Preclinical Pharmacokinetic Evaluation of Efavirenz Solid Dispersions in Two New Modified Starches.

Efavirenz, a widely prescribed anti retroviral drug belong to Class II under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility and it requires enhancement in solubility and dissolution rate for increasing its oral bioavailability. In our earlier studies solid dispersion of efavirenz in two new modified starches namely (i) starch citrate and (ii) starch phosphate has markedly enhanced the dissolution rate and dissolution efficiency of efavirenz. The objective of the present study is to evaluate the in vivo performance and pharmacokinetics of the efavirenz solid dispersions in the two new modified starches. Pharmacokinetic evaluation of efavirenz- starch citrate (1:2) and efavirenz- starch phosphate (1:2) solid dispersions was done in healthy rabbits weighing 1.5 – 2.5 kg (n=6) of either sex in a cross over RBD at a dose equivalent to 10 mg/kg of drug in comparison to efavirenz pure drug. All the pharmacokinetic parameters namely Cmax, Tmax, Ka and (AUC) 0 ∞ indicated rapid and higher absorption and bioavailability of efavirenz when administered as solid dispersion in the two new modified starches. A 9.90 and 9.14 fold increase in the absorption rate (Ka) was observed respectively with efavirenz- starch citrate (1:2) solid dispersion and efavirenz- starch phosphate (1:2) solid dispersion when compared to efavirenz pure drug. A 1.46 and 1.47 fold increase in (AUC) ∞ 0 was also observed respectively with these solid dispersions when compared to efavirenz pure drug. The solid dispersions of efavirenz in the two new modified starches (starch citrate and starch phosphate) exhibited markedly higher rates of absorption and bioavailability of efavirenz when compared to efavirenz alone in the in vivo evaluation.

Formulation Development of Efavirenz TabletsEmploying β Cyclodextrin- PVP K30- SLS: AFactorial Study.

Efavirenz, a widely prescribed anti retroviral drug belongs to class IΙ under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability. The objective of the study is to evaluate the feasibility of formulating efavirenz –βCD– PVP K30/SLS inclusion complexes into tablets and to evaluate the effects of βCD, PVP K30and SLS on the dissolution rate and dissolution efficiency of efavirenz tablets in a 23 factorial study. A comparative evaluation of wet granulation and direct compression methods was made for the preparation of tablets employing drug – βCD – PVP K30/ SLS inclusion complexes. Drug – βCD- PVP K30/ SLS inclusion complexes were prepared by kneading method. Tablets each containing 50 mg of efavirenz were prepared by wet granulation and direct compression methods employing various βCD complexes as per 23 factorial design and the tablets were evaluated for dissolution rate and other physical properties. Efavirenz tablets formulated employing dug – βCD – PVP K30/ SLS inclusion complexes and prepared by direct compression method disintegrated rapidly when compared to those made by wet granulation method. Efavirenz dissolution was rapid and higher from the tablets formulated employing drug- βCD- PVP K30 /or SLS inclusion complexes when compared to the tablets containing efavirenz alone in both wet granulation and direct compression methods. The individual as well as combined effects of the three factors involved i.e., βCD ( factor A), PVP K30( factor B) and SLS( factor C) were highly significant (P< 0.01) in enhancing the dissolution rate (K1) and dissolution efficiency (DE 30) of efavirenz in both wet granulation and direct compression methods. Among the three factors βCD (factor A) gave highest enhancement in the dissolution rate (K1) and dissolution efficiency (DE 30) of efavirenz tablets in both wet granulation and direct compression methods. SLS (factor C) alone gave low dissolution rate in both wet granulation and direct compression methods .Overall direct compression method gave higher dissolution rates (K1) and dissolution efficiency (DE 30) values than the wet granulation method in all the cases. Combination of βCD with either PVP K30 or SLS or both gave a significantly higher dissolution rate (K1) of efavirenz in both wet granulation and direct compression methods. Hence a combination of βCD with either PVP K30 or SLS or both is recommended to enhance the dissolution rate and efficiency of efavirenz tablets.

A factorial study on the effects of HPβ cyclodextrin, PVP K30 and SLS on the solubility and dissolution rate of efavirenz.

The objective of the study is to evaluate the individual main effects and combined (or interaction) effects of Hydroxy propyl β cyclodextrin (HPβCD), poly vinyl pyrrolidone (PVP K30) and sodium lauryl sulphate (SLS) on the solubility and dissolution rate of efavirenz in a series of 23 factorial experiments. The solubility of efavirenz in eight selected fluids containing HPβCD, PVP K30 and SLS as per 23 factorial study was determined. The solubility of efavirenz was markedly enhanced by HPβCD (2.95 fold), PVP K30 (2.49 fold) and SLS (226.96 fold) individually. Combination of HPβCD with PVP K30 and SLS gave a markedly higher enhancement in the solubility of efavirenz than is possible with them individually. HPβCD in combination with PVP K30 and SLS gave respectively 4.05 and 387.63 fold increase in the solubility of efavirenz. Solid inclusion complexes of efavirenz - HPβCD were prepared with and without PVP K30 and SLS as per 23- factorial design by kneading method and were evaluated. ANOVA indicated that the individual main effects of HPβCD, PVP K30 and SLS and their combined effects in enhancing the solubility and dissolution rate (K1 )and dissolution efficiency (DE30 ) were highly significant (P < 0.01).HPβCD alone gave a 16.74 fold increase in the dissolution rate of efavirenz. HPβCD in combination with PVP K30 and SLS gave respectively 19.98 and 25.13 fold increase in the dissolution rate of efavirenz. HPβCD in combination with both PVP K30 and SLS gave highest enhancement (41.61 fold) in the dissolution rate of efavirenz. Combination of HPβCD with PVP K30 and SLS has markedly enhanced the solubility as well as dissolution rate of efavirenz than is possible with them individually. Hence a combination of HPβCD with PVP K30 and / or SLS is recommended to enhance the solubility and dissolution rate of efavirenz, a BCS class II drug.

Formulation and evaluation of etoricoxib tablets employing cyclodextrin- poloxamer 407 - PVPK30 inclusion complexes.

Etoricoxib, a widely prescribed anti-inflammatory drug belongs to class IΙ under BCS and exhibit low and variable oral bioavailability due to its poor aqueous solubility. Its oral absorption is dissolution rate limited and it requires enhancement in the solubility and dissolution rate for increasing its oral bioavailability. The objective of the study is to evaluate the feasibility of formulating etoricoxib – CD (βCD/ HPβCD) – Poloxamer 407 and etoricoxib – CD (βCD/ HPβCD) –PVP K30 inclusion complexes into tablets and to evaluate the effects of CDs, Poloxamer 407 and PVP K30 on the dissolution rate of etoricoxib tablets. A comparative evaluation of wet granulation and direct compression methods was made for the preparation of tablets employing drug – CD –Poloxamer 407 / PVP K30 inclusion complexes. Drug – CD- Poloxamer 407 / PVP K30 inclusion complexes were prepared by kneading method. Tablets each containing 60 mg of etoricoxib were prepared by wet granulation and direct compression methods employing various CD complexes and the tablets were evaluated for dissolution rate and other physical properties. toricoxib tablets made by direct compression method disintegrated rapidly when compared to those made by wet granulation method. Tablets formulated employing βCD complexes disintegrated relatively more rapidly than those formulated employing HPβCD complexes. Etoricoxib dissolution was rapid and higher from the tablets formulated employing drug- CD- Poloxamer 407/ PVP K30 inclusion complexes when compared to the tablets containing etoricoxib alone and drug – CD complexes in both wet granulation and direct compression methods. In both the methods tablets formulated employing βCD complexes gave higher dissolution rates (K1) and DE30 values when compared to those formulated employing HPβCD complexes. Tablets formulated employing dug – βCD – Poloxamer 407 and drug – βCD – PVP K30 complexes and prepared by direct compression method gave higher dissolution rates, 0.0539 and 0.0459 min-1 respectively when compared to plain tablets (0.0124 min-1 ) as well as tablets containing drug – βCD complexes (0.0417 min-1). Hence a combination of βCD with Poloxamer 407 or PVP K30 is recommended to enhance the dissolution rate of etoricoxib tablets.

Enhancement of dissolution rate and formulation development of efavirenz tablets employing starch citrate-a new modified starch.

The objective of the study is to prepare, characterize and evaluate starch citrate, a new modified starch as a carrier in solid dispersions for enhancing the dissolution rate of efavirenz. The feasibility of formulating solid dispersions of efavirenz in starch citrate into compressed tablets with enhanced dissolution rate was also investigated. Starch citrate was prepared by reacting starch with citric acid at elevated temperatures. It was insoluble in water and has good swelling (1500%) property without pasting or gelling when heated in water. Solid dispersions of efavirenz in starch citrate were prepared by solvent evaporation method employing various weight ratios of drug: starch citrate such as 2:1(SD-1), 1:1(SD-2), 1:2(SD-3), 1:3(SD-4) and 1:9(SD-5) and were evaluated for dissolution rate and efficiency. All the solid dispersions prepared gave rapid and higher dissolution of efavirenz when compared to pure drug. A 12.94 and 40.41 fold increase in the dissolution rate (K1) of efavirenz was observed with solid dispersions SD-4 and SD-5 respectively. The DE30 was also increased from 10.66% in the case of efavirenz pure drug to 60.93% and 74.23% in the case of these solid dispersions. Efavirenz (50 mg) tablets were prepared employing efavirenz alone and its solid dispersions SD-3 and SD- 4 by wet granulation method and were evaluated. Efavirenz tablets formulated employing its solid dispersions in starch citrate gave rapid and higher dissolution rate and DE30 when compared to plain and commercial tablets. A 7.01 and 15.30 fold increase in the dissolution rate (K1) was observed with tablet formulations containing solid dispersions SD-3 and SD-4 respectively when compared to plain tablets.