alexa Challenges in Administration of Corticosteroids for the Treatment of Addison’s Disease: A Case Study of Fludrocortisone Acetate | Open Access Journals
ISSN: 1948-593X
Journal of Bioanalysis & Biomedicine
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Challenges in Administration of Corticosteroids for the Treatment of Addison’s Disease: A Case Study of Fludrocortisone Acetate

Najim A AL-Awwadi1* and Makarim Mohammad 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

*Corresponding Author:
Najim A AL-Awwadi
Faculty of pharmacy, Chair man of department
of pharmacognosy, University of Thi-Qar, Iraq
Tel: 00964 7810877994
E-mail: [email protected]

Received date: May 23, 2017; Accepted date: June 21, 2017; Published date: June 28, 2017

Citation: AL-Awwadi NA, Ali Hassan MM (2017) Challenges in Administration of Corticosteroids for the Treatment of Addison’s Disease: A Case Study of Fludrocortisone Acetate. J Bioanal Biomed 9:164-168. doi: 10.4172/1948-593X.1000172

Copyright: © 2017 AL-Awwadi NA. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

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Abstract

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.

Keywords

Fludrocortisone; Microparticles; Polymer; Sustained release; Poly(ε-caprolactone)

Introduction

In Addison’s disease, adrenal gland doesn’t produce enough hormones. It is categorized as either primary or secondary. In secondary adrenal insufficiency, adrenal gland is not stimulated by pituitary gland and there is lack of production of hormone cortisol.

It is categorized as autoimmune disorder as body’s own immune system is affected and it’s destroyed over period of time (Figure 1) [1-4].

bioanalysis-biomedicine-Addison-disease

Figure 1: Addison’s disease.

Symptoms of Addison’s disease

Most of the symptoms develops gradually in this case, it develop to severe stage at the time of progression.

• Weakness of muscle.

• Irritation.

• Salt carving.

• Pigmentation.

• Disorder like depression, Anxiety.

• Disturbance in menstrual period.

• Chronic fatigue.

It is very difficult to diagnose this disease due to similarity of symptoms with others, however hyperpigmentation is marker to diagnose this disease. Biochemical test is key for the diagnosis along with X-Ray of adrenal and pituitary gland (Figure 2) [4-9].

bioanalysis-biomedicine-Adrenal-gland

Figure 2: Adrenal gland.

If symptoms worsening, this leads to Adrenal Crisis which needs immediate medical attention. The common symptoms are as under:

• Excessive vomiting.

• Dehydration.

• Abdomen, back and leg pain.

• Sudden, severe pain in the lower back, abdomen, or legs.

• Severe vomiting.

• Severe diarrhoea.

• Dehydration.

• Low blood pressure.

• 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.

Corticosteroids (Fludrocortisone) are patented medicine and it is included in essential medicine by the World Health Organization’s list of Essential Medicines. In this study, different microparticles were developed with (poly(ε-caprolactone), Eudragit® RS and Eudragit® RL) and different processes were used like O/W solvent evaporation methods and S/O/W evaporation methods [10-18].

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:

Image

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).

Parameter studied Formulation name Method Concentrations in 10 ml of dichlorometane Aqueous phase (ml)
Fludrocortisone (mg/ml) PCL              (mg/ml) Eudragit®RS (mg/ml) Eudragit®RL (mg/ml)
Assay 1: Volume of the aqueous phase Flu5-PCL25-800
Flu5-PCL25-600
Flu5-PCL25-400
Flu5-PCL25-200
Flu5-PCL25-100
O/W
O/W
O/W
O/W
O/W
5
5
5
5
5
25
25
25
25
25
 -  - 800
600
400
200
100
Assay 2:  Concentration of fludrocortisone Flu1-PCL25-800
Flu2-PCL25-800
Flu5-PCL25-800
Flu7.5-PCL25-800
Flu10-PCL25-800
Flu15-PCL25-800
O/W
O/W
O/W
O/W
S/O/W
S/O/W
1
2
5
7.5
10
15
25
25
25
25
25
25
 -  - 800
800
800
800
800
800
Assay 3:  Concentration of fludrocortisone Flu1-RS25-800
Flu2-RS25-800
Flu5-RS25-800
Flu7.5-RS25-800
Flu10-RS25-800
Flu15-RS25-800
O/W
O/W
O/W
O/W
S/O/W
S/O/W
1
2
5
7.5
10
15
- 25
25
25
25
25
25
- 800
800
800
800
800
800
Assay 4: Polymer Flu7.5-PCL25-800 O/W 7.5 25   - 800
Flu7.5-PCL12.5/RS12.5-800 O/W 7.5 12.5 12.5   800
Flu7.5-PCL6.25/RS18.5-800 O/W 7.5 6.25 18.75   800
Flu7.5-RS25-800 O/W 7.5   25   800
Flu7.5-RS18.5/RL6.25-800 O/W 7.5   18.75 6.25 800
Flu7.5-RS12.5/RL12.5-800 O/W 7.5   12.5 12.5 800

Table 1: Formulations of fludrocortisone micro particles.

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).

Formulation name Volume of the aqueous phase Presence of crystals in the suspension Residual water (μg/mg MP) Mean Feret Diameter (μm) Roundness
Flu5-PCL25-100 100 ml + ND ND ND
Flu5-PCL25-200 200 ml + ND ND ND
Flu5-PCL25-400 400 ml + ND ND ND
Flu5-PCL25-600 600 ml _ 1.27 ± 0.18 45.12 ± 22.80 0.74 ± 0.27
Flu5-PCL25-800 800 ml _ 1.24 ± 0.16 47.21 ± 27.20 0.85 ± 0.21

Table 2: Characteristics of each suspension (assay 1) as function of the volume of the aqueous phase.

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.

The surface aspect, the size and the residual water were determined as described in the Experimental section (mean ± s.d.; n=3) (Table 3). *P<0.02 versus Flu1-PCL 25-800 to Flu 7.5-PCL 25-800.

Formulation name QOP (mg/mg of polymer) Presence of crystals on the MP surface Residual water (μg/mg MP) Mean Feret Diameter (μm) Roundness
Flu1-PCL25-800 40 -      1.21 ± 0.15 41.9 ± 20.0 0.81 ± 0.21
Flu2-PCL25-800 80 -      1.20 ± 0.12 43.2 ± 25.8 0.82 ± 0.21
Flu5-PCL25-800 200 -      1.24 ± 0.16 34.0 ± 17.6 0.87 ± 0.22
Flu7.5-PCL25-800 300 +      1.37 ± 0.10 38.7 ± 18.4 0.81 ± 0.21
Flu10-PCL25-800 400 +++ 1.74 ± 0.08 * 41.9 ± 22.9 0.82 ± 0.21
Flu15-PCL25-800 600 +++ 1.71 ± 0.09 * 44.4 ± 34.0 0.83 ± 0.25

(A)

Formulation name QOP (μg/mg of polymer) Presence of crystals on the MP surface Residual water (μg/mg MP) Mean Feret Diameter (μm) Roundness
Flu1-RS25-800 40 - 1.30 ± 0.11 40.6 ± 20.6 0.81 ± 0.20
Flu2-RS25-800 80 - 1.25 ± 0.06 41.7 ± 24.8 0.82 ± 0.20
Flu5-RS25-800 200 - 1.29 ± 0.05 32.2 ± 11.9 0.76 ± 0.24
Flu7.5-RS25-800 300 - 1.32 ± 0.09 33.7 ± 12.5 0.95 ± 0.22
Flu10-RS25-800 400 +++ 1.77 ± 0.10 * 32.6 ± 15.1 0.78 ± 0.23
Flu15-RS25-800 600 +++   1.83 ± 0.10 * 30.0 ± 13.5 0.85 ± 0.23

(B)

Table 3: Characteristics of microparticles as function of the fludrocortisone concentrations in the aqueous phase (QOP) (assays 2 and 3).

The in vitro release experiments performed with PCL-based and Eudragit®-based microparticles release experiment (in vitro) was performed which ‘showed that, from polymeric matrix, FLU was not able to release, hence release studies were prolonged up to 12 h. For the O/W PCL microparticles (FLU1-PCL25-800, FLU2-PCL25-800, FLU5- PCL25-800, FLU7.5-PCL25-800) the maximum release, estimated by Q∞, was higher (P<0.02) than for the correspondent S/O/W microparticles (FLU10-PCL25-800, FLU15-PCL25-800) and was not significantly different from this obtained with the free drug (Table 4).

Batch name Q (%) T75% (h)
Flu 86.8 0.19
Flu1-PCL25-800 70.1 0.41
Flu2-PCL25-800 75.1 0.28
Flu5-PCL25-800 76.9 0.30
Flu7.5-PCL25-800 82.5 4,00
Flu10-PCL25-800 59.8 3.94
Flu15-PCL25-800 54.6 3.88

(A)

Batch name Q (%) T75% (h)
Flu 86.8 0.19
Flu1-RS25-800 22.3 0.22
Flu2-RS25-800 20.6 0.23
Flu5-RS25-800 20.4 0.55
Flu7.5-RS25-800 12.6 3.50
Flu10-RS25-800 14.3 3.42
Flu15-RS25-800 14.9 3.30

(B)

Table 4: Release parameters of FLU and FLU-loaded microparticles (assays 2 and 3).

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].

bioanalysis-biomedicine-Microparticles-Suspensions

Figure 3: Microparticles-Suspensions obtained with (a) 200 ml of aqueous phase (Flu5-PCL25-200), and (b) 800 ml of aqueous phase (Flu5-PCL25-800).

bioanalysis-biomedicine-Incorporation-pro?le

Figure 4: Incorporation pro?le of Fludrocortisone (FLU) into microparticles of poly (ε-caprolactone) (assay 2: !) or Eudragit® RS (assay 3: ") as function of the ?udrocortisone concentration in the organic phase. QOP: Amount of FLU added in dichloromethane expressed in #g/mg of polymer; QPOL: Amount of FLU incorporated per mg of micro particles polymer. Each point represents the mean ± S.D. of three separate determinations.

bioanalysis-biomedicine-?udrocortisone-microparticles

Figure 5: Release of ?udrocortisone from microparticles in phosphate buffer (0.1M, pH 7.4, 37?C). In?uence of the ?udrocortisone concentrations (assays 2 and 3): (a) Poly (ε-caprolactone) microparticles: Flu5-PCL25-800(#) and Flu7.5-PCL25-800($), Flu15-PCL25-800 ("). (b) Eudragit® RS microparticles: Flu5-RS25-800 (#) and Flu7.5-RS25-800 ($), Flu15-RS25-800 ("). Each curve has been compared to free ?udrocortisone (FLU: ×).

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 emulsion solvent 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.

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