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Novel ibuprofen prodrugs with improved pharmacokinetics and non-ulcerogenic potential

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Abstract

In the present study, we evaluated the anti-inflammatory activity with pharmacokinetic, ulcerogenic properties of various synthesized prodrugs of ibuprofen in experimental animals. Prodrugs 2, 6, 9, 10, 12, and 14 were found to possess significant anti-inflammatory activity with almost non-ulcerogenic potential than standard drug ibuprofen 1a in both normal and inflammation-induced rats. Metabolic stability of prodrugs 2, 6, 9, 10, 12, and 14 were also studied in rat liver microsomes and oral bioavailability was determined by estimating area under curve (AUC) and plasma concentration of these prodrugs at various time intervals. The experimental findings elicited higher AUC and plasma concentration at 1 and 2 h indicating improved oral bioavailability as compared to parent ibuprofen. These prodrugs are found to have least gastric ulceration with retain anti-inflammatory activity observed in experimental animals. Therefore, present experimental findings demonstrated significant improvement of various pharmacokinetic properties with least ulcerogenic potential of ester prodrugs of ibuprofen an anti-inflammatory agent

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Abbreviations

NSAID:

Nonsteroidal anti-inflammatory drug

Tris–HCl:

Tris(hydroxymethyl)aminomethane hydrochloride

NADPH:

Nicotinamide adenine dinucleotide phosphate

HPLC:

High performance liquid chromatography

GC:

Gas chromatography

RLM:

Rat liver microsomes

RP:

Rat plasma

API:

Active pharmaceutical ingredient

UI:

Ulcer index

GI:

Gastrointestinal

DMAc:

Dimethyl acetamide

PTSA:

p-Toluene sulfonic acid

PXRD:

Powder X-ray diffraction

RT:

Room temperature

TMG:

1,1,3,3-Tetramethyl guanidine

18 Crown 6:

1,4,7,10,13,16-Hexaoxacyclooctadecane

EP:

European pharmacopoeia

Ar:

Aromatic

BDL:

Below detection limit

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Acknowledgments

The authors also gratefully acknowledge the support extended by Mr. Ashok Hiremath, Managing Director, Astec Lifesciences Ltd. Authors are also thankful to Dr. S. R. Naik and Dr. S.B. Bhise, Sinhgad Institute of Pharmaceutical Sciences, Lonavala for providing necessary facility for pharmacological experimentation.

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Authors and Affiliations

  1. Medicinal Chemistry Research Laboratory, School of Chemical Sciences, Solapur University, Solapur, 413 255, Maharashtra, India

    Valmik D. Dhakane, Hemant V. Chavan, Laxman K. Adsul, Sadanand N. Shringare & Babasaheb P. Bandgar

  2. Department of Pharmacology, Sinhgad Institute of Pharmaceutical Sciences, Kusgaon (Bk), Lonavala, 410 401, Maharashtra, India

    Vishnu N. Thakare

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  1. Valmik D. Dhakane
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  2. Hemant V. Chavan
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  3. Vishnu N. Thakare
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  4. Laxman K. Adsul
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  5. Sadanand N. Shringare
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  6. Babasaheb P. Bandgar
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Correspondence to Babasaheb P. Bandgar.

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Dhakane, V.D., Chavan, H.V., Thakare, V.N. et al. Novel ibuprofen prodrugs with improved pharmacokinetics and non-ulcerogenic potential. Med Chem Res 23, 503–517 (2014). https://doi.org/10.1007/s00044-013-0639-8

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