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- The delivery of drugs using microspheres was developed in late 1940's. It is the process by which solids and liquids are packaged and sealed into microcapsules release their contents at controlled rate. The shell of the microcapsule can be made up of polysaccharides, proteins, lipids, gums or sugars. Chitosan is a cationic polysaccharide derived by the deacetylation of chitin. Chitosan as a polymer has great potential for pharmaceutical application as it is biocompatible, biodegradable, non-toxic, and has a high charge density and mucoadhesive properties. In 1980, chitosan was investigated as a matrix for sustained release in granules as well as tablets. In addition, chitosan has been investigated as a component of gel and membranes and as a film matrix.
Microsphere based therapy allows the drug to be released to a specific target site; this is carried out by using various types of drug-polymer combinations. The employment of chitosan microspheres provides controlled release of drugs and improves bioavailability of degradable substances such as proteins or the uptake of hydrophilic substances across epithelial membranes. Chitosan microspheres have been investigated for oral and parentral drug delivery. Chitosan microspheres are prepared by addition of multivalent anion to chitosan in controlled amounts resulting in cross linking of multivalent anion with the chitosan molecules.
Paclitaxel is a widely used drug that is found from a plant extract. It is one of the most effective anti-cancer drugs used to treat many types of cancers such as ovarian, lung and Kaposi's sarcoma. Paclitaxel inhibits cell replication by blocking the cells in the late G2-mitotic phase of cell cycle. Paclitaxel is a lipophilic compound; as it has no ionisable functional groups, paclitaxel is insoluble in aqueous medium.
Paclitaxel is highly lipophilic and poorly soluble in aqueous medium; however it is soluble in organic solvents. Several reports have been published on the solubility of Paclitaxel and the reported value of aqueous solubility is 0.6mM. In addition, Pacliaxel doesn't have functional groups thus; manipulation in pH doesn't improve its solubility. Currently, Paclitaxel is solubilised in mixture of Cremophor EL and ethanol; this is delivered intravenously and requires hospitalisation of the patient. Therefore suggesting further research is required for oral delivery of the drug, as Paclitaxel is aimed for long term use by cancer patients. Chitosan is a natural polymer that shows to improve dissolution of poorly soluble drugs such as Paclitaxel. Chitosan microspheres are widely used as drug delivery system to control the release of drugs. This type of drug delivery system allows drug release to be modified to a target site by choosing different types of drug-polymer combinations. The kinetics of release and the dose of Paclitaxel are the main variables; these variables could be controlled in order to attain desired effect. However, the rate at which the dose is released may be altered by many other factors such as the rate of transit in the gut. This suggests the rate of release from one dose to another may vary.
Nsereko and Amiji, 2002; conducted a study on delivering Taxol using chitin microspheres due to the poor solubility of Taxol. The formulation was designed to deliver the drug to solid tumours, and the delivery of drug was assessed by the percentage change in volume of the tumour. The result of this study has shown chitosan microspheres to enhance localised delivery of Taxol in solid tumours, which is due to enhanced solubility of the Taxol when incorporated in chitosan matrix. Whilst Taxol is hydrophobic drug, chitosan is soluble only under acidic conditions. It is possible that the coating of the dosage form undergoes sudden damage which may lead to an overdose; this leads to severe side effects such as difficulty breathing, swelling of lips, fatigue, tarry stools etc.
Dhanikula et al, 2004; carried out a study where chitosan films contained paclitaxel, the study had following observations. The drug was not released using high molecular weight chitosan because of the hydrophobicity. This suggests delivery of Taxol using chitosan films could be improved by using other forms of chitosan such as microspheres; this is because under in vitro conditions only 10-15% of Paclitaxel was released. However, the delivery system improved considerably in vivo as over time it lost integrity therefore showing it is biocompatible. Overall, Chitosan microspheres would increase the solubility of Taxol and at the same time attain controlled release of Taxol and improve bioavailability.
Fessi et al, 1989; efficiently encapsulated drug substances inside nanocapsules by nanoprecipitation method. Studies carried out by Allémann et al, 1993; Barichello et al, 1999; and Govender et al, 1999; their studies reported that entrapment of hydrophobic drug substances into a polymer such as chitosan microsphere was complex using nanoprecipitation method. This is due to the hydrophobic drug e.g. Paclitaxel, it has low affinity towards the polymer. Many factors affect entrapment efficiency of Paclitaxel in chitosan microspheres, such as concentration of chitosan, nature of the drug (Paclitaxel), drug-polymer ratio, speed of stirring during formulation etc.
If there is a low concentration of chitosan, this will show low encapsulation efficiency. Nishioka et al, 1990; conducted a study and observed that an increase in chitosan concentration has an increase in entrapment efficiency. This is possible as an increase in the concentration of chitosan causes the viscosity to also increase, therefore preventing drug from leaving the matrix. However, Wu et al, 2005; reported if chitosan concentration is high there is a decrease in the entrapment efficiency. This may only be true for the encapsulation of certain drugs such as ammonium glycyrrhizinate. Kumar et al, 2002; found that the concentration of cross linking influenced drug release. In vitro studies were carried out and pointed out chitosan undergoes a biphasic drug release pattern. This is characterised by an initial burst of the drug then slow release of the drug for a number of days.
Genta et al, 1998; have reported chitosan microspheres containing a mixture of high and low molecular weight of the polymer demonstrated good encapsulation efficiency which was independent of the drug to polymer ratio. Wu et al, 2005; observed that a steady increase in particle size with an increase in molecular weight, there was no improvement in entrapment efficiency. Dini et al, 2003; observed microspheres containing a higher molecular weight of chitosan and/or low drug concentration had a slow release rate of the drug. Furthermore, the release of the drug can be dependent on polymer cross linking density and the level of swelling in the matrix.
Chitosan microspheres have many advantages. Firstly, chitosan microspheres may allow the incorporated drug to be targeted to tumour site and provide a controlled rate of release. This means the drug may be more effective as there will be targeted localisation of the drug, hence it will be easier to optimise the concentration of the drug. As chitosan microspheres provide a prolonged therapeutic effect therefore this would reduce the frequency of dosing and may also increase patient compliance. As the microsphere contains a high drug load it may cause toxicity problems if coating of dosage form is damaged
Moreover, chitosan microspheres improve the bioavailability of degradable substances such as proteins or the uptake of substances across epithelial cells such as Taxol. In addition, chitosan is a biodegradable polymer this may widen pharmaceutical potential as it is biocompatible, non-toxic, mucoadhesive and has a high charge density. Also, the process of preparing chitosan microspheres to deliver taxol is very quick; this process can be reproduced and is easy to scale up. Another advantage is the preparation method of chitosan microspheres does not use high temperatures and does not require the usage of other solvents. Overall, the production of chitosan microspheres is an economical process.
Furthermore, some aspects of chitosan particles can be manipulated such as internal morphology, sphericity and internal cross section. This may improve the chemical stability and mechanical properties. However, Berthold et al, 1996; reported that the acid stability of chitosan microspheres is poor; it is possible in this case instability of microspheres may be due to the manufacturing process as microspheres were prepared by sodium sulphate precipitation.
Currently the drug Taxol is administered intravenously, this means the patients' would have to be hospitalised for the administration of Taxol, this process is costly as it is time consuming and requires infusion equipment e.g.- Aseptic environment. If the drug is delivered orally using chitosan microspheres, money would be saved as hospitals would be used less and the patients' quality of life would be improved. However, if the administration of Paclitaxel would take place at hospital, the patient may be monitored for adverse drug reactions. Overall, if the patient is self administering the drug this may increase risk factors.
There are disadvantages of chitosan microspheres. Firstly, the rate at which the drug is released can be altered by many factors such as the rate of transit through the gut and co administration of food. This may alter the rate of release from one dose to another. Also, microspheres should contain a high drug load in order to provide extended release. If the coating of the dosage form is suddenly damaged this could possibly lead to an overdose, therefore harming the patient. The patient may suffer from belonephobia therefore infusion of Paclitaxel may be distressing and in some cases it may be unacceptable. If Paclitaxel could be delivered orally using chitosan microspheres this problem would be overcome.
In addition, many extended release products in the pharmaceutical industry can be divided into two halves in order to provide half a dose. However, chitosan microspheres cannot be crushed or chewed as the controlled release of the drug would be lost and potential toxicity may be produced possibly harming the patient. Furthermore, controlled release drugs tend to be larger in size; this may cause difficulty in transit through the gut or cause indigestion. Due to the larger size of the dosage form the patient may have difficulty in swallowing however; this may be preferred to being hospitalised for the administration of drug.
Moreover, chitosan microspheres are known to have a compact structure therefore, this would lead to a very slow release of the drug. This would reduce the therapeutic effect. When the conventional method is applied in the preparation of chitosan microspheres drug is released that demonstrates varying size distribution, this can result in side effects. This suggests chitosan prepared using conventional method would have a poor reproducibility.
In conclusion, chitosan improves the dissolution rate of poorly soluble drugs such as Taxol. There are several methods to prepare chitosan, cross linking is generally used. Also, chitosan microsphere's particle size can be manipulated suiting the administration route (Parentral, nasal and oral). The entrapment efficiency may increase with an increase in the concentration of chitosan and the release of the drug from microspheres is dependent on factors such as, concentration, molecular weight, density of cross linking and the drug polymer ratio.