Lipid-Gelucire based rectal delivery of ramipril prodrug exhibits significant lowering of intra-ocular pressure in normotensive rabbit: sustained structural relaxation release kinetics and IVIVC

Abstract

Carboxylesterase enzymes convert a prodrug ramipril into the biologically active metabolite ramiprilat. It is prescribed for controlling ocular hypertension after oral administration. High concentrations of carboxylesterase enzymes in rectal and colon tissue can transform ramipril significantly to ramiprilat. Sustained rectal delivery of ramipril has been developed for intra-ocular pressure lowering effect using a normotensive rabbit model. Rectal suppositories have been formulated using a matrix base of HPMC K100-PEG 400-PEG 6000, incorporating varying amounts of Gelucire by the fusion moulding method. The presence of Gelucire in the suppository exhibited sustained structural relaxation-based release kinetics of RM compared to its absence. Intravenous and oral administration of ramipril has decreased IOP in the treated rabbit up to 90 and 360 min, respectively. Treated rabbits with suppositories have revealed decreased IOP for an extended period compared to the above. Formulation containing GEL 3% reduced intra-ocular pressure to 540 min, with the highest area under the decreased IOP curve. Compared to oral, the pharmacodynamic bioavailability of ramipril has been improved significantly using a sustained-release rectal suppository. A rectal suppository for sustained delivery of ramipril could be used to lower IOP significantly.

Keywords:

• Sustained rectal delivery
• in vitro in vivo correlation (IVIVC)
• pharmacodynamic bioavailability
• structural relaxation kinetics
• ramipril prodrug

Acknowledgement

The authors thank DST- Ministry of Science & Technology, New Delhi, India, for giving the INSPIRE scholarship to Souvik Nandi (IF 180534). The authors are very thankful to the president of Siksha ‘O’ Anusandhan and Dr Reddy’s Laboratory, India, for providing the necessary instrument facilities and RM gift samples.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Author contributions

Souvik Nandi: Writing original draft, Data analysis, Software; Rakesh Swain: help during In vivo analysis; Sk Habibullah: Writing, reviewing and editing original manuscript, data curation, Software; Rudra Narayana Sahoo: Data curation; Amit Kumar Nayak: Data curation; Subrata Mallick: Conceptualization, Analysis, approve the final manuscript.

Data availability statement

Data is made available upon request from the authors.

Additional information

Funding

The author(s) reported there is no funding associated with the work featured in this article.