Design, development and evaluation of formulations of poorly water soluble drugs intended for oral delivery

Abstract

Ledipasvir and Daclatasvir, belonging to the BCS class 2, and Velpatasvir, belonging to the BCS class 4, are directly acting anti-viral agents used to treat Hepatitis C virus infections. Owing to poor aqueous solubility and oral bioavailability, development of effective delivery system for these drugs has been enormously challenging. Moreover, suitable dosage forms for pediatric and geriatric patients and patients having difficulty in swallowing as well pose added burden. Therefore, the aim of the present study was to develop a nanosuspension, via solid dispersion technique, based liquid oral suspension using Quality by Design (QbD) approach. Primarily, the compatible polymers for Ledipasvir were screened using FTIR and DSC, and finally the polymers - Poloxamer 188, Poloxamer 407, HPC and HMPC were selected, considering their ability to convert the API into amorphous state in solid dispersions. Design of formulation and analysis with the DOptimal design using Design Expert ® software revealed that Poloxamer 188 and Poloxamer 407 in 0.3:0.7 ratio of Ledipasvir:Polymer produced the optimized nanosuspension formulations with a statistically significant mathematical model. Subsequently, the formulations were stabilized using suspension vehicle optimized via Box Behnken Design using the amount of xanthan gum (gm), avicel ® RC-591 (gm) and citric acid monohydrate (gm) as independent variables whereas viscosity (cp) and zeta potential (mv) as responses. The dissolution profiles revealed that the prepared suspensions of Ledipasvir had much faster dissolution than pure API, suspensions prepared with micronized and nonmicronized

API, and the market products available as tablet dosage form. In-vivo simulation studies using PKSolver ® suggested that the absorption of drug from the formulated suspensions was comparable to that of market product up to single dose level (90mg) and superseded in triplicate dose level (270 mg). The formulated suspensions were found to be stable over three- and six-months periods, identified via accelerated stability studies. Interestingly, dissolution profile of the stabilized suspensions was found to be similar after six months. An RP-HPLC method to determine the assay content of Ledipasvir in the finished product has also been developed using 3 2 full factorial design with a Diphenyl column (250 mm X 4.6 mm, 5 µm), the detection wavelength of 330 nm and the injection volume of 20 µL. The optimized method consisted a mobile phase of buffer:acetonitrile at 48:52 ratio and flow rate of 1.7 ml/min. A simple and rapid UV method was developed simultaneously to analyze Ledipasvir and shown to be equivalent to the developed RP-HPLC method. To determine the content of the residual solvent in Ledipasvir solid dispersions, a GC method was developed using the same 3 full factorial design and fused silica GC capillary column (30-m x 0.32-mm x 1.8-µm), Nitrogen with 14.0 psi through head space as carrier gas. Validation of all the developed methods were carried out by following ICH Q2 (R1) guideline. The best results were found with Poloxamer 188 in the Ledipasvir study at a drug:polymer ratio of 0.7:1.3 in terms of in-vivo simulation. Therefore, both Daclatasvir and Velpatasvir were further studied to develop solid dispersion based nanosuspensions and finally a stabilized oral suspension using Poloxamer 188. In case of Daclatasvir, the drug failed to produce amorphous solid dispersion and hence, was not further evaluated for nanosuspension preparation. On contrary, Velpatasvir produced amorphous solid dispersion and thus, nanosuspension was prepared using the same approach applied for Ledipasvir. Afterward, the nanosuspension of Velpatasvir were stabilized using the same method used to stabilize Ledipasvir nanosuspension. The study of the dissolution profiles revealed that stabilized suspension of Velpatasvir had much faster dissolution than its market product available as tablet dosage form. Finally, in-vivo simulation study revealed that single dose of formulated suspension gave the comparable absorption profile to that of the market product.