Injectable Biodegradable Silica Depot: Two Months of Sustained Release of the Blood Glucose Lowering Peptide, Pramlintide

Abstract

Diabetes mellitus is a major healthcare challenge. Pramlintide, a peptide analogue of the hormone amylin, is currently used as an adjunct with insulin for patients who fail to achieve glycemic control with only insulin therapy. However, hypoglycemia is the dominant risk factor associated with such approaches and careful dosing of both drugs is needed. To mitigate this risk factor and compliance issues related to multiple dosing of different drugs, sustained delivery of Pramlintide from silica depot administered subcutaneously (SC) was investigated in a rat model. The pramlintide-silica microparticle hydrogel depot was formulated by spray drying of silica sol-gels. In vitro dissolution tests revealed an initial burst of pramlintide followed by controlled release due to the dissolution of the silica matrix. At higher dosing, pramlintide released from subcutaneously administered silica depot in rats showed a steady concentration of 500 pM in serum for 60 days. Released pramlintide retained its pharmacological activity in vivo, as evidenced by loss of weight. The biodegradable silica matrix offers a sustained release of pramlintide for at least two months in the rat model and shows potential for clinical applications.

Keywords: biologics; long acting; silica microparticles; sustained delivery.

Figure 1

SEM images of pramlintide loaded silica microparticles. Magnification ×1000.

Figure 2

Dynamic viscosity of the pramlintide depot gel formulation in shear rates 0.1 1/s–400 1/s. The data confirm the shear thinning properties of the formulation.

Figure 3

Injection Force and pressure on syringes filled with pramlintide-silica sol-gel system. A 25 G needle was attached to the plunger, and the plunger was pushed at 60 mm/minute.

Figure 4

Cumulative estimates of in vitro silica degradation and release of pramlintide from pramlintide-silica depot. Silica dissolution was carried out in 50 mM TRIS–buffer (pH 7.4) and pramlintide release was carried out in PBS (pH 7.4) containing 0.01% Tween 80. Both the studies were carried out at 37 °C under in sink conditions. Data represented as mean for n = 3. SD of each data point was less than 2.5%.

Figure 5

(A) Pramlintide plasma concentration in the rat after subcutaneous injection of pramlintide-silica depot at two doses (containing 5 mg/kg and 15 mg/kg pramlintide). Mean and SD, n = 5 rats. (B) Cumulative concentration vs. time plot depicting the zero-order release of pramlintide from silica depot at higher dosing (15 mg/kg) from 14 to 49 days.

Figure 6

Change in body weight (normalised to % change in body weight in vehicle group) of dietinduced obese rats after a single injection of pramlintide depot containing three different dose strengths. Data is represented as Mean and SEM, n = 8 rats.