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Physicochemical Characterization of Cyclosporine A Liposomal and Colloidal Systems


In this paper the respective authors have given a review on the possibilities of testing different cyclosporine formulations with an importance on different parameters which can improve  biocompability and stability of cyclosporine administration. They have chosen cyclosporine A (CsA) for their investigation. The compound CsA is an organic compound and has the formula C62H111N11O12. It is a cyclic polypeptide which has 11 amino acids. CsA is associated with biocompatibility and bioavailability problems. This is due to its poor or low solubility in physiological fluids because of having lipophilic structure. It has been reported that there were considerable efforts made to design a suitable vehicle for cyclosporine A oral administration which can have improved absorption and reduced side effects (1-9). The aim of the review is to see the potential of CsA formulations in respect with physiochemical properties of cationic CsA.

They have tested the feasibility of cyclosporine colloidal system for oral administration in various techniques and compared with investigations which are similar. Dipalmitoylphosphocholine (DPPC) and cholesterol were used as lipid matrix to develop the cyclosporine A colloidal system. Furthermore the matrix was stabilized using ethanol and soybean oil or n-tetradecane as oil phase in emulsion via high pressure homogenizer for obtaining droplet size and narrow size distribution. This was then placed under normal pH and physiological temperature. They have used CsA (98.5%), ethanol (96%), cholesterol and dipalmitoylphosphocholine (DPPC) both 99% respectively. They have also reviewed the usage of antibacterial chitosan for the bioavailability of CsA. The authors have reviewed the different aspects or parameters of formulations of CSA such as solubility, liposomal system and the use of DLS or BAM analysis in different subtopics. They have reported that with their findings and comparison with published literature that Cyclosporine A is not a suitable oral drug formulation due to its poor solubility and bioavailability however the drug can be easily produced in the size range of 200-500 and can show better absorption and bioavailability in To improve the bioavailability of CsA in liposomal system.They have suggested the use of Chitosan, lipid or other oil-water formulation.

These formulations can improve the bioavailability of the drug and can reduce the side effects with low dose regimen. Dynamic light scattering(DLS) technique has been used to find zeta potential and size distribution for both liposomal system and oil-water emulsion to assess the physio-chemical characeterteristics of CsA and its stability in the mentioned systems followed by BAM analysis for morphological study. Based on assessing the manuscript, I will be discussing the strength and weaknesses of the manuscript followed by novelty of the review article and finally my recommendation.Strength and Weaknesses of the Manuscript The authors have discussed on the CsA solubility in water where they have recorded the data with increased temperature. The solubility slowed with increased temperature. So the problem in solubility had been shown to give low bioavailability where the oral bio-availability of the drug can be in the range of 10 % to 89%.. It should be noted that they have given reasoning for this is because of the compound having intramolecular H-bonds that has a rigid configuration . They have also explained that is most likely for the D-alanine amino acid having a conformational change which is the residue of the drug that loses water with temperature increase. The lipid based liposomal system was developed by injecting alcohol into the DPPC and homogenized where the phase temperature was 41 ?C For measuring particle size distribution they have used Dynamic Light Scattering (DLS) where different CsA formulations mean particle size was measured in 5 1- minute cycle using Zeta Potential-Bi mass (Brookhaven, Preston, UK). The zeta potential also determined in the same apparatus.

Dynamic light scattering

The particle size distribution was also measured using laser light scattering technique for the liposomal formulations with and without CsA. The recorded size distribution was CsA, CaCl2 > CsA, H2O > CsA, KCl. In the subtopic 3.1 they have discussed stability of Liposomal CsA where they have briefly described the usage of Cyclosporine A as a good candidate for including into liposomes. In this chapter they have mentioned about different charged liposome and the particle size for good stability. Study of Czogalla et al. was reported where liposomal formulations were developed less than 200 nm . This size is small compared with literature reports where existing literature has found liposome in blood frequently to be more than or equal to 200 nm. The author also recommended that despite there is proven research for all types (charges) liposome can be developed into powders, only positive and neutral liposomes showed to have more stability high stability in blood. According to their research depending on the type of application and location of action cyclosporine A in water or KCl is a better approach for small sized liposomal system but for liposomal stability as a key indicator CsA in calcium chloride solution is a good choice. Brewster Angle microscopy (BAM) was used to look into the pure DPPC monolayer which showed irregular domains where CsA monolayer had no irregular domain and appeared to be homogenous. In this BAM analysis and surface-pressure area isotherms images were used to investigate the CsA effect on model DPPC membrane. The images obtained are helpful to understand the interaction of living cell membranes with drug CsA.

In the oil-water emulsion subtopic, they reported the possible formation of tetragonal crystalline particle in one study which was not present in the other. The comparison showed that the differences meant stability of the emulsion is dependent on the different formation of CsA. The characteristics of the formulation in soybean oil and cholesterol to look into the zeta potential and size diameter. From the DLS data it can be noted that size distribution in Cyclosporine A – oil was narrow than the CsA oil and ethanol. Therefore it can be said that formulation system by addition of phospholipid-ethanol has better bioavailability. They have also looked into the alternative such as using Chitosan where they have mentioned a study of Hermans et al. In this study rabbits were used for in-vivo experiment where concentration of CSA was found in conjunctiva and cornea and showed to be active against inflammation (11). Wiacek et al used soybean oil as oil phase where poor concentration and poor penetration was found in tear film and cornea respectively due to poor solubility of CsA. With the in-vitro reports showing almost no toxic effect the chitosan-CsA can be helpful delivery system for optical drug delivery system.

The use of CsA in the formulation of oral drug delivery system was also discussed where data and notable findings were presented from previous literature. It was concluded that the oral bioavailability data correlated with particle size distribution. The comparison studies showed that in one particular study CsA administered invasively for a lung patient showed no toxic effects or hepatotoxicity however oral administration had shown hepatotoxicity. The author had also described about ocular and skin CSA drug delivery system where different studies were compared for a better understanding. As mentioned cationic o/w emulsion showed efficiency in ophthalmic drug. Overall the different subtopic covers most of the type of delivery from oral to skin and the potential use of CsA as a drug delivery with existing literature and their comparative research. The topics are well covered and understandable with clarity given on reasoning behind results. Furthermore existent literature published and mentioned in this article was cross-matched for accuracy which proved to be correct. The graphs and tables were explained in a detailed manner especially the DLS data for two different systems were helpful in making conclusive decision in regards to the size distribution and zeta potential parameter.

In table 2 of the manuscript they have shown the characterization DPPC liposome with and without CsA with the help of DLS to show the particle size distribution and zeta potential values. The order of the particle sizes were not less than 100 nm which is rather high for an optimal liposomal drug delivery system (10). They have also looked into the alternative such as using Chitosan and described a few studies however the studies were not adequate to state the usage of chitosan. It was mentioned that a particular chitosan formulation had shown good absorption in an in-vivo system but the chapter needed more in depth analysis. The chitosan nanoparticle mentioned didn’t have much information regarding the different types of method to be used for its efficacy as a drug delivery system where additional information with more safety and toxicity information would have made the effectiveness of chitosan as a potential nanoparticle which can be used for better therapeutic vehicle apart from its antimicrobial activity.

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