Challenges in Administration of Corticosteroids for the Treatment of Addison’s Disease: A Case Study of Fludrocortisone Acetate

Fludrocortisone is a known corticosteroid used to control the amount of sodium and fluids in body. Fludrocortisone act by decreasing the amount of sodium that is excreted in your urine. It is indicated to take orally and it is recommended not to stop Fludrocortisone treatment without Physician consent as sudden stoppage leads to several moderate to severe adverse effects. There are several moderate to severe adverse effects reported with treatment of Fludrocortisone including high Blood Pressure (BP), Heart failure, weakness of muscles, changes in mood and low immune system function. Considering this there is need to develop sustained release formulation as microparticles which help to improve patient compliance by reducing dosage frequency which overall help to reduce side effects reported with Fludrocortisone. The aim of this research is to develop different formulations of Fludrocortisone (FLU) by using various polymers (poly(ε-caprolactone, PLC), Eudragit® RS and Eudragit® RL) and different processes (oil-in-water (O/W) solvent evaporation methods and suspension-in-oil-in-water (S/O/W) evaporation methods). Small poly(ε-caprolactone (PCL)-based microparticles have successfully developed during study which was leading to good efficiency when it was prepared by oil-in-water (O/W) emulsion method with 7.5 mg/ml of FLU. Challenges in Administration of Corticosteroids for the Treatment of Addison’s Disease: A Case Study of Fludrocortisone Acetate Najim A AL-Awwadi1* and Makarim M. Ali Hassan2 1Faculty of pharmacy, Chair man of department of pharmacognosy, University of Thi-Qar, Iraq 2Faculty of pharmacy, Department of basic science, University of Thi-Qar, Iraq

• Loss of consciousness.
If this condition is not treated on time, this will leads to death. It is treated with adrenal hormones and an IV hormone is ideal in this case.
Some of the hormones produced by the cortex are important for life; they are the glucocorticoids and the mineralocorticoids.
• Glucocorticoids. It is hormone, which influence key role in immune system and help to convert food in to energy which help to respond during stress condition.
• Mineralocorticoids. It is important to maintain sodium and potassium balance in body. It is useful for BP maintenance.
• Androgens. These are sex hormones which influence muscle mass, libido and sense of wellbeing in male and female.

Material and Methods
Microparticles were obtained by O/W and S/O/W emulsionsolvent evaporation method. There batches were prepared during this study by using below steps:

Preparation of microparticles
To obtain the Microparticles (MP), a modified O/W emulsionsolvent evaporation method was used [7]. In each case, 250 mg of polymer (PCL, Eudragit ® RL, Eudragit ® RS or mixtures of these polymers) was dissolved in 10 ml of dichloromethane and various amount of FLU (QOP) ranging from 10 to 150 mg (1-15 mg/ml) were added under magnetic stirring.
It is generally admitted that the release of dispersed drugs from polymers, needs an initial diffusion of the solvent, a dissolution step and a retrodiffusion of the solution. It is also often assumed that the rate-limiting step is the diffusion of the drug from the matrix. Several studies have demonstrated that the release of low molecular drugs such as progesterone or phenothiazines from PCL-based microparticles    was rapid, as the dissolution rate of pure drug crystals or faster; this phenomenon being attributed to the molecular dispersion of the drugs in the polymer [7].
The release of solid drugs randomly dispersed in homogeneous matrices, described by Baker and Lonsdale is a very gradual process: The solid drug dissolves from the surface layer and when it becomes exhausted of drug the next layer begins to be depleted [3].

Particle size analysis
Optical microscopy was used to estimate the microparticle size distribution. About 5 mg of particles were vortexed in 1 ml of 0.1 % PVA. The sphericity of the MP was estimated by the roundness parameter where a value of unity corresponds to a perfect circle, which was given by: The ferret diameter, which is a measure of an object size along a specified direction, was used during particle size analysis. The Feret diameter averaged over all directions (<F>) is equal to the ratio of the object perimeter (P) and pi, i.e., <F> = P/π. There is no such relation between <F> and P for a concave object.

Release studies
In order to investigate the release of FLU from microparticles, various batches were suspended in 100 ml of phosphate buffer (0.1 M, pH 7.40) preheated at 37°C. The fludrocortisone microparticles were suspended at a concentration of 10 µg of fludrocortisone per ml of medium, near "sink conditions" but taking account of the sensibility of the analytical method (Table 1).

Results and Discussion
The volume of aqueous phase and presence of crystals in the suspension was studies with different formulation of polymers. The volume of aqueous phase was taken from 100 to 800 ml. In some cases, presence of crystal was also found ( Table 2).
The surface aspect, the size and the residual water were determined as described in the experimental section (mean ± s.d.; n=3), ND: Not Determined.
Results are calculated according Equation 4-6. Q∞ denotes the release percentage at infinite time and T75% indicates the time to obtain 75%. Different mixture of poly(ε-caprolactone) and of Eudragit ® were used. Mixtures of Eudragit ® to study the permeability characteristics of coating. It was found that PCL is more biodegradable and having good release profile (Figures 3-5) [19,20].

Conclusion
The objective of this study was to obtain slow release FLU loaded microparticles, having goof efficacy parameters. In this study, small PCL  based microparticle of FLU was obtained when the O/W emulsionsolvent evaporation method was used with 7.5 mg/ml of FLU.
It was found that, the drug incorporation is directly link to its concentration. With low level of FLU, low level if drug drugs in microparticles were found, which is of no clinical use. However  with saturated concentration, excellent release profile was obtained and sufficient quantity of FLU is found which is needed for the manufacturing purpose.
When saturated solution of FLU was used, it was leading to heterogeneous microparticles with several crystals embedded on the polymeric surface and it is found to be one of good alternative to achieve clinical goal. Poly(ε-caprolactone) (PCL) is found to be well tolerated by tissues without release of acidic metabolites unlike PLA/PLG. It is recommended for the development of sustained release formulation.