycemic efficacy was investigated using STZ-induced diabetic rats and in comparison to insulin injection and Lantus® and the histological irritation was also evaluated.
Section snippets
Materials
Insulin was purchased from Xuzhou Wanbang Jinqiao Pharmaceutical Co., Ltd (Jiangsu, China). Poloxamer 407 (P407) and poloxamer 188 (P188) were purchased from BASF company Co.,Ltd (Shanghai, China). Anhydrous sodium sulfate, ethanolamine and acetonitrile were purchased from Tianjin Kemiou Chemical Reagent Co., Ltd (Tianjin, China). Anhydrous ethanol was purchased from Tianjin Fenghua Chemical Reagent Co., Ltd (Tianjin, China). Phosphate was purchased from Tianjin Beichen Reagent Factory
Gelation temperature and time
Gelation temperature (T) and gelation time (t) were two important parameters in situ hydrogel formation. P407 did not gelate when its concentration below 16% (v/v) and only a thick solution was formed (Table 1). The gelation temperature decreased with the increase of P407 concentration.
The ideal gelation temperature of thermosensitive hydrogel for pharmaceutical use should be about 32–35 °C. A low gelation temperature could result in increased viscosity, and increased injectable difficulty when
Conclusion
In this study, injectable hydrogels based on P407 and P188 with the incorporation of SA and HPMC were prepared as a sustained insulin delivery system. The properties of hydrogels were characterized. In order to prolong the sustained release time, coated insulin microcrystal was loaded into the hydrogels. In vivo pharmacodynamic studies showed the combination of Polo/HPMC hydrogel with coated insulin microcrystal had optimum sustained release effect. The tissue irritation experiments showed
Declaration of interest
The authors report no declarations of interest.
Acknowledgments
The protocol of the study was approved by “Ethics Committee of Hebei Medical University” (approval number 1509076). The European Community guidelines as accepted principles for the use of experimental animals were adhered to.This work was supported by the fund of the Top Young Talents Program of Hebei Province, the Scientific Research Project of Hebei Provincial High School (No. ZD2016136).
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