Concomitant delivery of doxorubicin and cisplatin through liposome-based thermosensitive nanoparticles: perspective in the treatment of cancer in animal models.

The temperature sensitive liposomal formulations are a promising tool to improve the therapeutic index of the drugs with minimal toxicity. The aim of this study was to investigate the potential of concomitant delivery of cisplatin (Cis) and doxorubicin (Dox) containing thermosensitive liposomes (TSLs) with mild hyperthermia against cancer in vitro and in vivo. The polyethylene glycol coated DPPC/DSPC, thermosensitive and DSPC, non-thermosensitive liposomes incorporating Cis and Dox were prepared and characterized. A conventional Differential Scanning Calorimetry (DSC) technique and Fourier Transform Infrared Spectroscopy (FT-IR) were applied to study drug-phospholipid interaction and compatibility. The chemotherapeutic efficacy of these formulations was evaluated in benzo[a]pyrene (BaP) induced fibrosarcoma under hyperthermic condition. The size diameter of prepared thermosensitive liposomes was measured to be 120 ± 10 nm. The DSC data exhibited the changes in the curves of DSPC + Dox and DSPC + Cis while comparing the pure DSPC and drugs. However, the FITR showed same spectrum of phospholipids and drugs individually and in the mixture as well. The data showed higher efficacy of Cis-Dox-TSL as 84% inhibition in tumor growth was recorded in this group of animals in hyperthermic condition. The Kaplan-Meir curve revealed, 100% and 80% survival of the animals in the groups treated with Cis-Dox-TSL under hyperthermia and Cis-Dox-NTSL without hyperthermia, respectively. However, Cis-TSL as well as Dox-TSL exhibited 50% survival, while only 20% survival was recorded in the groups of animals treated with Dox-NTSL and Cis-NTSL. The flow cytometry analysis revealed that Cis-Dox-NTSL augments the induction of apoptosis in the tumor cells which was recorded as 18%. As expected, Cis-Dox-TSL showed great potential as 39% of cells were measured as apoptotic cells, significantly very high in comparison to Cis-Dox-NTSL, Dox-TSL and Cis-TSL as well. The apoptotic analysis of the cells by flow cytometry clearly indicated the effect of hyperthermia during the treatment while Cis-Dox-TSL formulation was administered. Finally, the immunohistochemical analysis of the tumor tissues by confocal microscopy exhibited several fold increases in the expression of pAkt in the animals treated with vehicles in Sham-NTSL as well as Sham-TSL. However, Cis-Dox-TSL showed great reduction in the expression of Akt, as it declined by 11-fold. The results of the present study directed the role of concomitant delivery doxorubicin and cisplatin containing thermosensitive liposomes under hyperthermic conditions for the development of a novel therapeutic strategy for the treatment of cancer.

DISSOLUTION AND COMPATIBILITY STUDY OF BINARY AND TERNARY INTERACTIVE MIXTURES OF INDOMETHACIN: COMPARISON WITH COMMERCIALLY AVAILABLE CAPSULES.

The main objective of this work was to use Weibull distribution function and Baker-Lonsdale models to study the dissolution kinetics of prepared binary and ternary interactive mixtures containing indomethacin in comparison with three commercially available capsules of indomethacin, namely, Rothacin®, Indomin® and Indylon®. Differential scanning calorimetry (DSC) in conjunction with cloud point method was used to study the compatibility of indomethacin with polyvinylpyrrolidone (PVP) and lactose and to provide an explanation(s) for the insignificant increase in dissolution rate observed in the ternary interactive mixture as well as for the reduction in the dissolution rate observed from the binary system in our previous study. Results showed that the Weibull distribution function equation was the best fit to the dissolution data for all formulations used in this study. DSC curves showed that the decrease in dissolution rate from the binary and ternary interactive mixtures was due to incompatibility of indomethacin with PVP. Also DSC curves showed that lactose was compatible with indomethacin and that lactose was used as excipient in two commercial products (Rothacin® and Indylon®). Results from the cloud point method showed that the addition of indomethacin to 1% PVP solution containing ammonium sulfate (with cloud point at 76°C) reduces the cloud point of PVP indicating that there is an interaction between indomethacin and PVP, while the cloud point of 1% PVP containing ammonium sulfate was not affected by the addition of lactose.

Coadministration of doxorubicin and etoposide loaded in camel milk phospholipids liposomes showed increased antitumor activity in a murine model.

Small unilamellar vesicles from camel milk phospholipids (CML) mixture or from 1,2 dipalmitoyl-sn-glycero-3-phosphatidylcholine (DPPC) were prepared, and anticancer drugs doxorubicin (Dox) or etoposide (ETP) were loaded. Liposomal formulations were used against fibrosarcoma in a murine model. Results showed a very high percentage of Dox encapsulation (~98%) in liposomes (Lip) prepared from CML-Lip or DPPC-Lip, whereas the percentage of encapsulations of ETP was on the lower side, 22% of CML-Lip and 18% for DPPC-Lip. Differential scanning calorimetry curves show that Dox enhances the lamellar formation in CML-Lip, whereas ETP enhances the nonlamellar formation. Differential scanning calorimetry curves also showed that the presence of Dox and ETP together into DPPC-Lip produced the interdigitation effect. The in vivo anticancer activity of liposomal formulations of Dox or ETP or a combination of both was assessed against benzopyrene (BAP)-induced fibrosarcoma in a murine model. Tumor-bearing mice treated with a combination of Dox and ETP loaded into CML-Lip showed increased survival and reduced tumor growth compared to other groups, including the combination of Dox and ETP in DPPC-Lip. Fibrosarcoma-bearing mice treated with a combination of free (Dox + ETP) showed much higher tumor growth compared to those groups treated with CML-Lip-(Dox + ETP) or DPPC-Lip-(Dox + ETP). Immunohistochemical study was also performed to show the expression of tumor-suppressor PTEN, and it was found that the tumor tissues from the group of mice treated with a combination of free (Dox + ETP) showed greater loss of cytoplasmic PTEN than tumor tissues obtained from the groups of mice treated with CML-Lip-(Dox + ETP) or DPPC-Lip-(Dox + ETP).

Etoposide incorporated into camel milk phospholipids liposomes shows increased activity against fibrosarcoma in a mouse model.

Phospholipids were isolated from camel milk and identified by using high performance liquid chromatography and gas chromatography-mass spectrometry (GC/MS). Anticancer drug etoposide (ETP) was entrapped in liposomes, prepared from camel milk phospholipids, to determine its activity against fibrosarcoma in a murine model. Fibrosarcoma was induced in mice by injecting benzopyrene (BAP) and tumor-bearing mice were treated with various formulations of etoposide, including etoposide entrapped camel milk phospholipids liposomes (ETP-Cam-liposomes) and etoposide-loaded DPPC-liposomes (ETP-DPPC-liposomes). The tumor-bearing mice treated with ETP-Cam-liposomes showed slow progression of tumors and increased survival compared to free ETP or ETP-DPPC-liposomes. These results suggest that ETP-Cam-liposomes may prove to be a better drug delivery system for anticancer drugs.

Anti-inflammatory activity of Achillea and Ruscus topical gel on carrageenan-induced paw edema in rats.

The anti-inflammatory activity of Achillea and Ruscus extracts was studied in comparison with diclofenac sodium topical gel (diclosal Emulgel), using the carrageenan induced paw edema model in Albino rats. Gel formulation was prepared containing 6% of each extract in gel base, namely sodium carboxymethylcellulose (NaCMC). The kinetics of drug release from the prepared formulation was studied separately in each case. Results showed that the release follows the Higuchi square root equation. The pharmacological screening revealed that the percent reduction of edema for Achillea extract and Ruscus extract were 48.1% and 18.8%, respectively, while diclosal Emulgel produced 47% reduction of edema.

In vitro dissolution kinetic study of theophylline from hydrophilic and hydrophobic matrices.

Oral dosage forms containing 300 mg theophylline in matrix type tablets, were prepared by direct compression method using two kinds of matrices, glycerylbehenate (hydrophobic), and (hydroxypropyl)methyl cellulose (hydrophilic). The in vitro release kinetics of these formulations were studied at pH 6.8 using the USP dissolution apparatus with the paddle assemble. The kinetics of the dissolution process were studied by analyzing the dissolution data using four kinetic equations, the zero-order equation, the first-order equation, the Higuchi square root equation and the Hixson-Crowell cube root law. The analysis of the dissolution kinetic data for the theophylline preparations in this study shows that it follows the first order kinetics and the release process involves erosion / diffusion and an alteration in the surface area and diameter of the matrix system, as well as in the diffusion path length from the matrix drug load during the dissolution process. This relation is best described by the use of both the first-order equation and the Hixson-Crowell cube root law.