Efficient aqueous remote loading of peptides in poly(lactic-co-glycolic acid).

Poly(lactic-co-glycolic acid) (PLGA) long-acting release depots are effective for extending the duration of action of peptide drugs. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common uncapped PLGA to bind and absorb into the polymer phase net positively charged peptides from aqueous solution after short exposure at modest temperature. Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional methods. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products. Remote absorption encapsulation further removes the need for a critical organic solvent removal step after encapsulation, allowing for simple and cost-effective sterilization of the drug-free microspheres before encapsulation of the peptide.

Adequate formulation approach for oral chemotherapy: Etoposide solubility, permeability, and overall bioavailability from cosolvent- vs. vitamin E TPGS-based delivery systems.

Injectable-to-oral conversions for anticancer drugs represent an important trend. The goal of this research was to investigate the suitability of formulation approaches for anticancer oral drug delivery, aiming to reveal mechanistic insights that may guide oral chemotherapy development. TPGS vs. PEG-400 were studied as oral formulations for the anticancer drug etoposide, accounting for drug solubility, biorelevant dissolution, permeability, solubility-permeability interplay, and overall bioavailability. Increased etoposide solubility was demonstrated with both excipients. Biorelevant dissolution revealed that TPGS or PEG-400, but not aqueous suspension, allowed complete dissolution of the entire drug dose. Both TPGS and PEG-400 resulted in decreased in-vitro etoposide permeability across artificial membrane, i.e. solubility-permeability tradeoff. While PEG-400 resulted in the same solubility-permeability tradeoff also in-vivo, TPGS showed the opposite trend: the in-vivo permeability of etoposide was markedly increased in the presence of TPGS. This increased permeability was similar to the drug permeability under P-gp inhibition. Rat PK study demonstrated significantly higher etoposide bioavailability from TPGS vs. PEG-400 or suspension (AUC of 72, 41, and 26 µg·min/mL, respectively). All in all, TPGS-based delivery system allows overcoming the solubility-permeability tradeoff, increasing systemic etoposide exposure. Since poor solubility and strong efflux are common to many anticancer agents, this work can aid in the development of better oral delivery approach for chemotherapeutic drugs.

Concomitant solubility-permeability increase: Vitamin E TPGS vs. amorphous solid dispersion as oral delivery systems for etoposide.

Vitamin E TPGS (TPGS) has both surfactant and P-glycoprotein (P-gp) inhibitory effects. While surfactants were previously found to cause solubility-permeability tradeoff, TPGS P-gp inhibitory effects may change this unfavorable interplay. The purpose of this research was to investigate the solubility-permeability interplay when using TPGS vs. amorphous solid dispersions (ASD) as oral drug delivery systems for the anticancer, P-gp substrate, lipophilic drug etoposide. The concentration-dependent effects of TPGS (0-100mg/mL) vs. ASD on the solubility of etoposide, as well as the in-vitro (PAMPA) vs. in-vivo (intestinal rat perfusion) permeability of the drug were studied, and the resulting solubility-permeability interplay was analyzed. TPGS above CMC (0.3mg/mL) increased etoposide solubility linearly, and ASD allowed significant supersaturation. Etoposide in-vitro PAMPA permeability decreased markedly with increasing TPGS levels, similarly to the solubility-permeability tradeoff previously defined for surfactants. In contrast, the presence of TPGS significantly increased etoposide in-vivo rat permeability, attributable to P-gp inhibition, similarly to the effect of the potent P-gp inhibitor GF120918 (10µg/mL). High supersaturation achieved via ASD increased the drug's in-vivo permeability to the level obtained by TPGS or GF120918, supporting P-gp saturation. In conclusion, unique pattern of solubility-permeability interplay was found, involving concomitant increase of both the solubility and the permeability, as opposed to the previously reported tradeoff for solubilization methods and the unchanged permeability for supersaturation; P-gp inhibition/saturation by TPGS or by supersaturation allows simultaneous increase of both solubility and permeability, representing a significant advantage of such drug delivery approaches when suitable.

Head-To-Head Comparison of Different Solubility-Enabling Formulations of Etoposide and Their Consequent Solubility-Permeability Interplay.

The purpose of this study was to conduct a head-to-head comparison of different solubility-enabling formulations, and their consequent solubility-permeability interplay. The low-solubility anticancer drug etoposide was formulated in several strengths of four solubility-enabling formulations: hydroxypropyl-ß-cyclodextrin, the cosolvent polyethylene glycol 400 (PEG-400), the surfactant sodium lauryl sulfate, and an amorphous solid dispersion formulation. The ability of these formulations to increase the solubility of etoposide was investigated, followed by permeability studies using the parallel artificial membrane permeability assay (PAMPA) and examination of the consequent solubility-permeability interplay. All formulations significantly increased etoposide's apparent solubility. The cyclodextrin-, surfactant-, and cosolvent-based formulations resulted in a concomitant decreased permeability that could be modeled directly from the proportional increase in the apparent solubility. On the contrary, etoposide permeability remained constant when using the ASD formulation, irrespective of the increased apparent solubility provided by the formulation. In conclusion, supersaturation resulting from the amorphous form overcomes the solubility-permeability tradeoff associated with other formulation techniques. Accounting for the solubility-permeability interplay may allow to develop better solubility-enabling formulations, thereby maximizing the overall absorption of lipophilic orally administered drugs.

The twofold advantage of the amorphous form as an oral drug delivery practice for lipophilic compounds: increased apparent solubility and drug flux through the intestinal membrane.

The purposes of this study were to assess the efficiency of different nifedipine amorphous solid dispersions (ASDs) in achieving and maintaining supersaturation and to investigate the solubility-permeability interplay when increasing the apparent solubility via ASD formulations. Spray-dried ASDs of nifedipine in three different hydrophilic polymers, hydroxypropyl methylcellulose acetate succinate (HPMC-AS), copovidone, and polyvinylpyrrolidone (PVP), were prepared and characterized by powder X-ray diffraction and differential scanning calorimetry. The ability of these formulations to achieve and maintain supersaturation over 24 h was assessed. Then, nifedipine's apparent intestinal permeability was investigated as a function of increasing supersaturation in the parallel artificial membrane permeability assay model and in the single-pass rat intestinal perfusion model. The efficiency of the different ASDs to achieve and maintain supersaturation of nifedipine was found to be highly polymer dependent; while a dispersion in HPMC-AS enabled supersaturation 20× that of the crystalline aqueous solubility, a dispersion in copovidone enabled 10×, and PVP allowed supersaturation of only 5× that of the crystalline solubility. Nifedipine flux across the intestine from supersaturated solutions was increased, and the apparent intestinal permeability was constant, irrespective of the degree of supersaturation or the polymer being used. In conclusion, while with other solubility-enabling approaches (e.g., surfactants, cyclodextrins, cosolvents), it is not enough to increase the apparent solubility, but to strike the optimal solubility-permeability balance, which limits the chances for successful drug delivery, the amorphous form emerges as a more advantageous strategy, in which higher apparent solubility (i.e., supersaturation) will be readily translated into higher drug flux and overall absorption.

The solubility-permeability interplay when using cosolvents for solubilization: revising the way we use solubility-enabling formulations.

We have recently reported the interplay between apparent aqueous solubility and intestinal membrane permeability, showing the trade-off between the two when using cyclodextrin- and surfactant-based systems as solubility-enabling formulations. In these cases, the decreased permeability could be attributed directly to decreased free fraction of drug due to the complexation/micellization inherent in these solubilization methods. The purpose of this study was to investigate the direct solubility-permeability interplay, using formulations in which complexation is not the mechanism for increased solubilization. The apparent aqueous solubility (S(aq)) and rat intestinal permeability (P(eff)) of the lipophilic drug progesterone were measured in systems containing various levels of the cosolvents propylene glycol and PEG-400, since this solubilization method does not involve decreased free fraction. Thermodynamic activity was maintained equivalent in all permeability studies (75% equilibrium solubility). Both cosolvents increased progesterone S(aq) in nonlinear fashion. Decreased P(eff) with increased S(aq) was observed, despite the constant thermodynamic activity, and the nonrelevance of free fraction. A mass-transport analysis was developed to describe this interplay. The model considers the effects of solubilization on the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall P(eff) dependence on S(aq). The analysis revealed that (1) the effective UWL thickness quickly decreases with ↑S(aq), such that P(aq) markedly increases with ↑S(aq); (2) the apparent membrane/aqueous partitioning decreases with ↑S(aq), thereby reducing the thermodynamic driving force for permeability such that ↓P(m) with ↑S(aq); (3) since ↑P(aq) and ↓P(m) with ↑S(aq), the UWL is shorted out and P(eff) becomes membrane control with ↑S(aq). The model enabled excellent quantitative prediction of P(eff) as a function of S(aq). This work demonstrates that a direct trade-off exists between the apparent solubility and permeability, which must be taken into account when developing solubility-enabling formulations to strike the optimal solubility-permeability balance, in order to maximize the overall oral absorption.

The solubility-permeability interplay: mechanistic modeling and predictive application of the impact of micellar solubilization on intestinal permeation.

Surfactants are routinely employed to increase the apparent aqueous solubility of poorly soluble drugs. Yet the impact of micellar solubilization on the intestinal membrane permeability of a lipophilic drug is often overlooked and poorly understood. In this work, the interplay between the apparent solubility increase and intestinal membrane permeability decrease that exists when surfactants are used as drug solubility enhancers is described. A quasi-equilibrium mechanistic mass transport analysis was developed and employed to describe the effect of micellar solubilization by sodium taurocholate (STC) and sodium lauryl sulfate (SLS) on the intestinal membrane permeability of the lipophilic drug progesterone. The model considers the effects of micellar solubilization on both the membrane permeability (P(m)) and the unstirred water layer (UWL) permeability (P(aq)), to predict the overall effective permeability (P(eff)) dependence on surfactant concentration (C(S)). The analysis reveals that (1) the effective UWL thickness (h(aq)) quickly decreases with increasing C(S) above the critical micelle concentration (CMC), such that P(aq) markedly increases with increasing C(S); (2) the free fraction of drug available for membrane permeation decreases with increasing C(S) above CMC, such that P(m) decreases with increasing C(S); and (3) P(aq) increases and P(m) decreases with increasing C(S) above CMC, consequently the UWL is effectively shorted out and the overall P(eff) tends toward membrane control with increasing C(S). The model enabled excellent quantitative prediction of the progesterone P(eff) as a function of C(S) in the rat jejunal perfusion model. This work demonstrates that a trade-off exists between micellar apparent solubility increase and permeability decrease that must be taken into account to strike the optimal solubility-permeability balance. The model presented in this work offers the formulation scientist a simple method for a priori prediction of this interplay, in order to maximize the overall oral absorption.