In Situ Stimulated Raman Scattering (SRS) Microscopy Study of the Dissolution of Sustained-Release Implant Formulation.

Localized drug delivery systems (DDSs) provide therapeutic levels of drug agent while mitigating side effects of systemic delivery. These systems offer controlled release over extended periods of time making them attractive therapies. Monitoring drug dissolution is vital for developing safe and effective means of drug delivery. Currently, dissolution characterization methods are limited to bulk analysis and cannot provide dissolution kinetics at high spatial resolution. However, dissolution rates of drug particles can be heterogeneous with influences from many factors. Insights into finer spatiotemporal dynamics of single particle dissolution could potentially improve pharmacokinetic modeling of dissolution for future drug development. In this work, we demonstrate high-resolution chemical mapping of entecavir, a hepatitis B antiviral drug, embedded in a slow release poly(d,l-lactic acid) formulation with stimulated Raman scattering (SRS) microscopy. By tracking the volume change of individual micron-sized drug particles within the polymer matrix, we establish an analytical protocol for quantitatively profiling dissolution of single crystalline particles in implant formulations in an in situ manner.

Estimation of drug solubility in polymers via differential scanning calorimetry and utilization of the fox equation.

The solubility of drugs in polyethylene glycol 400 (PEG 400) was estimated and rank ordered using a differential scanning calorimetry (DSC) method and the Fox Equation. Drug-polymer binary mixtures of six compounds (Ibuprofen, Indomethacin, Naproxen, and three proprietary compounds: PC-1 through PC-3) with PEG 400 were heat treated using a three-cycle DSC method to establish a correlation between equilibrium solubility and temperature. Thermal events such as heat of fusion, heat of recrystallization and glass transition temperature, T(g), were used to calculate the drug solubility at multiple higher temperatures through the Fox Equation. Subsequently, a van't Hoff plot was constructed to estimate the drug solubility at room temperature, and the values were compared with those measured by HPLC. With the exception of Naproxen, room temperature solubilities of the remaining drug compounds in PEG 400 were determined by this thermal method approach, and compared with those measured by HPLC: 26.7% vs. 24.7% for Ibuprofen, 5.8% vs. 9.6% for Indomethacin, 3.1 % vs. 1.5% for PC-1, 2.3% vs. 1.3% for PC-2, and 1.4% vs. 0.2% for PC-3 in PEG 400. There was good concordance in solubility rank order estimates between the two methods. These collective results support the potential utility of the thermal method as an alternative to other methods for estimation of drug solubility in polymers which is an important determinant in the design of physically-stable amorphous systems.

Carbopol-mediated paracellular transport enhancement in Calu-3 cell layers.

The interaction of Carbopol polymers with mucus producing Calu-3 human bronchial epithelial cells was evaluated to test for potential paracellular transport enhancement. Using desmopressin (1-deamino-8-arginine-vasopressin, DDAVP) as the model peptide, apical treatment with Carbopol polymer gel formulations resulted in molecular size-dependent permeability enhancement with a concomitant drop in the transepithelial electrical resistance (TEER). Permeability enhancement of DDAVP was dependent on the formulation vehicle composition and polymer concentration, was noncytotoxic, and completely reversible. Carbopol 971P displayed the greatest permeability enhancement across Calu-3 cells compared to other more viscous Carbopol polymers 934P and 974P, and other mucoadhesive cellulosic polymers. The greatest enhancement was observed when C971P formulation was prepared in water at a concentration of 0.25% w/v. Enhancement was confirmed in rabbit dosed with intranasal fluorescent dextran 4400. The C(max) and absorption rate each increased by 48% in C971P formulations compared to control, while the relative exposure increased 30%. In conclusion, Carbopol polymers are potentially useful excipients to enhance intranasal peptide absorption. We hypothesize that the permeation enhancement is related to the chelation of extracellular or tight-junctional Ca(2+) by charged polymer carboxylate groups that leads to temporary disruption of tight-junctions, thereby facilitating paracellular transport.

Sustained release subcutaneous delivery of BMS-686117, a GLP-1 receptor peptide agonist, via a zinc adduct.

BMS-686117 is an 11-mer GLP-1 receptor agonist with a short intrinsic pharmacokinetic half-life (t(1/2)) of approximately 2h. In order to develop an extended release formulation for once-daily (QD) subcutaneous administration, a non-covalently bonded Zn/BMS-686117 adduct with very low aqueous solubility was prepared through mixing zinc acetate and BMS-686117 solutions, followed by filtration or spray drying. At pH 6.8, free BMS-686117 concentration decreased continuously with the increase of Zn:BMS-686117 ratio. Furthermore, free BMS-686117 concentration increases in the presence of ethylenediaminetetraacetic acid (EDTA), indicating the reversibility of the zinc-peptide association. As solids, the glass transition temperature of Zn/BMS-686117 adduct increases with the increase of Zn:BMS-686117 ratio. A Zn/BMS-686117 adduct suspension, with a molar ratio of zinc:BMS-686117 of 3:1, was dosed subcutaneously to dogs along with two other solution formulations. The Zn/BMS-686117 adduct showed a prolonged BMS-686117 terminal t(1/2) of 8.5h, a mean residence time (MRT) of 16h, and a C(max) value 6-8 times lower than the solution formulations. Additionally, the Zn/BMS-686117 was encapsulated into poly(lactide-co-glycolide) (PLGA) microspheres. The Zn/BMS-686117 microspheres showed an almost zero-order release profile in vitro for at least 18 days, with minimal initial burst, indicating the potential of using this approach for long-term sustained release.

Mechanistic investigation of Pluronic based nano-crystalline drug-polymer solid dispersions.

PURPOSE: To understand the mechanism of nano-crystalline drug formation in Pluronic (i.e., poly(ethylene oxide-block-propylene oxide) triblock copolymers) based drug-polymer solid dispersions. MATERIALS AND METHODS: Four polymers, Pluronic F127, F108, F68 and PEG 8000, which have different poly(ethylene oxide) (PEO) and poly(propylene oxide) (PPO) ratio and chain length, were co-spray dried with BMS-347070, a COX-2 inhibitor, to form 50/50 (w/w) drug-polymer solid dispersions. The solid dispersions were analyzed by powder X-ray diffraction (PXRD), modulated differential scanning calorimetry (mDSC), and hot-stage microscopy. Average size of drug crystallites in different polymers was calculated by the Scherrer equation based on peak-broadening effect in PXRD. Two other drug compounds, BMS-A and BMS-B, were also spray dried with Pluronic F127, and the solid dispersions were analyzed by PXRD and mDSC. RESULTS: The average size of BMS-347070 crystallites in PEG 8000, F127, F108 and F68 polymers was 69, 80, 98 and 136 nm, respectively, and the degree of BMS-347070 crystallinity is the lowest in PEG 8000. Hot-stage microscopy showed that 50/50 drug-polymer dispersions crystallized in a two-step process: a portion of the polymer crystallizes first (Step 1), followed by crystallization of drug and remaining polymer (Step 2). The T (g) value of the BMS-347070/Pluronic dispersions after Step 1 (i.e., T(g1)) was measured and/or calculated to be 15-26 degrees C, and that of BMS-347070/PEG 8000 was 60 degrees C. Solid dispersions of BMS-A and BMS-B in Pluronic F127 have T(g1) of 72 and 3 degrees C, respectively; and PXRD showed BMS-A remained amorphous after approximately 3 weeks under ambient condition, while BMS-B crystallized in F127 with an average crystallite size of 143 nm. CONCLUSIONS: The size of drug crystallites in the drug-polymer solid dispersions is independent of polymer topology, but is caused kinetically by a combined effect of nucleation rate and crystal growth rate. When drug-Pluronic solid dispersions crystallize at room temperature, that is close to the T(g1) of the systems, a fast nucleation rate and a relatively slow crystal growth rate of the drug synergistically produced small crystallite size. While the much higher T(g1) value of drug-PEG 8000 led to a slower nucleation rate and an even slower crystal growth rate at room temperature, therefore, small crystallite size and low drug crystallinity were observed. Results from BMS-A/Pluronic and BMS-B/Pluronic systems confirmed this kinetic theory.