Nevirapine nanosuspension: comparative investigation of production methods

Abstract

Increasing number of antiretroviral drugs coming from high throughput screening besides their high dose has poor solubility profile. Formulation development of these drugs is a major obstacle to their clinical application. To overcome extremely low water solubility and associated poor bioavailability they can be formulated as nanosuspensions. This paper is not only focuses on production of parenteral nevirapine nanosuspensions but also on scaling up of formulations for clinical use. Lab scale (APV LAB 40, 40 mL) and medium scale (Avestin C50, 2 kg) production was performed using piston gap high pressure homogenization (HPH), while the feasibility for pilot scale up was checked using a bead milling technique in continuous mode (PM, Bühler PML-2). Nanosuspension was characterized for particle sizes, zeta potential, crystallanity and stability. The mean particle sizes for lab scale, medium scale and pilot scale production obtained were 481 nm, 429 nm and 211 nm, respectively. Independent of the production method (lab and pilot scale) all processed formulations showed more or less similar zeta potential (~15 mV) in conductivity adjusted water. Long term stability over 1 year showed significant increase in particle size at all storage conditions for lab scale and medium scale production (high energy size reduction) whereas they remained physically stable (with negligible increase) for the milled product (low energy size reduction). As the technology has been scaled up successfully for nevirapine nanosuspension, the product can be considered for commercial exploitation. The prepared nevirapine nanosuspensions can be administered for parenteral or oral use.

Drug nanocrystals: A way toward scale-up

“…The choice of equipment should consider the final dosage form requirements of administration. In general, the PS obtained from HPH process could be more suitable for oral application and that obtained from milling could suit parenteral application because of the smaller particle sizes achievable with milling (Lieberman et al, 1998, Shegokar et al, 2011, Moeschwitzer, 2010a).…”

Preparation and Pharmacokinetic Characterization of an Anti-Virulence Compound Nanosuspensions

“…The nanosuspensions can be formulated in diverse dosage forms to achieve higher loading capacities via different formulation methods such as wet milling, high-pressure homogenization, and nanocrystal powder-loaded tablets, which have the potential to further improve their bioavailability and exposure in tissues [ 33 , 34 ]. In addition, the pharmacokinetic properties of CCG-211790 nanosuspensions can be further optimized by surface modification with, for example, layer-by-layer assembled polyelectrolytes [ 74 ] or by coating with enteric polymers for controlled and extended release [ 75 ].…”

“…Nanosuspension is defined as the colloidal dispersion of nanosized drug particles (100–1000 nm) in an aqueous vehicle such as water, aqueous solution or non-aqueous media stabilized with surfactants or polymeric stabilizers [ 28 ]. Nanosuspension technology is a promising approach for addressing poor-solubility problems and has many advantages including: (1) enhanced dissolution rate and oral bioavailability compared with raw drugs or coarse suspensions [ 31 , 32 ]; (2) high drug payload (e.g., 20–30% concentrated nanosuspensions produced via wet milling method, and up to 90% nanocrystal powder-loaded tablets) is available with benefits to high-dosing situations [ 33 , 34 ]; (3) nanoparticles contain almost 100% pure drug with low content of irritant excipients (e.g., surfactant and/or co-solvents) that reduces excipient-induced toxicity and improves drug safety [ 35 ]; (4) diverse dosage forms such as tablets, pellets, nanosuspensions, suppositories and hydrogels are available giving flexibility for various administration routes such as intravenous (IV) [ 36 ], intramuscular [ 37 ], oral [ 38 ], ocular [ 39 ], and nebulization [ 40 ].…”

Comparison of Downstream Processing of Nanocrystalline Solid Dispersion and Nanosuspension of Diclofenac Acid to Develop Solid Oral Dosage Form

“…Drug nanocrystals are produced using “top-down”, “bottom-up” or “combination” technologies [ 5 , 6 , 7 , 8 , 9 , 10 , 11 ]. The product obtained using these approaches is a liquid dispersion of nanocrystals—i.e., a nanosuspension [ 1 , 12 , 13 ]. It possesses inherent physical and chemical instability issues such as sedimentation, crystal growth due to Ostwald ripening, solid-state transformation and hydrolysis.…”