Optimized nanoemulsifying systems with enhanced bioavailability of carvedilol

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Abstract

The current studies entail a novel approach of formulating the solid self-nanoemulsifying drug delivery systems (S-SNEDDS) of carvedilol solely using rational blends of lipidic and emulsifying excipients without using equipment-intensive techniques and/or inert porous carriers. Delineating the nanoemulsion regions, the amounts of Capmul MCM (i.e., lipid) and Nikkol HCO 50 (i.e., emulgent) were selected as the critical factors for systematically formulating the optimized S-SNEDDS employing face centered cube design. The optimized formulation (mean globule size: 40.8 nm) indicated marked improvement in drug release profile vis-à-vis pure drug and marketed formulation. Augmentation in the values of Cmax (134.2%) and AUC (85.2%) indicated significant enhancement in the rate and extent of bioavailability by the S-SNEDDS formulation compared to pure drug. In situ SPIP studies ascribed the significant enhancement in absorptivity parameters of SNEDDS formulations to transport through the lymphatic system and reduced P-gp efflux. Successful establishment of various levels of in vitro/in vivo correlations (IVIVC's) substantiated the judicious choice of the in vitro dissolution milieu for simulating the in vivo conditions. The optimized formulation was found to be quite stable during six months of study period. The current investigations, therefore, report the successful development of systematically optimized S-SNEDDS with enhanced bioavailability potential of carvedilol.

Highlights

► Novel approach for formulation of solid self nanoemulsifying drug delivery systems obviates the use of specialized machines and/or porous carriers. ► The optimized S-SNEDDS formulation possessed mean globule size of 40.8 nm. ► Augmentation in values of Cmax (134.2%) and AUC (85.2%) was observed. ► Various levels of IVIVC were established. ► Marked improvement in in situ perfusion profiles was observed.

Introduction

Nano-based drug delivery systems, especially the lipidic ones, have lately gained wide acceptance for enhancing the bioavailability of poorly soluble and permeable drugs [1]. Of late, self-nanoemulsifying drug delivery systems (SNEDDS) have emerged as an effective delivery systems owing to their inherent meritorious visages. Several potential advantages of SNEDDS include, capability of bypassing hepatic portal route and promoting the lymphatic transport of lipophilic drugs, reducing metabolism by cytochrome-P450 family of enzymes present in the gut enterocytes and liver hepatocytes and/or inhibiting P-glycoprotein (P-gp) efflux [1], [2]. This has been rationally related to the nano-sized globules coupled with specific formulation components like lipids and emulgents [3]. Solid SNEDDS (S-SNEDDS) are highly sought-after owing to their myriad benefits like better portability, improved stability and higher drug loading, coupled with ease and economy of their production [4], [5], [6].

The S-SNEDDS are usually prepared by using equipment-intensive techniques like spray drying and extrusion-spheronization and/or adsorbing the liquid SNEDDS (L-SNEDDS) on to the porous inert carriers like magnesium aluminometasilicate and colloidal silicondioxide [4]. As these specialized techniques are mired with various potential issues of robustness, process optimization, scalability and high production costs, adoption of apt formulation approach(es) obviating the use of such machination and additional excipients is thus called for.

Systematic optimization of self-nanoemulsifying formulations for various product variables viz. lipids, emulgents and co-emulgents using formulation by design (FbD) tends to reveal (any) synergism amongst the variables [5], [7]. Plus, it yields the most promising SNEDDS formulations with advantages of economics in terms of time, money and developmental effort. As the formulation of any self-nanoemulsifying system depends upon the composition of rational blends of such lipidic and emulsifying agents to yield the optimal solid SNEDDS, the use of “FbD” studies is considered almost imperative for the purpose [7], [8], [9].

Carvedilol is a poorly water-soluble drug with a log P of 4.115. It is clinically indicated not only in the management of hypertension, but for myocardial infarction and congestive heart failure too [10], [11]. It undergoes extensive first-pass metabolism in liver, leading to marked reduction in its absolute oral bioavailability in humans (about 20%) as well as in animals [12], [13]. Various formulation approaches like solid lipid nanoparticles (SLNs) and nasal microspheres have been employed to circumnavigate the hepatic route in order to increase its bioavailability [14], [15].

Thus, the aim of the present work was to develop S-SNEDDS of carvedilol using a novel approach solely involving the rational selection and optimization of high-melting lipids and emulsifiers, thus circumnavigating the need of high-end machines and/or inert carriers. Further, the work also investigates the oral bioavailability enhancement potential of S-SNEDDS using pharmacokinetic studies, and embarks upon in vitro and in vivo performance comparison between the optimized S-SNEDDS (OPT S-SNEDDS) and the optimized L-SNEDDS (OPT L-SNEDDS) reported earlier by our research group [16].

Section snippets

Materials and methods

Carvedilol was provided ex-gratis by M/s Ranbaxy Research Labs., Gurgaon, India. Labrafac PG (propylene glycol dicaprylocaprate), Labrafac Lipophilic WL 1349 (medium chain triglycerides), Labrafil M 2125CS (linoleoyl macrogolglycerides) and Transcutol HP (lauroyl macrogolglycerides) were received as gift samples from M/s Gattefosse, Saint-Priest, France. Cremophor EL (polyoxyethylene castor oil) was supplied ex-gratis by M/s Signet Chemical Co. Pvt. Ltd., Mumbai, India. Capmul MCM (glyceryl

Solubility studies

Among various lipids studied (Fig. 1A of Supplementary Data) the maximum solubility of carvedilol was observed in Capmul MCM (64.26 mg mL−1). However, the minimum solubility was found in Labrafac lipophilic WL1349 (0.73 mg mL−1). Similarly, amongst various emulgents and/or co-emulgents, (Fig. 1B of Supplementary Data) the maximum solubility of carvedilol was observed in Nikkol HCO 50 (72.24 mg mL−1), and the minimum solubility was found in Nikkol HCO 40 (24.46 mg mL−1).

Pseudo-ternary phase studies

Fig. 1(A and B) depicts the phase

Discussion

The current research work entails the development of optimized S-SNEDDS formulation of carvedilol and its subsequent pharmacokinetic evaluation for ratifying its biopharmaceutical superiority.

Equilibrium solubility studies were carried out in an attempt to find out the maximum soluble fraction of carvedilol in different lipids and emulgents/co-emulgents. Minimum solubility of carvedilol was observed in triglycerides, while maximum solubility in monoglycerides, attributable to the reduction in

Conclusions

Despite the bioavailability enhancement potential of liquid self-nanoemulsifying systems, it is highly desirable to have these as solid dosage form(s) owing to their stellar merits. These include better transportability, simpler and cheaper production, higher drug loading, improved stability and reproducibility, and above all, the improved therapeutic success owing to better patient compliance. Invariably, such solid formulations are prepared using specialized equipment like

Financial assistance

Financial grant obtained from the All Indian Council of Technical Education (AICTE, New Delhi, India) is gratefully acknowledged.

Conflict of interest

The authors have no conflict of interest.

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