INTRODUCTION:

Glucocorticoid steroids such as cortisol or budesonide have potent anti-inflammatory actions that reduce inflammation and hyper-reactivity (spasm) of the airways caused by asthma. Budesonide is a man-made glucocorticoid steroid related to the naturally-occurring hormone, cortisol or hydrocortisone which is produced in the adrenal glands. Athletes use budesonide mainly for the treatment of exercise induced asthma and it is a frequently administered corticosteroid by inhalation. Budesonide is rapidly metabolised to different metabolites of which 16-hydroxyprednisolone is the major one in man. Its use in sport competitions is prohibited when administered by oral, intravenous, intramuscular, or rectal routes.¹

Budesonide is a glucocorticoid used in the management of asthma, the treatment of various skin disorders, and allergic rhinitis. Budesonide is provided as a mixture of two epimers (22R and 22S). The 22R form is two times more active than the 22S epimer.

The two forms do not interconvert^1,2. Structurally, budesonide is a 16d, 17d-ace-tal prepared by reaction of the 16d, 17d-dihy-droxy steroid (16d-hydroxyprednisolone) with n-butyraldehyde^3,4.

Fig. 1: The chemical structure of epimer 22R of budesonide. The S epimer inverts the position of the proton and the propyl grouping on C-22².

Pharmacodynamics of Budesonide:

Budesonide has a high glucocorticoid effect and a weak mineralocorticoid effect. It binds to the glucocorticoid receptor with a higher binding affinity than cortisol and prednisolone. When budesonide is systemically administered, suppression of endogenous cortisol concentrations and an impairment of the hypothalamus-pituitary-adrenal (HPA) axis function has been observed. Furthermore, a decrease in airway reactivity to histamine and other entities has been observed with the inhaled formulation. Generally, the inhaled formulation has a rapid onset action and improvement in asthma control can occur within 24 hours of initiation of treatment.¹

Mechanism of action of Budesonide:

Budesonide is an anti-inflammatory corticosteroid that exhibits potent glucocorticoid activity and weak mineralocorticoid activity. The precise mechanism of corticosteroid actions on inflammation in asthma, Crohn's disease, or ulcerative colitis is not known. Inflammation is an important component in the pathogenesis of asthma. Corticosteroids have been shown to have a wide range of inhibitory activities against multiple cell types (eg, mast cells, eosinophils, neutrophils, macrophages, and lymphocytes) and mediators (eg, histamine, eicosanoids, leukotrienes, and cytokines) involved in allergic and non-allergic-mediated inflammation. These anti-inflammatory actions of corticosteroids may contribute to their efficacy in the aforementioned diseases. Because budesonide undergoes significant first-pass elimination, the both oral preparations are formulated as an extended release tablet. As a result, budesonide release is delayed until exposure to a pH ≥ 7 in the small intestine.^1,2

Various analytical methods including UV, HPLC, LC-MS techniques has been developed for Budesonide as single constituent in dosage form, as the information summarized in table 1. Methods indicating HPLC bioanalytical method, stability indicating HPLC method, ion pairing chromatographic method and chemometrics assisted HPLC methods are also described for Budesonide. Also different methods are described for determination of Budesonide in combination with other active constituents in various dosage forms, as details are summarized in table 2. For qualitative and quantitative estimation of Budesonide these analytical methods can be used.

Table 1: Methods for determination of Budesonide Single and combination with other drugs by UV Spectroscopy, Chromatography and other techniques

DRUGS	METHOD	DESCRIPTION	REF. NO.
Budesonide in plasma	HPLC bioanalytical method	Mobile phase: ammonium acetate, phosphate buffer pH 3.5 and Acetonitrile at ratio of (3:5) Flow rate: 1.5 ml/min Run time: 20 min Column temperature: 40 ο C. Wavelength: 246 nm Linearity: range of 50 % to 150 % Correlation coefficient: 0.99916 LOD: 191.3μg/ml LOQ: 579.9μg/ml.	5
Budesonide in pharmaceutical capsules formulations	Stability-indicating LC-MS/MS	Mobile Phase: Ammonium formate and Methanol(35:65%v/v) Flow rate: 0.8 ml/min Wavelength: 247nm. Linearity: 2-10μg/ml Correlation coefficient: 0.9996 LOD: 0.20936 (μg/ml) LOQ: 0.6344 (μg/ml)	6
Budesonide in pure sample.	UV spectrophotometric method	Detection wavelength: 246.0 nm Solvent: Methanol Beers law in range: 1.4 to 25 μ g/ml Recovery: 99 - 100% Standard deviation: < 1%.	7
Budesonide	Stability-indicating HPLC method	Mobile phase: Ethanol–acetonitrile–phosphate buffer (pH 3.4; 25.6 mM) (2:30:68, v/v/v) Flow rate: 1.5 ml/min Wavelength: 240 nm concentration range: 2.5 to 25.0 mg:ml LOD: 0.30 mg/ml	4
Budesonide	Spectrophotometric method Using Mixed Hydrotropic Solubilization Technique	λmax: 244.8 nm Beer’s law limit (range): 5-30μg/ml linearity: 0.999 Limit of detection: 0.0443μg/ml Limit of quantification: 0.1343μg/ml Accuracy (recovery study): 98.75 %	8
Budesonide	Highly sensitive quantitative analysis of budesonide from plasma using LC/MS/MS	Mobile Phase: A: Buffer B: Acetonitrile Flow rate: 0.4ml/min Column temp: 40^oC MS interface: Electro spray ionization Correlation Coefficient: 0.9992	9
Budesonide	Chemometrics assisted HPLC method	Mobile phase: Buffer (4.0 g of Sodium phosphate anhydrous,added 2 ml of phosphoric acid and adjusted pH to 3.2 with diluted Orthophosphoric acid), Methanol and Ethanol (68:32:2 v/v). Column temperature: 40⁰ C Flow rate: 1.0 ml/min Wavelength: 246 nm Linearity range: 45.9545μg/ml-134.8634μg/ml Correlation coefficient: 0.999	10
Budesonide	HPLC method	Mobile phase: 10 mM ammonium acetate (pH 5 adjusted with orthophosphoric acid):acetonitrile (37:63) Column temperature: 40⁰ C Wavelength: 254 nm. Flow rate: 1.0 mL/min. correlation coefficient: 0.9999 LOD: 0.02 g/mL LOQ:0.06 g/mL,	11
Budesonide	LC-MSMS by Human Plasma	Mobile Phase: Acetonitrile: 5 Mm ammonium formate buffer in 0.1% formic acid, 60:40, v/v) Run time: 2.5 min Linearity range: 0.103-3.010 ng/ml Correlation Coefficient: 0.9989 Recovery range: 72.48-81.48%.	12
Budesonide	LC-MS/MS in human plasma	Mobile phase: acetonitrile and 10mM ammonium acetate adjusted to pH 3.2 (35:65, v/v) Flow-rate: 1.0ml/min	13

Table 2: Methods for determination of Budesonide in combination with other drugs by UV Spectroscopy, Chromatography and other techniques

DRUGS	METHOD	DESCRIPTION	REF. NO.
Formoterol Fumarate and Budesonide in pressurised meter dose inhaler form	RP-HPLC	Mobile phase: Buffer: acetonitrile (65:35v/v) (buffer pH 3.0, adjusted with orthophosphoric acid) Flow rate: 2.0 mL min-1. Concentration range: Formoterol Fumarate: 0.96 -1.44 ppm Budesonide: 64-96 ppm correlation coefficients: Formoterol fumarate: 0.9907 Budesonide 0.9953 Slope: formoterol fumarate = 438.66 Budesonide: 57.90	14
Formoterol Fumarate and Budesonide Epimers	Ion-pairing chromatographic method	Mobile phase: acetonitrile:0.05M sodium acetate buffer (40:60% v/v) containing 0.03% SDS Flow rate: 1.0 mL/min. Concentration ranges: Formoterol Fumarate -0.05–5.0 μg/mL Budesonide epimers -0.5–50.0 μg/mL LOQ: Formoterol Fumarate -0.05 μg/mL Budesonide epimers B- 0.568 μg/mL A- 0.459 μg/mL LOD: Formoterol Fumarate -0.018 μg/mL Budesonide epimers B -0.187 μg/mL A -0.151 μg/mL % RSD: Formoterol Fumarate -0.61 Budesonide epimers B- 0.53 A- 0.55 Correlation coefficient (r2): Formoterol Fumarate -0.9999 Budesonide epimers B -0.9999 A -0.9999	15
Budesonide and Formoterol Fumarate	RP-HPLC method	Mobile phase : Potassium dihydrogen phosphate buffer pH - 4.5) :Acetonitrile (30:70) Flow rate : 1 mL/min. Detection wavelength : 280 nm. Injection volume: 20.00 μL. Run time: 10.00 min. Retention Time: Formoterol Fumarate: 2.051 min. Budesonide: 4.234 min.	16
Budesonide and Nifedipine	PR-HPLC	Mobile Phase: phosphate buffer solution (pH 3.0 )and acetonitrile in 30:70v/v ratio Flow rate : 1 ml/min. Wavelength: 260 nm Linearity range: Budesonide: 10 -50 μg/ml Nifedipine: 25 -150 μg/ml Retention time: Budesonide: 3.2 min Nifedipine: 2.1 Correlation coefficient: Budesonide: 0.999 Nifedipine: 0.999 LOD (ng/ml): Budesonide: 3.0 Nifedipine: 2.98 LOQ (ng/ml): Budesonide: 10 Nifedipine:9.98	17
Formoterol fumarate and Budesonide	Stability-indicating RP-HPLC	Flow rate: 1.5 ml/min Wavelength: Formoterol fumarate :214nm Budesonide:247 nm Linearity range: Formoterol fumarate :0.3-0.9 μg/ml Budesonide :20-60 μg/ml Correlation Coefficient: Formoterol fumarate:0.9997 Budesonide :0.9994 column temperature :30°C Run time :30 min	18
Budesonide and 16 a-hydroxyprednisolone	LC–MS/MS method in dog plasma	Flow speed : 2mL/min. Mobile phase : A: water containing 0.1% formic acid B:acetonitrile containing 0.1% formic acid column temperature :35⁰C	19

CONCLUSION:

This review compile the reported Spectroscopic and Chromatographic methods developed and validated for estimation of Budesonide. According to this review it was concluded that for Budesonide different Spectroscopic and Chromatographic methods are available for single and combination. It was found that the mobile phase containing Acetonitrile, buffer and ammonium formate were common for most of the chromatographic method to provide more resolution. It was observed that most common combination of Budesonide with Formoterol fumarate. For chromatographic method flow rate is observed in the range 1.0-2.0 ml/min. It was also observed that LC-MS method was performed in Human plasma. Most of Methods were of RP-HPLC and UV absorbance detection.

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Received on 13.06.2019 Modified on 16.09.2019

Research J. Pharm. and Tech. 2021; 14(5):2873-2877.

DOI: 10.52711/0974-360X.2021.00505